samples/ACE.instances.sval

<corpus lang="english">
<lexelt item="LEXELT">
<instance id="10155299.xx.x">
<answer instance="10155299.xx.x" senseid="C0022709"/>
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Clinical and economic factors in the treatment of congestive heart failure. Congestive heart failure (CHF) is a disease of massive clinical and economic importance throughout the developed world. Approximately 1% of the population are affected, with incidence and prevalence of CHF increasing with age. The major aetiological factor is ischaemic heart disease and, despite advances in treatment, mortality from CHF remains appallingly high, and comparable to that of many malignancies. The majority of patients with CHF require treatment with a diuretic, though there is now clear evidence that the addition of an <head> ACE</head> inhibitor will not only improve symptoms but also reduce mortality and delay the progression of the disease. The vast economic impact of CHF is now becoming fully appreciated, with the majority of expenditure on hospital admissions. The earlier and more widespread use of ACE inhibitors in the treatment of CHF would be highly cost effective, with substantial savings in hospitalisation costs, though new and effective treatments are still urgently required.
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</instance>
<instance id="10432941.xx.x">
<answer instance="10432941.xx.x" senseid="C0022709"/>
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Effects of inpatient rehabilitation on cardiovascular risk factors in patients with coronary heart disease. PIN-Study Group. BACKGROUND AND OBJECTIVE: The prognostically favourable effect of secondary prevention in patients with proven coronary heart disease (CHD: documented myocardial infarction, angiographically proven coronary artery stenosis > 60% and/[or] status after coronary artery surgery) has been demonstrated. But it has not been adequately shown to what extent the guidelines laid down by specialist societies is being followed in routine clinical practice. Nor have there been any large-size standardized investigations of whether in-hospital rehabilitation decreases cardiovascular risk factors. It was the aim of this study to investigate the acute effects on cardiovascular risk factors of in-hospital post-infarction rehabilitation. PATIENTS AND METHODS: From January to May 1997, at 18 rehabilitation clinics, 2441 consecutive patients (22% women, aged 65 +/- 10 years, 78% men, aged 60 +/- 10 years) with proven CHD were included in this post-infarction after-care (PIN) study. During their hospital stay (26 +/- 5 days) they undertook physical training appropriate for cardiological follow-up treatment, as well as various other modes of treatment to affect risk factors. Diagnosis, treatment and standardized data were prospectively recorded on admission and discharge. RESULTS: At discharge the proportions of patients with conventionally defined risk factors were significantly lower than on admission (P < 0.001). The proportion was 8% in patients with arterial blood pressure > 140/90 mm Hg (vs. 24% on admission), 5% in smokers (vs. 39% on admission), 30% vs. 60% in patients with cholesterol levels > 200 mg/dl, 67% vs. 87% in those with low density lipids > 100 mg/dl, 15% vs. 22%, in those with serum triglyceride levels > 200 mg/dl, 11% vs. 14% in those with glucose levels > 140 mg/dl, and 15% vs. 18% in patient with a body/mass index > 30 kg/m2. There was an increase in the proportion of patients who during their hospital stay were prescribed additional drugs: from 85% to 86% for acetylsalicylic acid (P < 0.05), 61% to 77% for beta-adrenergic receptor blockers, 33% to 67% for cholesterol synthesis enzyme (CSE) inhibitors, and 51% to 57% for angiotensin converting enzy <head> ACE</head> difiable cardiovascular risk factors can be reduced by various methods of rehabilitation and more intensive drug treatment during hospitalization. By taking account of evidence-based medicine favourable conditions can be created for longterm ambulant after-care.
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</instance>
<instance id="17379330.xx.x">
<answer instance="17379330.xx.x" senseid="C0022709"/>
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AGT and <head> ACE</head> genes influence classic mitral valve prolapse predisposition in Marfan patients. BACKGROUND: In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen (AGT) M235T, ACE I/D and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients. METHODS: We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis. RESULTS: The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one (p=0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p=0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse (OR 3.02, p=0.016). CONCLUSIONS: Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.
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<instance id="3038395.xx.x">
<answer instance="3038395.xx.x" senseid="C0022709"/>
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Perindopril, a new angiotensin converting enzyme inhibitor--clinical pharmacological studies in healthy subjects. Perindopril is a new <head> ACE</head> inhibitor which is activated after hydrolysis in vivo to a diacid (S9780). Oral administration of perindopril (1-16 mg) to groups of 6 healthy males led to a long lasting and dose-elated inhibition of plasma ACE and rises in plasma renin activity with no evidence of accumulation of drug or effect. At higher doses there was a modest fall in blood pressure. S9780 given intravenously in doses of 1,2 or 4 mg caused an immediate inhibition of plasma ACE. The concentration of S9780 in plasma which led to 50% inhibition of plasma ACE was 1.55 +/- 1.14 ng/ml (mean +/- S.D.). Clinical trials with 2-8 mg once daily in essential hypertension are currently in progress.
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</instance>
<instance id="1343270.xx.x">
<answer instance="1343270.xx.x" senseid="C0022709"/>
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Reversibility of left ventricular hypertrophy. Left ventricular hypertrophy (LVH) is a powerful independent risk factor for coronary artery disease. This overview of 104 studies examines the ability of various types of antihypertensive therapies to reverse LVH as assessed by echocardiography. Combination therapy, <head> ACE</head> inhibitors, and methyldopa were the most effective in reversing LV mass; vasodilators such as minoxidil and hydralazine had no effect on LVH. These differences were independent of the degree of fall in blood pressure and duration of therapy. beta-blockers were as effective as ACE inhibitors in decreasing LV wall thickness. Possible reasons for drug differences in reversing LVH are discussed. Preliminary evidence suggests that reversing LVH by antihypertensive drug therapy is associated with a reduction in cardiovascular complications.
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</instance>
<instance id="9524044.xx.x">
<answer instance="9524044.xx.x" senseid="C0022709"/>
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Short-term effects of withdrawing angiotensin converting enzyme inhibitor therapy on home self-measured blood pressure in hypertensive patients. The aim of this study was to compare blood pressure rise after interruption of two <head> ACE</head> inhibitors in hypertensive patients. After a 2-week placebo run-in period, hypertensive patients were treated with either trandolapril 2 mg once daily or perindopril 4 mg once daily for 4 weeks in a double-blind design. A placebo was then administered for 1 week. Three periods of 1-week home self-measured blood pressure (SMBP) were programmed: end of placebo run-in period, end of treatment period, and final withdrawal placebo period. Every day, three consecutive measurements were requested both in the evening and in the morning. Individual reversion to baseline BP level was studied in the subgroup of patients responding to therapy (evening diastolic SMBP decrease > or =6 mm Hg). The ratio (R) of mean post-drug DBP lowering (residual effect) over evening on-drug DBP lowering (full effect) was used to study reversion to baseline. Patients exhibiting a lower value than the median of this ratio were called Reverters, whereas others were called Nonreverters. One hundred-nineteen patients entered the analysis. During the treatment period, mean SMBP decreased significantly, from 150 +/- 14/97 +/- 7 mm Hg to 139 +/- 15/91 +/- 9 mm Hg (all P < .001). The on-drug BP level was similar in the evening in the two treatment groups. However, both systolic and diastolic morning SMBP levels were significantly lower in the trandolapril group. After drug discontinuation, the mean BP level significantly rose to 144 +/- 14/94 +/- 9 mm Hg (all P = .01) but remained lower than the baseline BP values (P = .003 for SBP and P = .002 for DBP). The post-drug BP level was significantly lower in the trandolapril group than in the perindopril group. Seventy-four patients were responders to therapy. In this subgroup, the median of the R ratio used to analyze reversion to baseline after drug discontinuation was 44%. Nonreverters were characterized by a sustained on-drug BP decrease, compared to Reverters. We therefore conclude that ACE inhibitor treatment withdrawal is accompanied by a rapid rise in BP (within 48 h), followed by a 5-day BP plateau that is lower than the initial level. Reverters to baseline after drug discontinuation were more likely to be insufficiently controlled during therapy, particularly in the morning. The longer duration of action of trandolapril was associated with a lower BP level during both the morning during the active treatment phase and the 1-week posttreatment phase.
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</instance>
<instance id="9846641.xx.x">
<answer instance="9846641.xx.x" senseid="C0022709"/>
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Dual pathway for angiotensin II formation in human internal mammary arteries. 1. <head> ACE</head> is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non-ACE conversion of angiotensin I remains unclear. 2. To study the effects of ACE- and chymase-inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery. 3. Organ bath experiments showed that 100 microM captopril inhibited slightly the response to angiotensin I (pD2 from 7.09+/-0.11-6.79+/-0.10, P<0.001), while 100 microM captopril nearly abolished the response to [pro10] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83+/-19%-23+/-17% of the control response (P=0.01). A significant decrease of the pD2 of angiotensin I similar to captopril was observed in the presence of 50 microM chymostatin (pD2 from 7.36+/-0.13-6.99+/-0.15, P<0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I. 4 These results indicate the presence of an ACE and a non-ACE angiontensin II forming pathway in human internal mammary arteries.
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</instance>
<instance id="16918342.xx.x">
<answer instance="16918342.xx.x" senseid="C0022709"/>
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The role of insertion allele of angiotensin converting enzyme gene in higher endurance efficiency and some aspects of pathophysiological and drug effects. BACKGROUND: None of the genetic markers are selectively associated with elite athletes, but potential candidates are found in the renin-angiotensin system, which plays a key role in the regulation of cardiovascular physiology. The most extensively examined gene in connection with the hemodynamics category is the <head> ACE</head> . This review paper has focused on ACE I/D allele polymorphism regarding the evidence of the effects of physiological and pathophysiological drugs and has completed with an original work in the exercise physiology. METHODS: In this study we examined genetic polymorphisms of ACE in female (n=26) and male (n=24) athletes as well as in a well-trained control group (n=24). MVV(ex), VE and VO(2max) were determined at rest and during an exhaustive step test. RESULTS: The frequency of the ACE I allele was significantly higher (p<0.041) in the group showing a higher intensity of breathing metabolism. The ACE D allele frequency was significantly higher in the excellent endurance athletes group than in unsuccessful athletes (p<0.054). CONCLUSION: The ACE I allele is a genetic marker for higher endurance efficiency in acute physical activity and higher adaptation of the cardiovascular system. The measurement of acute physical status needs to be completed with examination of genotype, which is related to the athletic excellence also, because the D allele could be associated with good performance by endurance athletes in future world championships. Further studies are needed to assess the view that the ACE D allele has a significant role in athletic efficiency.
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</instance>
<instance id="11963285.xx.x">
<answer instance="11963285.xx.x" senseid="C0022709"/>
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Neurohumoral activation, regulation of sodium excretion and vasodilator treatment in heart insufficiency. BACKGROUND: The benefits of vasodilator therapy guided by hemodynamic goals in patients with severe heart failure (HF) are well documented. Nevertheless, therapy induced arterial underfilling may activate compensatory neurohumoral mechanisms and sodium retention. OBJECTIVES: To evaluate the effect of vasodilator therapy on neurohumoral activation and sodium excretion in severe HF patients submitted to tailored therapy guided by hemodynamic parameters. METHODS: Ten male patients (aged 70.2 +/- 2.9 years) with severe HF (left ventricle ejection fraction = 15.2 +/- 1.1%) were evaluated according to hemodynamic parameters and plasma levels of brain natriuretic peptide (BNP), norepinephrine, aldosterone, plasma renin activity (PRA), sodium and creatinine and urinary levels of sodium and creatinine, prior to beginning of nitroprusside therapy, every six hours thereafter (for 24 hours) and again after five days of inhibition of <head> ACE</head> with lisinopril. RESULTS: Nitroprusside therapy caused marked increase in cardiac index and substantial reduction in systemic vascular resistance index. Plasma levels of BNP failed significantly while those of PRA, aldosterone and norepinephrine markedly rose, causing substantial reduction of sodium urinary excretion. There were no changes in renal function. Following ACE inhibition by lisinopril, BNP and sodium plasma levels rose, but BNP values remained significantly lower than the initial ones. Norepinephrine and aldosterone returned to base levels and PRA rose sharply. There was an intense natriuretic response and significant elevation of urinary volume. Urinary creatinine and creatinine clearance decreased non-significantly. CONCLUSIONS: Our results show that intensive vasodilator therapy in patients with severe HF improves hemodynamic parameters and causes activation of renin-angiotensin-aldosterone and adrenergic systems, resulting in sodium retention. Nevertheless, this neurohumoral activation is reversed by ACE inhibitors, thus supporting the "wide spectrum" neurohumoral modulation role attributed to these drugs.
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</instance>
<instance id="16257064.xx.x">
<answer instance="16257064.xx.x" senseid="C0022709"/>
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Cloning and characterization of angiotensin converting enzyme related dipeptidylcarboxypeptidase from Leishmania donovani. We report the first identification, gene cloning, recombinant expression and biochemical characterization of an <head> ACE</head> related dipeptidylcarboxypeptidase (DCP) in a protozoan parasite. The mammalian counterpart of this enzyme, peptidyl dipeptidase A (a carboxyl dipeptidase) also known as ACE leads to the cleavage of angiotensin I to produce a potent vasopressor. The catalytic enzyme activity of its Escherichia coli DCP counter part can be inhibited by the antihypertensive drug captopril, suggesting that this class of enzymes constitutes a novel target for drugs and vaccines. By utilizing a DNA microarray expression profiling approach, we identified a gene encoding a DCP enzyme for the kinetoplast protozoan Leishmania donovani (LdDCP) that was differentially expressed in promastigote and amastigote stages of the parasite life cycle. Both RNA and protein levels of LdDCP are higher in axenic amastigotes compared to promastigotes. Immuno-fluorescence analysis revealed the cytosolic expression of the protein. Primary structure analysis of LdDCP revealed the presence of an active Zn binding site. When expressed in E. coli, the recombinant enzyme showed carboxy-dipeptidase activity with synthetic substrates. Replacement of two histidine and one glutamic acid at positions 466, 470 and 467, respectively, with alanine residues in its active site resulted in loss of enzyme activity. Captopril, an ACE specific inhibitor was able both to reduce significantly LdDCP enzyme activity and to inhibit promastigote growth. Both its cytosolic location and close homology to DCPs from bacterial species suggests a role in parasite nutrition. Further, identification of LdDCP now provides an opportunity to investigate Leishmania peptidases for their potential as drug and vaccine targets.
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</instance>
<instance id="16755291.xx.x">
<answer instance="16755291.xx.x" senseid="C0022709"/>
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Localisation of renin-angiotensin system (RAS) components in breast. Angiotensin II has mitogenic and angiogenic effects and its receptors are widespread, particularly in epithelial tissue. Tissue renin angiotensin systems (tRASs) may be a local source of angiotensin II that has specific paracrine functions. To investigate the presence of a tRAS in normal human breast and tumours. Immunocytochemistry, and quantitative RT-PCR was used to establish: (i) the presence and localisation of RAS components, (ii) the possibility of their involvement in cancer. (1) mRNA coding for angiotensinogen, prorenin, <head> ACE</head> , and both AT1 and AT2 receptors was demonstrated in normal and diseased breast tissues. (2) (pro)renin was identified in epithelial cells in both normal and diseased tissue, but in invasive carcinoma, its distribution was mostly confined to fibroblasts or could not be detected at all. (3) Angiotensin converting enzyme was shown in epithelial cells in both normal and malignant tissue. The results are consistent with the hypothesis that a tRAS is present in the breast, and is disrupted in invasive cancer.
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</instance>
<instance id="7881659.xx.x">
<answer instance="7881659.xx.x" senseid="C0022709"/>
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Transient increase in interleukin-8 and pulmonary microvascular permeability following aortic surgery. Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin <head> ACE</head> in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="8891745.xx.x">
<answer instance="8891745.xx.x" senseid="C0022709"/>
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Local renin-angiotensin system in sympathetic overactivity of spontaneously hypertensive rats. The present study was designed to clarify whether modulation of norepinephrine (NE) release by vascular angiotensin (Ang) II is involved in the increased peripheral sympathetic activity of spontaneously hypertensive rats (SHR). In the perfusion system of isolated mesenteric vascular beds, periarterial nerve stimulation (PNS)-evoked NE overflow was significantly greater in SHR than Wistar-Kyoto rats (WKY). Administration of Ang II increased PNS-induced NE overflow, which could be reversed by pretreatment with the AT1 receptor antagonist CV-11974 in both types of rats; the facilitation by Ang II was more potent in SHR. Moreover, CV-11974 by itself could attenuate PNS-evoked NE overflow, the extent of which was also significantly greater in SHR, suggesting an augmented sympatho-facilitatory effect of endogenous Ang II in SHR. Consistently, sympatho-facilitation by Ang I, which could be abolished by the <head> ACE</head> inhibitor imidaprilat, was apparently greater than that of Ang II in SHR, despite no difference in WKY. These findings suggest that the increased peripheral sympathetic activity in SHR is attributed not only to the elevated sensitivity of nerve endings to Ang II but also to the increased local generation of Ang II, an effect possibly mediated by augmented vascular ACE activity.
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</instance>
<instance id="7484425.xx.x">
<answer instance="7484425.xx.x" senseid="C0022709"/>
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Angiotensin as a renal growth promoting factor. The kidney has been traditionally considered to be one the pivotal organs involved in the systemic actions of the renin-angiotensin system (RAS) with renin produced in the juxtaglomerular apparatus and angiotensin II (ANG II) as a key player in the regulation of glomerular hemodynamics. However, many studies in the last decade, facilitated by a throughout molecular characterization of all elements of the RAS, have provided convincing evidence that the kidney exhibits a local RAS which may independently function from the systemic actions of the endocrine RAS. Moreover, even local distinct cell populations along the nephron possess all components of a functioning RAS. For example, proximal tubular cells express mRNA and protein for angiotensinogen, renin, and <head> ACE</head> . They bear different types of ANG II receptors with the appropriate signal transduction systems, and these cells also exhibit surface proteases like angiotensinase A which are required for the inactivation of ANG II. Moreover, recent studies in the isolated perfused kidney have clearly shown that proximal tubular cells produce considerable amounts of ANG II and these concentrations exceed approximately hundred times the systemic concentration of the peptide. Besides the well-known regulation of glomerular hemodynamics by contraction of the efferent glomerular arteriole and mesangium cells, ANG II influences transport and acidification processes in proximal and distal tubules. In addition, the octapeptide stimulates metabolic pathways like tubular gluconeogenesis and ammoniagenesis. Accumulating data over the last years derived from in vivo and in vitro studies have demonstrated that ANG II is also a growth factor for renal cells. For example, cell culture experiments have shown that the octapeptide stimulates proliferation or hypertrophy of mesangial cells. In contrast, proliferation of cultured proximal tubular cells is inhibited by ANG II and cellular hypertrophy of these cells is induced. Many studies have provided evidence that early mesangial proliferation/hypertrophy and tubular hypertrophy is a predecessor of the subsequent development of glomerulosclerosis and interstitial fibrosis, situations with irreversible morphological changes of the kidney's architecture leading finally to end-stage renal disease. Therefore, the identification of ANG II as a renal growth factor and a better understanding of its local intrarenal synthesis and growth stimulating effects on different cell types along the nephron may help to develop rational therapeutic interventions to prevent the progression of renal disease.
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</instance>
<instance id="11213033.xx.x">
<answer instance="11213033.xx.x" senseid="C0022709"/>
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Coronary capillary remodeling in non-insulin-dependent diabetic rats: amelioration by inhibition of angiotensin converting enzyme and its potential clinical implications. Using Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM) that exhibits hypertension, obesity, hyperglycemia and hyperlipidemia, the role of local angiotensin II in cardiovascular complications at early stages of NIDDM was characterized. OLETF rats were given an <head> ACE</head> inhibitor, cilazapril (10 mg/kg/day) or vehicle from the age of 5 weeks to 20 weeks. Arteriolar, intermediate and venular capillary proportions were determined by the double-staining method and levels of collagen and non-collagenous proteins were determined by the selective dye-binding method in heart tissues. In OLETF rats at 20 weeks of age, capillary network remodeling (i.e., an increase in arteriolar portions and a decrease in venular portions) and an increase in collagen content were detected. Cilazapril not only exerted favorable effects on markers of diabetes, but also prevented capillary network remodeling and ameliorated the increase in collagen content. These results suggest that 1) capillary network remodeling and increase in extracellular matrix protein levels precede the onset of overt NIDDM in OLETF rats, and 2) angiotensin II may be involved in the pathogenesis of cardiac complications in the early stages of NIDDM.
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</instance>
<instance id="14718831.xx.x">
<answer instance="14718831.xx.x" senseid="C0022709"/>
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Renovascular disease: effect of <head> ACE</head> gene deletion polymorphism and endovascular revascularization. BACKGROUND: Renal artery stenosis (RAS) is associated with high cardiovascular mortality and significant clinical complications, including resistant hypertension and ischemic nephropathy. Despite availability of endovascular revascularization techniques, determining which patients should undergo revascularization and the timing of the procedure still are controversial. Several studies have reported a higher frequency of the DD genotype of the insertion/deletion (I/D) polymorphism of the ACE gene in patients with RAS, and one study found higher mortality in patients with the DD genotype. Material and methods We retrospectively studied 100 patients with documented atherosclerotic RAS and evaluated long-term (median follow-up, 28 months) mortality, blood pressure control, and renal function in relation to the ACE genotype and two therapeutic strategies, that is, endovascular treatment with percutaneous renal transluminal angioplasty or stenting (ET group) versus conservative drug therapy (CT group). RESULTS: Comparison between therapeutic groups showed a higher cumulative probability of survival (86.7% vs 67.1%), better blood pressure control (57.4% vs 29%), and slower decline in renal function (17.9% vs 48.4%) in the ET group. The DD genotype was strongly represented in our study patients (DD, 50%; II, 15.5%; I/D, 34.5%), but bore no relation to mortality, blood pressure control, decline in renal function, or rate of recurrent stenosis. CONCLUSIONS: Conservative medical treatment of RAS, compared with endovascular treatment, is associated with higher mortality, poorer blood pressure control, and impaired renal function over the long term. Early endovascular treatment enables amelioration of this unfavorable evolution. The DD genotype does not predict clinical outcome of RAS.
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</instance>
<instance id="8225420.xx.x">
<answer instance="8225420.xx.x" senseid="C0022709"/>
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Angiotensin converting enzyme activity in female reproductive tract of domestic fowl (Gallus domesticus) and its interactions with semen. Presence of <head> ACE</head> , EC 3.4.15.1) in female reproductive tract and its interaction with semen has been investigated in domestic fowl. Higher activity of ACE was detected in homogenates of infundibulum region followed by magnum and relatively low level was noticed in rest of the parts of the oviduct (i.e. isthmus, uterus, uterovaginal-junction and vagina). This decreasing order in ACE activity was, however, reversed when these segments were incubated with semen. ACE in the ovarian follicular wall increased with corresponding increase in the follicle size. Presence of some stimulatory or inhibitory substances for ACE in the oviduct of fowl is suggested.
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</instance>
<instance id="7535899.xx.x">
<answer instance="7535899.xx.x" senseid="C0022709"/>
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Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: hypertension, cardiac hypertrophy and renal insufficiency. Inhibition of the <head> ACE</head> with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME). Chronic treatment with L-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 +/- 16 mmHg) as compared to controls (155 +/- 4 mmHg). Animals receiving simultaneously L-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56 +/- 0.73 ml.kg-1.min-1) and renal plasma flow (RPF: 6.93 +/- 1.70 ml.kg-1.min-1) as compared to control (GFR: 7.29 +/- 0.69, RPF: 21.36 +/- 2.33 ml.kg-1.min-1). Addition of ramipril prevented L-NAME-induced reduction in GFR and renal plasma flow. L-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with L-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="15950509.xx.x">
<answer instance="15950509.xx.x" senseid="C0022709"/>
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No association between Angiotensin Converting Enzyme ( <head> ACE</head> ) gene variation and endurance athlete status in Kenyans. East African runnerACEernational distance running. The extent to which genetic factors influence this phenomenon is unknown. The insertion (I) rather than deletion (D) of a 287 bp fragment in the human angiotensin converting enzyme (ACE) gene is associated with lower circulating and tissue ACE activity and with endurance performance amongst Caucasians. To assess the association between ACE gene variation and elite endurance athlete status in an African population successful in distance running, DNA samples were obtained from 221 national Kenyan athletes (N), 70 international Kenyan athletes (I), and 85 members of the general Kenyan population (C). Blood samples were obtained from C and assayed for circulating ACE activity. ACE I/D (rs????--from NCBI SNPdb first time poly mentioned) genotype was determined, as was genotype at A22982GD (rs????--from NCBI SNPdb first time poly mentioned) which has been shown to associate more closely with ACE levels in African subjects than the I/D polymorphism. ACE I/D and A22982G genotypes explained 13 and 24% of variation in circulating ACE activity levels (P = 0.034 and <0.001 respectively). I/D genotype was not associated with elite endurance athlete status (df = 4, chi(2) = 4.1, P=0.39). In addition, genotype at 22982 was not associated with elite endurance athlete status (df = 4, chi(2) = 5.7, P = 0.23). Nor was the A allele at 22982, which is associated with lower ACE activity, more prevalent in N (0.52) or I (0.41) relative to C (0.53). We conclude that ACE I/D and A22982G polymorphisms are not strongly associated with elite endurance athlete status amongst Kenyans.
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</instance>
<instance id="11824872.xx.x">
<answer instance="11824872.xx.x" senseid="C0022709"/>
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Clinical trials of angiotensin receptor blockers in heart failure: what do we know and what will we learn? Although interruption of the renin-angiotensin system with <head> ACE</head> inhibitors has evolved as the therapy of choice in heart failure based on large-scale morbidity and mortality clinical studies, treatment with angiotensin type 1 receptor blockers (ARB) offers an alternative and potentially superior method of treating this condition. Early pilot studies were quite promising; however, two well designed, large-scale trials have shown that the reduction in heart failure mortality with ARB is not significantly different from the reduction with ACE inhibitors. Possible reasons for lack of ARB superiority include insufficient dosing of ARB, differences in effects mediated through angiotensin II type 2 receptors, interaction with beta-blockers, and bradykinin-mediated effects specific to ACE inhibitors. The ACE inhibitors remain the current therapy of choice in treating heart failure until further outcomes trial data become available; however, ARB are a reasonable alternative in patients intolerant of ACE inhibitors.
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</instance>
<instance id="16187132.xx.x">
<answer instance="16187132.xx.x" senseid="C0022709"/>
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General practitioners choose within a narrow range of drugs when initiating new treatments: a cohort study of cardiovascular drug formularies. OBJECTIVE: The aims of this study were (1) to develop and evaluate a new method for investigating personal drug formularies in general practice and (2) to test the hypothesis that there is a difference between personal drug formularies for incident and ongoing drug use. METHODS: In 2002, we studied prescribing patterns of beta-blockers, calcium channel blockers, <head> ACE</head> inhibitors, angiotensin-II antagonists and statins in the County of Funen, Denmark (180 general practices, 472,000 inhabitants). For each practice, we distinguished between an incident drug formulary consisting of prescriptions for new users and an ongoing drug formulary including prescriptions for patients already in treatment. Prescription data were retrieved from the Odense University Pharmacoepidemiologic Database (OPED). Four different formulary measures were evaluated and used for comparing incident and ongoing drug use. RESULTS: General practitioners' (GPs') incident drug formularies comprised significantly fewer drugs than their ongoing drug formularies for all drug groups except angiotensin-II antagonists. The difference in the total number of drugs used was between 1.8 and 3.3. We found differences between 0.5 and 1.6 analogues in the DU 90% (number of analogues accounting for 90% of the prescribed volume measured in defined daily doses) segment and the formulary selectivity index between 0.05 and 0.12. The preference for the most prescribed analogue was 9-18% higher among incident patients. The formulary selectivity index was highly correlated with the other formulary measures and quantified both range and skewed distribution of drug choice. CONCLUSION: Analysing GPs' prescriptions to incident patients is a simple and inexpensive method for studying their own current personal drug formularies. GPs choose within a narrow range of analogues for incident patients.
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</instance>
<instance id="9808682.xx.x">
<answer instance="9808682.xx.x" senseid="C0022709"/>
<context>
Effects of neutral endopeptidase inhibition and combined angiotensin converting enzyme and neutral endopeptidase inhibition on angiotensin and bradykinin peptides in rats. The combination of neutral endopeptidase 24.11 (NEP) and <head> ACE</head> inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.
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</instance>
<instance id="2572263.xx.x">
<answer instance="2572263.xx.x" senseid="C0022709"/>
<context>
The efficacy and safety of chronic oral administration of xamoterol to patients with severe heart failure treated with <head> ACE</head> inhibitors. Xamoterol 200 mg twice daily was given for 2 months to nine patients with severe heart failure already being treated with ACE inhibitors. Left ventricular end-diastolic pressure fell from 28 to 13 mmHg and end-systolic volume fell from 115 to 106 ml m-2; indices of contractility improved and ejection fraction rose from 33 to 38%. The time constant of ventricular relaxation, T1, improved from 62 to 44 ms. Exercise tolerance improved. Thus, in this group of patients with severe heart failure, xamoterol produced benefits in systolic and diastolic function. There were no adverse effects.
</context>
</instance>
<instance id="16574603.xx.x">
<answer instance="16574603.xx.x" senseid="C0022709"/>
<context>
Effect of lisnopril, an angiotensin converting enzyme ( <head> ACE</head> ) inhibitor on spermatogenesis in rats. The role of ACE inhiACE function remains controversial. Some benefits seem to be derivable even in non-hypertensive males with low doses. This study was done using rat model to establish this fact. Male rats were divided into different groups to receive different doses of lisinopril. A control group received no drugs. The mean arterial pressure fell the most with 5 mg of lisinopril. The greatest increase in sperm count and motility was recorded for this same group. This response was dose dependent, falling as the drug dose fell. Lisinopril appeared to, in a dose dependent manner, improve sperm count and motility. In low doses, there is no significant change in arterial pressure. Infertile males with poor quality semen could benefit from a low dose of ACE inhibition. Where they are also hypertensive, ACE inhibition would be an appropriate first line treatment.
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</instance>
<instance id="9321751.xx.x">
<answer instance="9321751.xx.x" senseid="C0022709"/>
<context>
Pressure overload per se rather than cardiac angiotensin converting enzyme activity may be important in the development of rat cardiac hypertrophy. OBJECTIVE: To investigate the roles of the renin-angiotensin system and blood pressure in cardiac hypertrophy caused by a pressure overload. METHODS: Cardiac hypertrophy was induced by constricting the abdominal aorta above the renal arteries. After they had been banded, the rats were treated with the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of quinapril [an <head> ACE</head> inhibitor], or the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of TCV-116 [an angiotensin II (AngII) AT1 receptor antagonist], for 4 weeks. Then, we measured the mean blood pressure (MBP), body weight, left ventricular weight (LVW), and serum and cardiac ACE activities. RESULTS: The higher dose of quinapril and that of TCV-116 prevented left ventricular hypertrophy and MBP elevation. Both the higher and the lower doses of quinapril reduced the serum and cardiac ACE activities significantly, whereas the higher dose of TCV-116 reduced the cardiac ACE activity and increased the serum ACE activity. The lower dose of quinapril, however, exerted no significant effect on MBP and the LVW:body weight ratio, although it reduced the cardiac and serum ACE activities significantly. There was a significant positive correlation between the MBP and the LVW:body weight ratio regardless of the cardiac ACE activity in data from all groups (r = 0.676, P < 0.0001). CONCLUSIONS: Our data indicate the importance of the blood pressure as a determinant of cardiac hypertrophy because inhibition of cardiac ACE activity alone without lowering of the blood pressure is insufficient to prevent cardiac hypertrophy. Our results suggest the presence of other pathways for AngII production not mediated by ACE, or growth factors other than AngII in pressure-overload cardiac hypertrophy.
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</instance>
<instance id="9474348.xx.x">
<answer instance="9474348.xx.x" senseid="C0022709"/>
<context>
Diagnosing left ventricular dysfunction after myocardial infarction: the Dundee algorithm. Large-scale trials of <head> ACE</head> inhibitors after acute myocardial infarction (AMI) suggest that the benefits are greatest in patients with left ventricular (LV) dysfunction. However, early evaluation of LV function in all patients after AMI by current methods can be difficult due to a lack of resources and skilled personnel. Thus a clinical algorithm that could be used at the bedside to reliably identify patients with a left ventricular ejection fraction (LVEF) < or = 40% would be helpful as an occasional alternative to echocardiography. We have devised such an algorithm based on the presence of one of: (i) clinical signs of heart failure; (ii) an index Q-wave anterior myocardial infarction; (iii) lack of thrombolytic therapy when there is a history of two or more previous myocardial infarctions and a CK rise > 1000 U/l. We tested this new algorithm prospectively in the coronary care units of two hospitals (one UK and one USA). In the UK centre, the sensitivity and specificity of the algorithm at identifying patients with a LVEF < or = 40% were 82% and 72%, respectively. In the US centre, the sensitivity of the algorithm was 91% and the specificity 78% at identifying patients with LV dysfunction. We have validated a simple clinical algorithm which can be used at the bedside for identifying patients who would benefit from an ACE inhibitor after AMI.
</context>
</instance>
<instance id="7768036.xx.x">
<answer instance="7768036.xx.x" senseid="C0022709"/>
<context>
Potentiation of natriuretic peptides by neutral endopeptidase inhibitors. 1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihypertensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an <head> ACE</head> inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose-related manner in conscious dogs with tachycardia-induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metalloprotease inhibitor BMS-182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="12410856.xx.x">
<answer instance="12410856.xx.x" senseid="C0022709"/>
<context>
Role of combination therapy with <head> ACE</head> inhibitors and calcium channel blockers in renal protection. Over recent years, a target blood pressure of 125/75 mm Hg has been sought in order to reduce the rate of chronic renal disease (CKD) progression and cardiovascular mortality. Some antihypertensive agents, such as ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers also may be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage. The possibility that combination treatments with ACE inhibitors and calcium-channel blockers may confer additive or even synergistic renoprotective effects other than blood pressure control is not only fascinating, but also particularly important because multidrug antihypertensive regimens are required to obtain adequate blood pressure in the majority of patients with CKD. This combination may provide better blood pressure control, appears to be better tolerated with fewer side effects than either drug alone, and may exert a greater renoprotective effect in patients at risk for renal failure than either an ACE inhibitors or a calcium channel blocker. However, the current available data are too few to confirm this hypothesis. Cardiovascular disease accounts for more than 50% of the deaths of hemodialysis patients. Thus, care must be taken to prevent and treat the cardiovascular risk factors optimally from the early phase of CKD, and for this reason effective antihypertensive therapy is the most important treatment, not only in order to delay CKD progression, but also to reduce the burden of cardiovascular disease. In this perspective combination therapy with ACE inhibitors and calcium channel blockers can give further advantages.
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</instance>
<instance id="12022243.xx.x">
<answer instance="12022243.xx.x" senseid="C0022709"/>
<context>
Ramipril improves hemodynamic recovery but not microvascular response to ischemia in spontaneously hypertensive rats. BACKGROUND: <head> ACE</head> inhibition exerts positive effects on the microvasculature of normotensive animals, although this concept is not universally accepted. Recently, ACE inhibitors have been suggested to be useful for rescue in peripheral ischemia. METHODS: We investigated whether chronic treatment with the ACE inhibitor ramipril may have a positive impact on the defective healing response to ischemia that is typical of spontaneously hypertensive rats (SHR). Unilateral limb ischemia was induced in 20-week-old SHR by surgically removing the left femoral artery. Rats were allowed to regain consciousness and then were randomly allocated to treatment with ramipril (1 mg/kg body weight in drinking water) or vehicle for 28 days. RESULTS: The SHR failed to develop reparative angiogenesis in response to ischemia, thus having inadequate perfusion recovery. Ramipril reduced both tail-cuff systolic blood pressure (180 +/- 7 v 207 +/- 2 mm Hg in the vehicle group at 28 days, P < .05) and intra-arterial mean blood pressure (115 +/- 6 v 135 +/- 5 mm Hg in the vehicle group, P < .05). These effects were associated with increased responsiveness to endothelium-dependent vasodilatation by acetylcholine. Treatment with ramipril did not influence muscular capillary and arteriole density but accelerated the rate of perfusion recovery, leading to complete healing within 28 days after surgery. CONCLUSIONS: These results indicate that ACE inhibition by ramipril may be useful for the treatment of peripheral vascular complications in hypertension.
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</instance>
<instance id="8542735.xx.x">
<answer instance="8542735.xx.x" senseid="C0022709"/>
<context>
Diabetic renal disease: the quest for normotension--and beyond. Over the past two decades there has been an increasing interest in hypertension as a risk factor for diabetic renal disease and in particular for the possibility of early antihypertensive intervention. Therefore, it would seem timely to review the history of hypertension in diabetes, with special reference to renal disease and the need for normotension, in a manner resembling glycaemic control. Elevated blood pressure (BP) associated with diabetes mellitus has been recognized since the beginning of the century and was initially particularly documented in association with the demonstration of the striking histological lesion in glomeruli, starting with the observation of Kimmelstiel and Wilson in 1936. These patients in many cases also showed hypertension, as confirmed in several subsequent reports, very similar to the studies of Kimmelstiel and Wilson. However, the development was hampered by the lack of effective antihypertensive agents and also by some who believed that elevated BP could be of importance to preserve renal function in these individuals. Indeed, it was suggested that reduction of BP could mean permanent deterioration in renal function. BP remained very high in the standard care of diabetic patients up to the middle 1970s. At this time it was documented that elevated BP was very closely related to development of diabetic renal disease in Type 1 (insulin-dependent) diabetic (IDDM) patients, and studies also showed a correlation between blood pressure and rate of progression. This correlation stimulated research in intervention, and indeed in the 1980s and 1990s several long-term studies reported that antihypertensive treatment can reduce the rate of decline in glomerular filtration rate (GFR) from about 12 ml min-1 yr-1 down to about 2 ml min-1 yr-1 in the most optimistic reports; usually a mean level of 2-5 ml min-1 yr-1 is achievable by antihypertensive treatment, in clinical situations where glycaemic control often is far from perfect. Many studies have also documented that BP starts to rise in the early phase of incipient diabetic nephropathy characterized by microalbuminuria. This is a stage with well-preserved GFR and therefore probably an ideal stage for intervention in these at risk patients. Many studies, in particular those employing <head> ACE</head> inhibitors based on important pathophysiological concepts proposed by Brenner, have shown that microalbuminuria can be reduced or stabilized by early antihypertensive treatment, just as we see with optimized glycaemic control. ACE inhibitors have also been widely used in patients with overt nephropathy and the rate of decline in GFR has been reduced considerably.(ABSTRACT TRUNCATED AT 400 WORDS)
</context>
</instance>
<instance id="9683927.xx.x">
<answer instance="9683927.xx.x" senseid="C0022709"/>
<context>
Atherosclerosis in Marek's disease virus infected hypercholesterolemic roosters is reduced by HMGCoA reductase and <head> ACE</head> inhibitor therapy. OBJECTIVES: Accelerated atherosclerosis is associated with herpesviral infection both in transplant patients and after balloon angioplasty. Marek's disease virus (MDV) is a herpesvirus that induces accelerated atherosclerosis associated with the development of an invasive lymphoma in hyperlipemic roosters. We have examined the effects of pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitor and quinapril, an ACE inhibitor, on atherosclerosis development in MDV infected, cholesterol fed rooster chicks. METHODS: The effects of these drugs on plaque growth after MDV infection were examined in two studies. In Study 1, MDV infected White Leghorn rooster chicks were divided into 4 groups assigned to normal or high cholesterol diet, and treated at three months of age with either pravastatin or saline. In Study 2, cholesterol fed rooster chicks infected with MDV were divided into 3 groups for treatment with either pravastatin, quinapril, or saline control. RESULTS: A significant decrease in plaque area was detected after 60 days of treatment with both pravastatin and quinapril in cholesterol fed chicks (P < 0.001). Lymphocyte infiltration into the arterial wall or target organs was not inhibited by treatment with either drug. CONCLUSIONS: (1) HMGCoA reductase inhibitor and ACE inhibitor therapy reduce atherosclerosis induced by virus infection and cholesterol diet, but this decrease in plaque growth is not due to a reduction in lymphocyte invasion. (2) MDV infection in cholesterol fed roosters provides a model for virus-induced arterial injury in atherogenesis.
</context>
</instance>
<instance id="10930307.xx.x">
<answer instance="10930307.xx.x" senseid="C0022709"/>
<context>
Induction of angiotensin-converting enzyme by oncostatin m in human endothelial cells. OBJECTIVE: To examine the role of oncostatin M (OSM) in the regulation of <head> ACE</head> in endothelial cells. METHODS: Cultured endothelial cells were incubated with OSM (25-200 pM) for 24 h. Incubations were performed without or with the tyrosine kinase inhibitor, herbimycin (87 nM), or the selective MAP kinase kinase inhibitor, PD98059 (50 microM). ACE amount in intact endothelial cells was measured by an inhibitor binding assay and ACE mRNA levels by RNase protection assay. RESULTS: OSM caused a dose dependent increase in ACE amount and increased the expression of ACE mRNA. The stimulatory effect of OSM was inhibited by pretreatments with herbimycin or PD98059. CONCLUSIONS: OSM induced ACE in cultured HUVECs. Tyrosine kinase and MAPK activation were probably involved in ACE induction. Local induction of ACE by OSM in the vascular wall may be a consequence of inflammatory processes leading to locally increased production of angiotensin II and breakdown of bradykinin.
</context>
</instance>
<instance id="7965267.xx.x">
<answer instance="7965267.xx.x" senseid="C0022709"/>
<context>
The advantages of angiotensin II antagonism. New approaches to renin-angiotensin blockade: The successful use of <head> ACE</head> inhibitors in the treatment of hypertension and congestive heart failure has generated a great deal of research interest in developing new pharmacological approaches to block the renin-angiotensin system. In recent years, several new non-peptide angiotensin II antagonists have been synthesized and some of them are available for experimental and/or clinical investigations. Now that experience with the antagonist losartan is accumulating, it is important to compare the effects, the efficacy and the side effects of this agent with those of ACE inhibitors. Effects of losartan compared with ACE inhibitors: So far, ACE inhibitors and the angiotensin II antagonist losartan appear to have similar systemic and regional hemodynamic effects. The impact of ACE inhibition and angiotensin blockade on the various components of the renin-angiotensin system is also comparable except for a marked increase in plasma angiotensin II levels during angiotensin II blockade. This increase in circulating angiotensin II might theoretically lead to an excessive stimulation of the AT2 receptor subtype, but since the function of this receptor is not known it is impossible to evaluate the implications of this reactive rise. Renal effects of losartan: The renal effects of angiotensin II antagonists are also very similar to those of ACE inhibitors. However, a marked increase in uric acid excretion has been observed with the administration of losartan. This uricosuric effect of losartan might represent a clinical advantage unless a state of urinary supersaturation of undissociated uric acid is achieved.(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="9715789.xx.x">
<answer instance="9715789.xx.x" senseid="C0022709"/>
<context>
Effects of the angiotensin converting enzyme inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system in essential hypertensive patients. The effects of the <head> ACE</head> inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system were investigated in essential hypertensive patients (EHT). Seven EHT were hospitalized and underwent a 2-h euglycemic hyperinsulinemic glucose clamp before and after 2 weeks' administration of temocapril (4 mg/day). Insulin sensitivity was calculated using the M value from the infusion rate of glucose with hyperinsulinemia using the glucose clamp method. Renal clearances of sodium, lithium, creatinine, and paraaminohippuric acid were used to calculate fractional proximal and distal tubular reabsorption of sodium (FPR(Na), FDR(Na)) and renal plasma flow (RPF) before and during insulin infusion by the glucose clamp method. Temocapril decreased blood pressure and increased M value significantly. Before temocapril treatment, hyperinsulinemia by the glucose clamp induced significant decreases of urinary excretion of sodium (U(Na) V) and fractional excretion of sodium (FENa). After treatment, these decreases were attenuated, and the change of U(Na) V (deltaU(Na) V) with hyperinsulinemia was significantly higher and deltaFENa showed a higher tendency, compared with before the treatment. FPR(Na) showed no change with hyperinsulinemia before treatment, but significantly decreased after treatment. DeltaFPR(Na) was significantly lower after treatment than that before treatment. FDR(Na) showed an increase with hyperinsulinemia, and deltaFDR(Na) was similar between before and after treatment. RPF showed no change with hyperinsulinemia, and no difference was found in deltaRPF between before and after treatment. Plasma norepinephrine level (PNE) and plasma renin activity (PRA) showed increases, whereas plasma aldosterone concentration (PAC) did not change with hyperinsulinemia. There were no significant differences in deltaPNE, deltaPRA, and deltaPAC between before and after treatment. From these results, it is suggested that in EHT 1) temocapril improves insulin resistance, and 2) although temocapril shows no significant influence on the augmentation of pressor systems by hyperinsulinemia, this agent attenuates the sodium-retaining action of hyperinsulinemia, which may be attributable to suppression of insulin-induced sodium reabsorption at the proximal tubules. These effects may lead to additional beneficial effects in the treatment of essential hypertensives with insulin resistance.
</context>
</instance>
<instance id="10544843.xx.x">
<answer instance="10544843.xx.x" senseid="C0022709"/>
<context>
Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme ( <head> ACE</head> ) gene. OBJECTIVE: ACE takes part in the renin-angiotensin and kallikrein-kininogen systems by cACEting bradykinin. ACE gene insertion/deletion polymorphism is associated with the level of circulating enzymes--subjects with the DD genotype have higher levels of circulating ACE than subjects with the II genotype and show an increased tendency towards impaired vascular function and structure. Patients with systemic lupus erythematosus (SLE) suffer from differentially expressed vascular pathology. We attempted to determine whether the type of ACE polymorphism could contribute to this pathology. METHODS: 101 SLE patients fulfilling the ACR criteria were investigated. The I/D polymorphism was ascertained by PCR, followed by electrophoresis of the amplified fragments and UV visualization. RESULTS: The frequency of the D allele was higher in the SLE group (0.623) than in the controls (0.520) (chi 2 test, p < 0.025). The distribution of the ACE genotype in SLE group was different from that in the control group (p < 0.05). An association between the DD genotype and visceral damage (p < 0.006) was observed. CONCLUSION: Our results suggest that in the multifactorially determined vascular pathology of SLE, changes associated with I/D polymorphism could influence vessel wall inflammation (monocyte adhesion and activation with cytokine release, T-lymphocyte metabolism), a tendency towards vascular impairment (neointimal proliferation, vasospasm, platelet activation, myocyte proliferation) and lead to the subsequent ischemia. The ACE gene could serve as the visceral damage indicator in SLE.
</context>
</instance>
<instance id="6093192.xx.x">
<answer instance="6093192.xx.x" senseid="C0022709"/>
<context>
Captopril and enalapril: <head> ACE</head> inhibitors.
</context>
</instance>
<instance id="17057137.xx.x">
<answer instance="17057137.xx.x" senseid="C0022709"/>
<context>
Rapid onset of haemodynamic effects after angiotensin converting enzyme-inhibitor overdose: implications for initial patient triage. BACKGROUND: <head> ACE</head> -inhibitor overdose may result in severe hypotension. Existing data do not adequately deal with the likely onset of haemodynamic effects, which has implications for the appropriate duration of monitoring in the acute-care setting. Therefore, the relationship between the interval after an ACE-inhibitor overdose and onset of hypotension was examined. METHODS: A retrospective case review of patients who attended our institution after an ACE-inhibitor overdose between 1 January 2000 and 31 December 2005 was carried out. Data collected were heart rate, blood pressure, electrolytes, electrocardiogram variables, and interval between ingestion and lowest recorded blood pressure. RESULTS: 33 patients (24 men) who presented after an ACE-inhibitor overdose were identified. Median (interquartile range (IQR)) age was 49 (42-56) years, and stated quantity ingested was 20 (7-42) times the defined daily dose. The median (IQR) interval between ACE-inhibitor ingestion and lowest recorded systolic blood pressure was 4.5 (3.8-5.5) h, diastolic blood pressure was 3.8 (3.3-6.5) h and mean blood pressure was 4.2 (3.5-5.5) h. Heart rate did not increase substantially in response. CONCLUSION: The lowest blood pressure was recorded within a short interval after an ACE-inhibitor overdose, irrespective of therapeutic intervention. Patients in whom hypotension has not occurred within 6 h of ingestion can be considered for discharge.
</context>
</instance>
<instance id="9249242.xx.x">
<answer instance="9249242.xx.x" senseid="C0022709"/>
<context>
Characterization of angiotensin II formation in human isolated bladder by selective inhibitors of <head> ACE</head> and human chymase: a functional and biochemical study. 1. Functional recordings of smooth muscle tension and biochemical experiments on membrane fractions were performed to characterize angiotensin II (AII) formation in human isolated bladder smooth muscle. 2. A novel human chymase inhibitor CH 5450 (Z-Ile-Glu-Pro-Phe-CO2Me) and a recently developed human chymase substrate Pro11-,D-Ala12)-angiotensin I, claimed to be resistant to ACE and carboxypeptidase, were used. 3. Angiotensin I (AI) (0.3 microM) induced a contractile response amounting to 58 +/- 5% (n=12) of the initial K+ (124 mM)-induced contractions. This response was reduced to 36 +/- 3% (n=8) by the ACE-inhibitor enalaprilat (10 microM), while pretreatment with soybean trypsin inhibitor (STI 200 microg ml(-1)) or CH 5450 (10 microM) had no effect. However, the combination of enalaprilat and STI reduced the AI-induced contractions to 19 +/- 5% (n=6), and the combination of enalaprilat and CH 5450 caused an almost complete inhibition of the AI-induced contractions to 1+/-1% (n=6). 4. The substrate (Pro11-,D-Ala12)-AI (3 microM) produced contractions which amounted to 57 +/- 4% (n=13) of the initial K+ (124 mM) contractions. These contractions were not affected by enalaprilat (10 microM). On the other hand, STI (200 microg ml(-1)) and CH 5450 (10 microM) added separately, depressed the (Pro11-,D-Ala12)-AI-induced contractions to 34 +/- 5% (n=6) and 24 +/- 4% (n=6), respectively. The combination of enalaprilat and STI or enalaprilat and CH 5450 did not produce any further inhibition. 5. Experiments with detrusor membrane fractions incubated with AI (50 microM) were performed. In the presence of enalaprilat (100 microM), carboxypeptidase inhibitor CPI (10 microg ml(-1)) and aprotinin (15 microM), CH 5450 (10 nM-1 microM) caused a concentration-dependent inhibition of AII formation. 6. The results confirm that AII is a potent contractile agent in the human isolated detrusor muscle. They also indicate that the serine protease responsible for AII formation in the human bladder in vitro is human chymase or an enzyme similar to human chymase.
</context>
</instance>
<instance id="14692507.xx.x">
<answer instance="14692507.xx.x" senseid="C0022709"/>
<context>
Characterization of new milk-derived inhibitors of angiotensin converting enzyme in vitro and in vivo. Inhibition of <head> ACE</head> has been observed with a variety of different peptides, and peptide fragments with inhibitory capabilities have been identified within many different proteins, including milk proteins. The purpose of this study therefore was to identify new short peptides with inhibitory properties from the primary structure of milk proteins and to characterize them in vitro and in vivo, since no milk derived ACE inhibitors have previously been evaluated for their ability to inhibit ACE in vivo. In vitro, 8 of 9 dipeptides were found to be competitive inhibitors of ACE. The IC50 was significantly lower when an angiotensin I-like substrate was used, than when a bradykinin-like substrate was used. Using three different in vivo models for ACE inhibition, a very moderate effect was observed for three of the new peptides, but only for up to 6 or 12 minutes. Nothing was observed with two reference compounds that are reported to be hypotensive ACE-inhibitors derived from milk proteins. This raises the question whether the mechanism of hypotensive action is straightforward inhibition of ACE in vivo.
</context>
</instance>
<instance id="15724789.xx.x">
<answer instance="15724789.xx.x" senseid="C0022709"/>
<context>
Therapeutic controversies in hypertension management: angiotensin converting enzyme ( <head> ACE</head> ) inhibitors or angiotensin receptor blockers in diabetic nephropathy? ACE inhibitors. Diabetic nephropathy is the number one cause of enACEStates. Blood pressure is most important in delaying the progression of renal disease in persons with diabetes and, agents that block the renin angiotensin system (RAS) should be the primary agents used to achieve blood pressure reduction. There is debate regarding which method of RAS blockade should be used as primary therapy in persons with diabetes. There are not significant differences between angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with regard to renal outcomes. Consideration of the enormously high rates of cardiovascular disease (CVD) in persons with diabetes and renal disease is the primary factor in choosing agents for blood pressure reduction. The ACE inhibitors and ARBs have been shown to reduce cardiovascular events in persons with diabetes and, there are recent comparable trials between the 2 classes. Some studies and meta-analyses show ACE inhibitors as being superior with regard to cardioprotection. In our nephrology clinic, we find that patients who presented on an ACE inhibitor had significantly lower CVD than those on ARBs (49.2% vs 70.1% prevalence of CVD, ACE inhibitor vs ARB respectively, P=.042). We conclude that ACE inhibitors should be strongly considered as the primary method of RAS inhibition in persons with diabetes.
</context>
</instance>
<instance id="15571918.xx.x">
<answer instance="15571918.xx.x" senseid="C0022709"/>
<context>
Zinc deficiency in patients with idiopathic taste impairment with regard to angiotensin converting enzyme activity. OBJECTIVE: The present study aimed at measuring the ratio of apo/holo activities of <head> ACE</head> ratio in the serum of patients with taste impairment to evaluate their status of zinc nutrition. METHODS: Nineteen patients complaining of taste impairment were divided into two groups: zinc-deficiency taste impairment (n=6) and idiopathic taste impairment (n=13) and compared to 30 volunteers. Zinc concentrations in the serum were measured by atomic absorption spectrometry (normal values: 64-111 microg/dl). Patients with zincemia values of <63 microg/dl with no history of other disorder or medication known to cause dysgeusia were diagnosed as zinc deficient, while those with the same condition and values >64 microg/dl were considered to belong to the idiopathic group. The activities of ACE in the serum were measured spectrophotometrically as the activity of the holo-ACE, and after addition of 80 microM of zinc to the serum in vitro, the increase of ACE activity over initial value in the serum was determined as that of the apo-ACE. Finally, the apo/holo-ACE activities ratio was used as an index of zinc nutritional status. RESULTS: The mean concentrations of zinc in the serum were 77.4+/-8.4 microg/dl in volunteers, 77.6+/-8.4 microg/dl in the idiopathic patients and significantly decreased at 55.7+/-5.8 microg/dl in zinc-deficiency patients. ACE activities in the serum were 14.7+/-7.6, 14.5+/-4.0 and 14.1+/-3.3 IU/l in volunteers, the idiopathic group and zinc-deficiency taste impairment group, respectively. The mean ACE ratios were 1.10+/-0.6% in volunteers and significantly increased at 9.8 +/- 4.0% in the idiopathic group and at 13.7+/-6.6% in zinc-deficiency taste impairment group. CONCLUSION: The results of the present study indicated that zinc deficiency is a predominant factor underlying hypogeusia even when zinc concentrations are within normal ranges in the serum and show that clinically, ACE ratio may be a more sensitive indicator of the zinc nutritional status than measuring zinc concentration in the serum.
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</instance>
<instance id="2986487.xx.x">
<answer instance="2986487.xx.x" senseid="C0022709"/>
<context>
Androgen dependence of testicular and epididymal angiotensin converting enzyme. Treatment with cadmium chloride (CdCl2) and cyproterone acetate (CA) depressed <head> ACE</head> activity significantly in testes and epididymal regions of the adult rats compared to the corresponding untreated controls. Exogenous testosterone to CA-treated rats significantly increased the enzyme activity both in the testes and epididymis, the effect in the latter being very significant comparable to CA-treated and untreated controls. Testosterone failed to induce ACE activity in the testes and caput epididymis of 30 day-old immature rats, but the enzyme activity was detected in corpus and cauda epididymis. Our findings indicate that ACE activity in the testicular complex is possibly linked with androgen and is concerned with spermatogenesis and sperm maturation.
</context>
</instance>
<instance id="17112788.xx.x">
<answer instance="17112788.xx.x" senseid="C0022709"/>
<context>
Synergistic actions of enalapril and tempol during chronic angiotensin II-induced hypertension. Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during <head> ACE</head> inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.
</context>
</instance>
<instance id="2424490.xx.x">
<answer instance="2424490.xx.x" senseid="C0022709"/>
<context>
Subretinal neovascularisation and snow banking in a case of sarcoidosis: case report. A 49-year-old Japanese man presented with chronic granulomatous uveitis in his left eye. Later he developed macular subretinal neovascularisation. The chest x-ray showed bilateral hilar lymphadenopathy. Bronchoscopy and gallium-67 scanning were positive, PPD skin test negative, and serum <head> ACE</head> levels increased. Ophthalmoscopy and fluorescein angiography of the left eye showed perivasculitis, retinochoroidal exudates, snow banking, and vitreous opacity. On these findings, the diagnosis of sarcoidosis was made. Treatment was based on topical corticosteroids, mydriatics, beta blockers, and oral carbonic anhydrase inhibitors. After 15 months the visual acuity decreased in the left eye, and a neovascular membrane was observed in the macula. Fluorescein angiography confirmed subretinal neovascularisation. Almost two years later the patient still has the neovascular membrane in his left eye.
</context>
</instance>
<instance id="1387799.xx.x">
<answer instance="1387799.xx.x" senseid="C0022709"/>
<context>
Attenuation of myocardial reperfusion injury by sulfhydryl-containing angiotensin converting enzyme inhibitors. Recent studies have suggested the beneficial effects of <head> ACE</head> inhibitors against myocardial ischemic-reperfusion injury. This study was designed to compare the cardioprotective effects of two sulfhydryl ACE inhibitors, captopril and zofenopril, with those of a nonsulfhydryl ACE inhibitor, fosinopril. The efficacy of these ACE inhibitors to scavenge oxygen radicals in vitro were also examined. Isolated rat hearts perfused by the Langendorff technique were preperfused in the presence or absence of ACE inhibitors (50 microns for 15 minutes, and the hearts were then subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Zofenopril and captopril, but not fosinopril, improved postischemic left ventricular functions and reduced myocardial cellular injury, as evidenced by improved recovery of the first derivative of left ventricular pressure development and reduced creatine kinase release compared with control (p less than .05). Coronary flow was significantly increased by captopril and zofenopril only. The same two drugs also inhibited the enhanced lipid peroxidation during reperfusion. Although significant differences were not noticed in the postischemic myocardial membrane phospholipid composition, captopril and zofenopril reduced nonesterified fatty acid contents, including palmitic, linoleic, oleic, and arachidonic acids. In vitro studies demonstrated that captopril and zofenopril were able to scavenge hydroxyl radicals. These results indicate that among three ACE inhibitors, two sulfhydryl-containing drugs, captopril and zofenopril, possess cardioprotective as well as free-radical scavenging abilities. Attenuation of phospholipid degradation and lipid peroxidation may be contributory to the protective effects observed in this study.
</context>
</instance>
<instance id="2170511.xx.x">
<answer instance="2170511.xx.x" senseid="C0022709"/>
<context>
An alternative strategy for the radioimmunoassay of angiotensin peptides using amino-terminal-directed antisera: measurement of eight angiotensin peptides in human plasma. We describe here a method of measuring angiotensin peptides and their carboxy-truncated metabolites in human plasma using N-terminal-directed antisera. Antisera raised against N-acetylated angiotensin (Ang) II and N-acetylated Ang III analogues were used to develop two radioimmunoassays. Extracted plasma samples were acetylated prior to separation of cross-reacting angiotensin peptides by high-performance liquid chromatography (HPLC). Fractions were assayed with both antisera to obtain measurements for eight angiotensin peptides. Angiotensin levels measured in normal males were (fmol/ml plasma, mean +/- s.e.m., n = 14): Ang-(1-7) 1.0 +/- 0.2, Ang II 13.9 +/- 2.0, Ang-(1-9) less than 0.4, Ang I 19.5 +/- 2.4, Ang-(2-7) less than 1.1, Ang III 2.9 +/- 1.0, Ang-(2-9) less than 2.1, Ang-(2-10) 2.4 +/- 0.8. Hypertensive patients receiving <head> ACE</head> inhibitor therapy (n = 8) had an increase in Ang I to 187.3 +/- 107.2 fmol/ml (P = 0.002), and a reduction in Ang II to 4.8 +/- 1.2 fmol/ml (P less than 0.001). Furthermore, these patients showed a ninefold increase in Ang-(1-7) to 9.7 +/- 4.3 fmol/ml (P less than 0.001), indicating a role for prolylendopeptidase in the metabolism of Ang I in vivo. These N-terminal assays have demonstrated that carboxy-truncated metabolites of Ang I and Ang II make little contribution to plasma angiotensin peptides, except during ACE inhibitor therapy. Furthermore, these antisera allow the measurement of Ang I and Ang II in the same radioimmunoassay of fractions from HPLC, providing a highly reliable estimate of the Ang II:Ang I ratio.
</context>
</instance>
<instance id="10168175.xx.x">
<answer instance="10168175.xx.x" senseid="C0022709"/>
<context>
Approach to the treatment of diabetic nephropathy. Renal failure is a common long-term complication of diabetes mellitus. Stages of diabetic nephropathy have been described that characterize its clinical course. Diabetic nephropathy develops secondary to long-standing hyperglycemia and hemodynamic changes that damage the glomerulus. Therapy that focuses on the control of glomerular pressures and systemic hypertension can slow the progression of proteinuria and deterioration of renal function. <head> ACE</head> inhibitors and calcium channel blockers have been demonstrated to be effective in the management of diabetic nephropathy. A systematic approach to the patient with diabetes with annual screening for proteinuria will help identify those individuals early in the course of disease when proper therapy may be most helpful.
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</instance>
<instance id="1650717.xx.x">
<answer instance="1650717.xx.x" senseid="C0022709"/>
<context>
Angiotensin converting enzyme: implications from molecular biology for its physiological functions. 1. The two isozymes of human <head> ACE</head> ; EC 3.4.15.1) have recently been cloned and sequenced. 2. The larger, endothelial isozyme has two highly similar internal domains each bearing a putative catalytic site. In contrast the smaller, testicular isozyme has a single catalytic site corresponding to the C-terminal domain of endothelial ACE and represents the ancestral, non-duplicated form of the gene. 3. Both isozymes are anchored in the plasma membrane by a single hydrophobic transmembrane polypeptide located near the C-terminus, and both are extensively N-glycosylated. 4. The testicular isozyme may also be O-glycosylated. 5. The soluble form of ACE in plasma, seminal fluid and other body fluids appears to be derived from the membrane-bound endothelial isozyme by a post-translational modification. 6. ACE has a complex substrate specificity with peptidyl tripeptidase or endopeptidase action on certain peptides, as well as the classical peptidyl dipeptidase activity. 7. Numerous potent inhibitors of the enzyme have been developed and used successfully in the treatment of hypertension, but some of the observed side effects may be due to inhibition of other zinc metalloenzymes. 8. Both endothelial and testicular ACE are highly conserved between species, indicative of the essential role(s) of the enzyme in blood pressure regulation and other physiological processes.
</context>
</instance>
<instance id="10391396.xx.x">
<answer instance="10391396.xx.x" senseid="C0022709"/>
<context>
Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a double-blind crossover study. AIMS: It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction. It has also been suggested that <head> ACE</head> inhibitors reduce insulin resistance and that, if used together with thiazide diuretics, the adverse effects of thiazides on insulin sensitivity may be eliminated. We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients. METHODS: Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomized, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendrofluazide (CB) (2.5 mg). RESULTS: Blood pressure was lower following CB compared to C (128/82 vs. 144/ 88 mmHg; P<0.005) and both were lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant increase in fasting plasma glucose compared to C (9.7+/-0.8 vs. 8.5+/-0.6 mmol/; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1) x min(-1); P < 0.05). Suppression of endogenous glucose production was reduced after CB compared to baseline (4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1) x min(-1); P< 0.05). CONCLUSIONS: Combination of bendrofluazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.
</context>
</instance>
<instance id="2829328.xx.x">
<answer instance="2829328.xx.x" senseid="C0022709"/>
<context>
The effect of streptozotocin-induced diabetes and insulin treatment on angiotensin converting enzyme activity. Diabetes mellitus is associated with an increased incidence of hypertension and renal failure. Alterations in the renin-angiotensin system may contribute to the development of cardiovascular disorders in diabetics. This study examined diabetic associated changes in <head> ACE</head> . ACE activity was measured in serum, lung and kidney tissue derived from normoglycemic or 3-48 day streptozotocin (STZ)-induced diabetic rats. Serum and tissue ACE activity were not altered 3 days post STZ treatment. Serum ACE activity significantly increased in the diabetic group relative to controls, beginning 12 days post STZ treatment. Insulin treatment for 10 days partially normalized serum ACE activity. Therefore, STZ-induced diabetes produced significant changes in ACE activity that are partially corrected by insulin treatment.
</context>
</instance>
<instance id="2846685.xx.x">
<answer instance="2846685.xx.x" senseid="C0022709"/>
<context>
Effects of the angiotensin converting enzyme inhibitor, lisinopril, on normal and diabetic rats. The comparative effects of lisinopril, a third generation <head> ACE</head> inhibitor, on components of the renin-angiotensin system were assessed in normal and in an animal model of diabetes-related hypertension, the streptozotocin-diabetic rat. Two weeks after injection of streptozotocin the mean systolic blood pressure of diabetic rats was elevated 11% above that of normal rats. This effect was prevented by daily injection of insulin. The mean serum ACE activity was elevated 71% above that of normal rats. Lisinopril reduced systolic blood pressure and inhibited serum ACE activity in both normal and diabetic rats in a dose-response fashion. In normal rats maximum inhibition of blood pressure occurred at a mean dose of 1.0 mg/kg and in the diabetic rat at a mean dose of 5.0 mg/kg. At a mean dose of 5 mg/kg, ACE was inhibited by 100 and 92% in normal and diabetic rats, respectively. Plasma renin activity (PRA) increased sharply in both groups of rats treated with the lower doses of lisinopril, only to decrease at the 5 mg/kg level. At 20 mg/kg, PRA continued to decline in normal animals, but not in diabetic rats. Formation of angiotensin II (Ang II) in both normal and diabetic rats was maximally inhibited at doses of 1.0 and 0.1 mg/kg of lisinopril, respectively without a significantly greater effect at the higher doses of the drug. In separate experiments the effects of chronic treatment with lisinopril at two dosage levels on various physiological parameters of streptozotocin-diabetic rats were compared with the effects of another hypotensive agent, hydralazine, an arteriolar vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)
</context>
</instance>
<instance id="12589410.xx.x">
<answer instance="12589410.xx.x" senseid="C0022709"/>
<context>
Roles of Galphaq/11 mediated- and platelet-derived growth factor mediated-signal transduction pathways in rat aorta restenosis. To observe the roles of Galphaq/11 mediated- and platelet-derived growth factor (PDGF) mediated-signal transduction pathways in proliferation and migration of vascular smooth muscle cells (VSMC) after arterial injury, a vascular cell proliferation model was established by balloon injury in rat aorta and the morphologic changes in injured vascular walls after the injury were studied. Activities of <head> ACE</head> and aorta phospholipase C (PLC) were tested, and levels of platelet-derived growth factor receptor-beta (PDGFR-beta) and Galphaq/11 protein were measured by Western blot analysis. At l day after operation, injured aortic segments showed denudation in endothelial cells. Medial VSMC proliferation and intimal hyperplasia were not observed. As compared with the sham group, ACE activities were increased by 382.7 percent; (P<0.0l), but the expression of PDGFR-beta and PLC activities did not show significant changes (P>0.05). In addition, the level of Galphaq/11 protein was decreased by 20.0 percent; (P<0. 05). At l4 days after operation, sections of injured aorta showed marked intimal thickening with large numbers of VMSCs proliferating throughout intima and media. In comparison with the sham group, ACE activity, PLC activity and the level of PDGFR-beta were increased by 420.2 percent; (P<0.01), 186.2 percent; (P<0.05) and 85.0 percent; (P<0.05), respectively. While the level of Galphaq/11 protein was decreased by 33.1 percent; (P<0.01). The above data suggest that the PDGF-mediated signal transduction pathway plays an important role in VSMC proliferation.
</context>
</instance>
<instance id="6289705.xx.x">
<answer instance="6289705.xx.x" senseid="C0022709"/>
<context>
Elevation of the bronchoalveolar concentration of angiotensin I converting enzyme in sarcoidosis. The concentration of <head> ACE</head> and that of albumin (AIb) were assayed in the serum (SACE, SAlb) and in bronchoalveolar lavage fluid (LACE, LAlb). Three groups of patients were studied: 14 healthy volunteers (Group I), 45 patients with active sarcoidosis (Group II), and 7 patients with sarcoidosis in remission (Group III). The SACE in Group II (4,466 +/- 2,202 U/100 ml, mean +/- SD) was higher (p less than 0.001) than in Group I (2,470 +/- 547 U/100 ml) or in Group III (2,640 +/- 610 U/100 ml); LACE was higher in Group II (65.2 +/- 48.4 U/100 ml, p less than 0.001) than in Group I (21.1 +/- 14.7 U/100 ml), or in Group III (25.7 +/- 14.6 U/100 ml). The SAlb was found to be, respectively, 3,908 +/- 385 mg/100 ml, 3,982 +/- 965 mg/100 ml, and 3.613 +/- 222 mg/100 ml in Groups I, II, and III. The LAlb in Group II (8.2 +/- 6.2 mg/100 ml) was higher (p less than 0.01) than in Group I (2.5 +/- 1.4 mg/100 ml) or in Group III )4.1 +/- 1.0 mg/100 ml). The LACE in Group II increased with the number of alveolar lymphocytes, in nonsmokers (4 = + 0.56, df = 34, p less than 0.001) and in smokers (4 = + 0.88, df = 7, p less than 0.01). In the smokers in this group, LACE was higher with respect to the number of lymphocytes than in the nonsmokers. We conclude from this study (1) that the permeability of the alveolocapillary membrane to albumin and to ACE is increased in active pulmonary sarcoidosis, (2) that LACE increases during sarcoidosis and returns to normal when the disease is cured, and (3) that the concentration of ACE in alveolar fluid increases with tobacco use.
</context>
</instance>
<instance id="8518539.xx.x">
<answer instance="8518539.xx.x" senseid="C0022709"/>
<context>
Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation. The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of <head> ACE</head> inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.
</context>
</instance>
<instance id="10227759.xx.x">
<answer instance="10227759.xx.x" senseid="C0022709"/>
<context>
Elevated bradykinin and decreased carboxypeptidase R as a cause of hypotension during tryptophan column immunoabsorption therapy. Tryptophan column immunoabsorption therapy is beneficial to the patient with a neuroimmunological disease, but some complications have been attributed to this treatment. There have been some instances of an abrupt shock state along with severe decreases in blood pressure. In regards to this shock state, it has been reported that plasma bradykinin levels increase during tryptophan column immunoabsorption therapy. In this study, we examined the correlation between plasma bradykinin levels and either blood pressure or the levels of its degrading enzymes, <head> ACE</head> and carboxypeptidase R (CPR) in 6 patients. Increased concentrations of bradykinin were present in the latter half of the therapeutic interval, and plasma bradykinin levels were found to be inversely correlated to CPR activity. The decreased CPR level could augment the activities of bradykinin. We speculate that bradykinin could be responsible for the hypotension occurring in patients during tryptophan column immunoabsorption therapy and that the metabolism of bradykinin could be caused by the decreased activity of CPR.
</context>
</instance>
<instance id="1334756.xx.x">
<answer instance="1334756.xx.x" senseid="C0022709"/>
<context>
Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one year study in rats. 1. <head> ACE</head> -inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.
</context>
</instance>
<instance id="10080484.xx.x">
<answer instance="10080484.xx.x" senseid="C0022709"/>
<context>
Abnormal flow-mediated epicardial vasomotion in human coronary arteries is improved by angiotensin-converting enzyme inhibition: a potential role of bradykinin. OBJECTIVES: This study was performed to determine whether <head> ACE</head> inhibition improves endothelium-dependent flow-mediated vasodilation in patients with atherosclerosis or its risk factors and whether this is mediated by enhanced bradykinin activity. BACKGROUND: Abnormal coronary vasomotion due to endothelial dysfunction contributes to myocardial ischemia in patients with atherosclerosis, and its reversal may have an antiischemic action. Previous studies have shown that ACE inhibition improves coronary endothelial responses to acetylcholine, but whether this is accompanied by improved responses to shear stress remains unknown. METHODS: In 19 patients with mild atherosclerosis, metabolic vasodilation was assessed during cardiac pacing. Pacing was repeated during separate intracoronary infusions of low-dose bradykinin (BK) and enalaprilat. Endothelium-dependent and -independent vasodilation was estimated with intracoronary BK and sodium nitroprusside respectively. RESULTS: Enalaprilat did not alter either resting coronary vascular tone or dilation with sodium nitroprusside, but potentiated BK-mediated dilation. Epicardial segments that constricted abnormally with pacing (-5+/-1%) dilated (3+/-2%) with pacing in the presence of enalaprilat (p = 0.002). Similarly, BK at a concentration (62.5 ng/min) that did not alter resting diameter in the constricting segments also improved the abnormal response to a 6+/-1% dilation (p < 0.001). Cardiac pacing-induced reduction in coronary vascular resistance of 27+/-4% (p < 0.001) remained unchanged after enalaprilat. CONCLUSIONS: Thus ACE inhibition: A) selectively improved endothelium-dependent but not-independent dilation, and B) abolished abnormal flow-mediated epicardial vasomotion in patients with endothelial dysfunction, in part, by increasing endogenous BK activity.
</context>
</instance>
<instance id="12598508.xx.x">
<answer instance="12598508.xx.x" senseid="C0022709"/>
<context>
Early dialysis in a neonate with intrauterine lisinopril exposure. In general, <head> ACE</head> inhibitors should be discontinued in pregnancy, as they can induce an ACE fetopathy. For the treatment of the latter, early peritoneal dialysis is recommended for in utero exposure to captopril and enalapril, although the outcome is poor. Early peritoneal dialysis has not previously been reported for lisinopril induced multiorgan failure. A case is reported in which treatment was given on postnatal day 3. The patient recovered from oligoanuria to almost normal renal function, and heart, brain, and musculoskeletal injury was reversible. This is despite relatively poor clearance of the drug through peritoneal dialysis. Analysis of the pharmacokinetic data suggests that haemodialysis or haemofiltration would be more efficacious for removal of the drug, and these treatments should be performed if available.
</context>
</instance>
<instance id="6327968.xx.x">
<answer instance="6327968.xx.x" senseid="C0022709"/>
<context>
Correlation between lung and plasma angiotensin converting enzyme and the hypotensive effect of captopril in conscious rabbits. We measured both pulmonary and plasma <head> ACE</head> activity in conscious rabbits before and for 6 days after administration of captopril (2 mg/kg i.v.). Pulmonary ACE activity was measured by means of modified indicator-dilution techniques after bolus injection of [3H]benzoyl-phenyl-alanyl-alanyl-proline ( BPAP , synthetic substrate for ACE). Plasma ACE activity was also determined radiometrically with [3H] BPAP as substrate. In addition, we measured the systemic pressor response to i.v. bolus dose of angiotensin I both before and after captopril. Twenty-four hours after captopril, pulmonary metabolism of BPAP had decreased from control of 73 +/- 5 to 8 +/- 2%; even 6 days after drug treatment there was still evidence of inhibition. In contrast, plasma ACE activity was significantly (P less than .05) reduced within 15 min of treatment (to 20% of control levels) but recovered within 24 hr. The time course of changes in the pressor response to angiotensin I, after captopril, resembled that of plasma ACE activity. Mean systemic arterial blood pressure was 81 +/- 4 torr at control and reached its nadir at 24 hr (64 +/- 2 torr; P less than .05); thereafter a gradual recovery ensued, similar in time course to that of pulmonary ACE. These data suggest that inhibition of plasma ACE and also the pressor response to angiotensin I are unrelated temporally to the hypotensive effects of captopril.
</context>
</instance>
<instance id="11843951.xx.x">
<answer instance="11843951.xx.x" senseid="C0022709"/>
<context>
What should the role of <head> ACE</head> inhibitors be in the treatment of diabetes? Lessons from HOPE and MICRO-HOPE. Experimental and clinical evidence suggest that ACE inhibition may reduce cardiovascular (CV) risk by directly affecting endothelial dysfunction, atherosclerosis and thrombus formation. These direct effects are in addition to effects on vascular tone or pressure. The Health Outcomes and Prevention Evaluation (HOPE) study assessed the role of an ACE inhibitor ramipril in reducing CV events in 9297 patients > or = 55 years who were at high risk of CV events but did not have left ventricular dysfunction, heart failure, or high blood pressure at the time of study entry. In the overall HOPE population, the risk of the primary composite outcome (cardiovascular death, myocardial infarction, or stroke) was reduced by 22% (p < 0.001), and in patients with diabetes plus one other CV risk, it was reduced by 25% (p = 0.0004). Ramipril treatment achieved risk reduction in patients with mild renal insufficiency (serum creatinine > or = 1.4 mg/dl). Ramipril treatment did not increase adverse events in patients with renal insufficiency. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E (SECURE) demonstrated that ramipril 10 mg significantly reduced the rate of carotid intimal medial thickening, suggesting a direct effect on atherosclerotic progression.
</context>
</instance>
<instance id="6095894.xx.x">
<answer instance="6095894.xx.x" senseid="C0022709"/>
<context>
Inhibition of angiotensin converting enzyme: dependence on chloride. In a previous report [Shapiro, R., Holmquist, B., & Riordan, J. F. (1983) Biochemistry 22, 3850], it was demonstrated that activation of angi <head> ACE</head> chloride is strongly dependent on substrate structure, and three substrate classes were identified on the basis of activation behavior. The present study examines the chloride dependence of the inhibition of ACE by nine inhibitors [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), L-Ala-L-Pro, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-L-Trp, N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, L-Phe-L-Arg, N alpha-(3-mercaptopropanoyl)-L-Arg, and N alpha-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Lys] containing structural features characteristic of the three classes of substrates. Apparent Ki values for all inhibitors are markedly (70-250-fold) decreased by 300 mM chloride. However, the enhancement of inhibition is achieved at significantly lower chloride concentrations with those inhibitors having an ultimate arginine or lysine than with the remainder. This variability parallels that previously found for activation of substrate hydrolysis. The effect of chloride on the individual steps in the formation and dissociation of the steady-state enzyme-inhibitor complexes was determined with the slow-binding inhibitor MK-422. Pre-steady-state analysis indicates that binding of both MK-422 and captopril follows a (minimally) two-step mechanism: (formula; see text) in which rapid formation of an enzyme-inhibitor complex is followed by a slow isomerization.(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="2346534.xx.x">
<answer instance="2346534.xx.x" senseid="C0022709"/>
<context>
Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with an omega-aminoalkyl group. A series of novel L-alanyl- and L-lysyl-L-proline derivatives having an omega-amino-1-carboxyalkyl group was prepared, and assayed for their inhibitory activity against <head> ACE</head> . The dicarboxylic acids possesing S,S,S configuration showed potent in vitro ACE inhibitory activity with IC50 values of 0.68-1.4 nmol/l. The length of the carbon chain in the omega-aminoalkyl moiety was varied from 6 to 9 to investigate the optimal structure for long-acting ACE inhibitors. The most prolonged activity in vivo was observed with N-[8-amino-1(s)-carboxyoctyl]-L-alanyl-L-proline upon i.v. and p.o.
</context>
</instance>
<instance id="1812274.xx.x">
<answer instance="1812274.xx.x" senseid="C0022709"/>
<context>
Pharmacology of a phosphorus-containing novel angiotensin converting enzyme inhibitor, SQ 29 852 in anesthetized dogs. The effects of (S)-1[6-amino-2[[hydrozy(4- phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29 852), a phosphorus-containing novel angiotensin converting enzyme inhibitor ( <head> ACE</head> I), which is synthesized aiming an ACEI with long-lasting activity and with few side effects, were studied using anesthetized dogs. SQ 29 852 was equipotent with captopril to modify blood pressure response of the animals to angiotensin I (Ang I) and bradykinin (Bdk). An intravenous infusion of SQ 29 852 at 0.1 mg/kg/min for 30 min caused a remarkable hypotension without reflex tachycardia in open-chest dogs. In these animals cardiac contractility (dP/dtmax of left ventricular pressure) appeared to be reduced by SQ 29 852 without any changes in right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP) and aortic blood flow (AoF, cardiac output). In sodium-restricted dogs, the hypotension and renal vasodilation by SQ 29 852 (at 0.01, 0.1, and 1 mg/kg, i.v.) were slightly pronounced compared with animals fed with normal diet. It is demonstrated from these results that SQ 29 852 has comparable potency with captopril to inhibit ACE activity and as common a pharmacological profile as ACEI. SQ 29 852 may be a favorable antihypertensive agent, if its long-lasting activity and few side effects are confirmed.
</context>
</instance>
<instance id="7594429.xx.x">
<answer instance="7594429.xx.x" senseid="C0022709"/>
<context>
Alpha-blockade and calcium antagonism: an effective and well-tolerated combination for the treatment of resistant hypertension. OBJECTIVE: To test whether the combination of calcium antagonism is additive with the other newer antihypertensives, namely alpha-blockers and <head> ACE</head> inhibitors. DESIGN: Three-way double-blind, Latin-square crossover studies in two groups of 12 patients with essential hypertension. The three treatment periods were amlodipine, doxazosin (study A) or enalapril (study B), and the combination of amlodipine with the second drug. METHODS: Each treatment was taken for 1 month, preceded by a 2-week single-blind run-in period, in which the patients received a low dose of doxazosin (study A) or enalapril (study B) to enable recruitment of patients with moderate or severe hypertension. Blood pressure, foot volume and plasma noradrenaline concentration were measured at the end of each run-in and treatment period. RESULTS: The combination of alpha-blockade and calcium antagonism caused a fall in supine and erect blood pressures. These falls were significantly greater than on either drug alone, and greater than the sum of the falls when taking the individual drugs. The combination of amlodipine and the ACE inhibitor was also additive. Both combinations with amlodipine were tolerated well by all patients. CONCLUSIONS: The combination of alpha-blockade and calcium antagonism has not previously been studied and should be useful for resistant hypertensives who have not tolerated beta-blockade or ACE inhibitors. The combination of ACE inhibition and calcium antagonism has previously been shown to be additive; its use as a positive control in the present studies suggests that the use of an active drug for a run-in period may be a useful design for permitting the study of patients from whom all treatment cannot safely be withdrawn.
</context>
</instance>
<instance id="2527535.xx.x">
<answer instance="2527535.xx.x" senseid="C0022709"/>
<context>
A pharmacokinetic study of cilazapril in elderly and young volunteers. 1. Cilazaprilat is an inhibitor of <head> ACE</head> and is the active metabolite of cilazapril. The pharmacokinetics of cilazaprilat, and the inhibition of plasma ACE were investigated in 12 elderly and 12 young healthy volunteers. 2. Single oral 1 mg doses of cilazapril were given to the elderly (age range 65-83 years) and the young (age range 18-31 years) in an open study. Plasma and urinary cilazaprilat concentrations, and plasma ACE activities were measured up to 72 h after dosing by radioenzymatic methods. 3. Cilazapril was well tolerated in both young and elderly subjects. Small falls in blood pressure were observed up to 8-24 h after dosing. 4. The mean peak plasma cilazaprilat concentration in the elderly (11.5 ng ml-1) was significantly greater (P less than 0.02) than the corresponding value in the young (8.3 ng ml-1). Total and renal clearances were significantly lower (both P less than 0.05) in the elderly (12.8 and 5.11 h-1) than in the young (16.0 and 7.21 h-1). Total urinary recovery of cilazaprilat was similar for the two groups at about 43% of dose. 5. Plasma ACE inhibition was slightly greater in the elderly but the mean inhibition in the two groups did not differ by more than 10% at any time-point from 1-72 h. 6. The plasma concentrations of cilazaprilat required for 90% ACE inhibition were similar at 4.7 and 4.8 ng ml-1 in the elderly and young respectively. 7. It is concluded that the age-related changes in cilazaprilat kinetics and in the degree of ACE inhibition are small.(ABSTRACT TRUNCATED AT 250 WORDS)
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</instance>
<instance id="10342782.xx.x">
<answer instance="10342782.xx.x" senseid="C0022709"/>
<context>
Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during <head> ACE</head> inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.
</context>
</instance>
<instance id="1662942.xx.x">
<answer instance="1662942.xx.x" senseid="C0022709"/>
<context>
Mediastino-pulmonary sarcoidosis in children. Clinical study, analysis of data of bronchoalveolar fluid lavage and respiratory function tests, therapeutic trends. A series of 27 children (mean age: 12 yrs, 5 mos.) presenting with thoracic sarcoidosis is reported. This series, collected from 1961 to 1988 shows the rarity of the disease at that age. However the low rate of asymptomatic forms (22%) suggests that the frequency of the disease is underestimated, as it is not diagnosed. The histological proof is necessary for the diagnosis. When peripheral lesions available for biopsy are lacking, a liver needle biopsy is helpful (93% of positivity). This study shows the frequency of multivisceral types, the intensity of the macrophagic and lymphocytic alveolitis. The therapeutic indications depend on the comparison of the radiological stage, the results of pulmonary function tests (PFT), those of the bronchoalveolar lavages (BAL) and of the serum granulomatous activity markers, especially concerning <head> ACE</head> . When present at the beginning of evolution, several risk factors lead to use a corticosteroid treatment: age of onset before 4 years, multivisceral involvement, presence of functional pulmonary signs, delayed diagnosis and onset of treatment, impaired respiratory function (especially concerning the alveolo-capillary diffusion), PMN cells greater than or equal to 2% in the initial BAL, and IgG proteins greater than 4 SD. Thus sarcoidosis in children differs from that seen in adults as it has a more marked evolutive tendency and leaves severe sequelae in one third of patients.
</context>
</instance>
<instance id="9784306.xx.x">
<answer instance="9784306.xx.x" senseid="C0022709"/>
<context>
Angiotensin II and angiotensin-converting enzyme as candidate compounds modulating the effects of testis ecdysiotropin in testes of the gypsy moth, Lymantria dispar1. Lymantria dispar testes synthesize immunodetectable ecdysteroid in vitro in response to the brain peptide, testis ecdysiotropin (TE), acting primarily via a cascade involving Gi protein, diacyl glycerol, and phosphokinase C. However, a component of TE activation also involves the opposite cascade, Gs protein, cAMP, and phosphokinase A. Excess cAMP inhibits the action of TE, acting as a feedback modulator. Here, we show that bovine angiotensin II (AII) and bovine <head> ACE</head> act like cAMP, inducing synthesis of immunodetectable ecdysteroid by pupal testes in vitro, but are antagonistic to coincubated TE. In addition, an insect ACE antibody clearly stains the spermatogenic cells through all stages of development, as well as testis sheath tissue where ecdysteroid is synthesized. AII induces synthesis of cAMP by pupal testes in vitro. Therefore, insect homologs of mammalian AII and ACE are good candidates for the peptides responsible for the cAMP cascade and as modulators of TE action in lepidopteran testes. Saralasin, an analog of AII that blocks angiotensin receptors in mammals, behaved like AII in inducing ecdysteroid secretion with ecdysteroidogenic effects additive to either angiotensin or ACE. Therefore, the receptors for the insect form of angiotensin on lepidopteran testis cells are probably different from those in mammals. Saralasin also inhibited ecdysteroid synthesis when combined with TE, as did AII.
</context>
</instance>
<instance id="18209432.xx.x">
<answer instance="18209432.xx.x" senseid="C0022709"/>
<context>
Single Center Experience with Pre-dialysis Patients. The objective of this study was to evaluate the effect of the management of factors accelerating renal injury such as hypertension and diabetes on progression of chronic renal failure (CRF). For this end, the records of 112 CRF patients with serum creatinine (SCr) level of 150- 850 micromol/L were retrospectively studied at King Khaled University Hospital in Riyadh, Saudi Arabia. The leading causes of CRF in the study patients were diabetes in 52 (46.4%) patients, glomerulonephritis in 25 (22.4%) and hypertension in 17 (15.2%). Progressive elevation of SCr level was recorded at 92 micromol/L/year in 62 (55.4%) patients with initial SCr level of 150-300 micromol/L; they progressed to end stage renal disease (ESRD) in a mean duration of 4 (1/2) years. Forty-three (38.4%) patients with SCr level of 300-450 micromol/L had an increase of SCr at 136 micromol/L/year and progressed to ESRD in a mean period of four years. Seven (6.2%) patients who had initial SCr level of > 450 micromol/L had an increase of 136 micromol/L/year and progressed to ESRD in a mean duration of 2 (1/2) years. Sixty-two (55.4%) patients had initial blood pressure (BP) readings above the recommended level of 130/80 mm Hg. Antihypertensive management stabilized 47 (75.8%) of these patients using multiple drug regimens such as an ang <head> ACE</head> hibitor and diuretics (20.5%). Though this center did not use erythropoietin (EPO) in these patients, the control of the levels of hemoglobin and hematocrit was obtained by aggressive iron supplementation including intravenous administration. In conclusion, the present management of CRF patients, which attempts to comply with the international standards, still needs refining in order to reach better outcome.
</context>
</instance>
<instance id="7620234.xx.x">
<answer instance="7620234.xx.x" senseid="C0022709"/>
<context>
Drug-induced orthostatic hypotension in older patients. Orthostatic hypotension occurs in 10 to 30% of the elderly. In several studies it has been linked to recurrent falls and syncope. Generally, it has multiple causes, of which autonomic dysfunction plays an important role in elderly people. Very often orthostatic hypotension is induced by the use of drugs. In other cases, it is already present subclinically, and is worsened by the use of drugs to become symptomatic. For most drugs, changing pharmacokinetics result in a delayed elimination and/or in a greater bioavailability in the elderly. This results in a more pronounced effect for drugs with a desired hypotensive action [e.g. diuretics, calcium channel blockers, beta-blockers, <head> ACE</head> inhibitors]. For those drugs in which hypotension is a known but unwanted adverse effect (e.g. nitrates, anti-Parkinsonian drugs, antidepressants, antipsychotics), responses will be greater in the elderly and orthostatic hypotension will occur more frequently. For elderly people, doses have to be reduced and/or the dose intervals prolonged in order to avoid such adverse reactions.
</context>
</instance>
<instance id="15066307.xx.x">
<answer instance="15066307.xx.x" senseid="C0022709"/>
<context>
Clinical perspectives of anti-inflammatory therapy in the elderly: the lipoxigenase (LOX)/cycloxigenase (COX) inhibition concept. Non steroidal anti-inflammatory drugs (NSAIDs) are one of the categories of drugs most frequently used by elderly people, and maybe the most self-prescribed drugs. Both coronary events, and stroke, can be prevented by daily aspirin assumption. Other NSAIDs, except selective COX-2 inhibitors (coxibs), seem to reduce the incidence of cardiovascular events, but a definitive judgement is yet impossible. Moreover, these drugs cause more than 100,000 serious gastric adverse events each year in the US, and the risk increases exponentially in the elderly. Coxibs cause less gastric damage, but their cost is very high. Moreover, NSAIDs inhibit renal function and reduce the efficacy of diuretics and <head> ACE</head> inhibitors, often used by elderly patients. Recent studies show that even COX-2 is important in the renal physiology, so that even coxibs appear not to be avoided of renal toxicity. Both gastric and renal toxicity induced by traditional NSAIDs and coxibs seem to be related to the fact that these drugs inhibit the synthesis of prostaglandins (PGs), but not those of leukotrienes (LTs), important mediators of inflammation and of many other physiopatological events. Newly developed anti-inflammatory drugs block both COX and the 5-LOX metabolic pathways, inhibiting the formation of PGs, thromboxanes (TXs) and LTs. The inhibition of the LT synthesis increases the anti-inflammatory efficacy (especially in pneumological and rheumatological diseases), reducing the risk of gastric damage. Even if preliminary data seem to be very interesting, further clinical safety data on these drugs obtained from elderly oriented trials need to be available before to give a final evaluation.
</context>
</instance>
<instance id="7533695.xx.x">
<answer instance="7533695.xx.x" senseid="C0022709"/>
<context>
Pharmacological management of hypertension in paediatric patients. A comprehensive review of the efficacy, safety and dosage guidelines of the available agents. The prevalence of hypertension in children, although lower than in adults, is still significant. An underlying cause is often identified in the younger patient, with essential hypertension accounting for the majority of cases in adolescents. The natural history of hypertension in childhood is still not well delineated. Previous Task Force recommendations are addressed to reflect current experience with the newer classes of agents, namely the <head> ACE</head> inhibitors and the calcium channel blockers (CCBs) where either limited or no experience was previously available. In addition, the current treatment recommendations of Joint National Committee V (JNCV) are reflected in our discussion. The current drug classes are reviewed with respect to dosage guidelines, adverse effects and potential drug-drug interactions. The advantages and disadvantages of a tailored or individualised therapeutic approach as opposed to rigid stepped care therapy will be presented. Clearly, more long term data need to be obtained with respect to the safety and efficacy of the newer classes of drugs.
</context>
</instance>
<instance id="1813122.xx.x">
<answer instance="1813122.xx.x" senseid="C0022709"/>
<context>
Converting enzyme inhibition after experimental myocardial infarction in rats: comparative study between spirapril and zofenopril. STUDY OBJECTIVE: The aim was to compare the effects of two novel <head> ACE</head> inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor. DESIGN: Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined. SUBJECTS: Normotensive male Wistar rats (220-240 g) were used. MEASUREMENTS AND MAIN RESULTS: Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals. CONCLUSIONS: Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.
</context>
</instance>
<instance id="2362274.xx.x">
<answer instance="2362274.xx.x" senseid="C0022709"/>
<context>
Crystallographic studies of angiotensin converting enzyme inhibitors and analysis of preferred zinc coordination geometry. The molecular structures of two potent inhibitors of <head> ACE</head> , EC 3.4.15.1, dipeptidyl carboxypeptidase), ketoace, (5S)-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline, and (1S,2R)-1-[[2-(benzoylthio)-cyclopentyl]carbonyl]-L-proline were determined by X-ray diffraction methods. The distances between the binding functions in both crystal structures are in agreement with the experimental results for the hypertension drug captopril and the enzyme substrate hippuryl-L-histidyl-L-leucine. The modified peptide skeletons of both inhibitors adopt extended conformations with the proline amide bond trans. Crystallographic data have been used to determine the coordination geometry for zinc-sulfhydryl and zinc-carbonyl interactions. Coordination distances and bond angles are found to be different from values assumed in models of the angiotensin converting enzyme active site. No preferred torsion angles for a zinc-sulfhydryl inhibitor interaction can be identified. Superposition of the crystallographic structures of four ACE ligands shows that the observed extended conformations place the pharmacophores, zinc atom ligand, carbonyl oxygen atom, and carboxyl group, in juxtaposition and provide an alternative model for the interaction of ligands with the ACE active site.
</context>
</instance>
<instance id="7868871.xx.x">
<answer instance="7868871.xx.x" senseid="C0022709"/>
<context>
Does lipophilicity of angiotensin converting enzyme inhibitors selectively influence autonomic neural function in human hypertension? INTRODUCTION: Angiotensin II has both central nervous system and peripheral effects on autonomic function. Ramipril is among the more lipophilic <head> ACE</head> inhibitors, and hence can penetrate the central nervous system readily. METHODS: We investigated whether rampiril has selective effects on autonomic control of the circulation in human hypertension, compared with the more hydrophilic ACE inhibitor enalapril. Blood pressure, hemodynamics and measurements of autonomic function were obtained in 13 essential hypertensive subjects after 10 days on placebo, and after crossover monotherapy with 10 days on enalapril versus 10 days on ramipril. RESULTS: Both enalapril and ramipril lowered systolic, diastolic and mean arterial blood pressures significantly, with no reflex increase in heart rate. Plasma renin activity increased substantially on each of the ACE inhibitors. There were no significant effects of either agent on plasma catecholamines (norepinephrine or epinephrine) or chromogranin A, biochemical indices of efferent sympatho-adrenal outflow. There were also no significant changes after either agent in baroreflex sensitivity (to high- and low-pressure stimuli), the response to cold stress or sympathetic (alpha-adrenergic) participation in blood pressure maintenance. There was a marginal effect of ACE inhibition on alpha 1-adrenergic pressor sensitivity, but the two compounds did not differ significantly in this respect. CONCLUSION: Autonomic control of circulatory function was maintained well after either lipophilic (ramipril) or hydrophilic (enalapril) ACE inhibitors, and the lipophilic compound ramipril had no additional effects on autonomic function beyond those shown by the hydrophilic agent enalapril.
</context>
</instance>
<instance id="3063784.xx.x">
<answer instance="3063784.xx.x" senseid="C0022709"/>
<context>
Hypertension in the elderly diabetic: therapeutic aspects. Elderly diabetic patients with hypertension present a difficult medical management problem. The guidelines published by the 1987 Working Group on Hypertension in Diabetes in the United States suggest a stepped care approach to drug therapy in these patients. The stepped care strategy is to add a series of antihypertensive medications sequentially until the blood pressure is controlled. The first step includes one of the following: thiazide diuretics, beta-blockers, alpha-adrenergic inhibitors, <head> ACE</head> inhibitors or calcium channel blockers. The second step adds a second agent from the same group, while the third step adds a vasodilator and step four adds a drug like guanethidine if the combination of other drugs fails. This approach presents many perils in the aged patient with diabetes. In these patients the physician should: (1) limit the use of diuretics and beta-blockers; (2) favour the use of calcium channel blockers and ACE inhibitors; (3) use a substitution approach rather than a stepped care approach; and (4) use monotherapy if possible.
</context>
</instance>
<instance id="1645981.xx.x">
<answer instance="1645981.xx.x" senseid="C0022709"/>
<context>
Acute and chronic effects of perindopril on tissue angiotensin converting enzyme activity. The pattern of inhibition of tissue <head> ACE</head> was studied in rats after acute and chronic (14 days) oral administration of perindopril. Free and total tissue ACE were measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and pressor responses to angiotensin I. Following oral perindopril, plasma perindoprilic acid and the pattern of inhibition of plasma ACE activity were maximal at 1 to 2 h, but recovered over 24 h. However, inhibition of the pressor response to angiotensin I was more prolonged, being 95% at 4 h, but had not fully recovered by 24 h. Acutely, ACE was markedly inhibited in renal proximal tubules, lung parenchyma, and aortic wall. At 24 h, ACE in these tissues had only partially recovered. Angiotensin converting enzyme in vascular endothelium of other organs showed a similar pattern of inhibition. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. After chronic (14 days) administration of perindopril, total plasma ACE increased 3-fold, of which 49% was occupied by the inhibitor. Total tissue ACE in kidney and aorta did not change, and the pattern of inhibition observed acutely was maintained during chronic treatment. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drugs.
</context>
</instance>
<instance id="11933555.xx.x">
<answer instance="11933555.xx.x" senseid="C0022709"/>
<context>
Role of angiotensin-converting enzyme inhibitors in the treatment of heart failure in the 21st century. The <head> ACE</head> inhibitors have progressively stood out in a large population of heart failure patients as a gold-standard treatment, in relation with their beneficial effects on mortality and morbidity. In a recent meta-analysis published in the Lancet collecting 12,763 patients, Flather demonstrates global mortality decrease of 25% compared to placebo. This risk reduction not only concerns the mortality due to heart failure but also that due to myocardial infarction. The same goes for the morbidity. Thus, in international as well as European recommendations, ACE-inhibitors are indicated as a first lane treatment in heart failure due to systolic LV dysfunction. Nonetheless several questions remain unanswered. The ACE-inhibitors are under-utilised, not only they are under-prescribed (only 60% of heart failure patients benefit from them) but also when prescribed, the dosage (comparing to those used in clinical trials) is generally as low as the half expected. This under-utilisation seems to be related to the side effects as renal failure, hypotension or more often due to the concern of their occurrence especially in the elderly and in those with other concomitant morbidities. They are actually related in part to an under-estimation of the benefit/risk ratio. The ATLAS study suggests that high doses of ACE-inhibitors are associated with a deeper reduction of morbidity without significant differences compared to low doses concerning global mortality or side effects. However this study compared very high (extreme) doses to low ones and comparison between heavy- and mid-doses remains to be performed. After the HOPE study, new indications appear promising: heart failure with preserved systolic function; patients with risk factors without heart failure: risk reduction of subsequent heart failure and reduction of mortality. Tolerance of their association with beta-blocking agents. In conclusion, the optimisation of the ACE-inhibitors treatment goes through a wider prescription with higher doses, probably extended to new indications.
</context>
</instance>
<instance id="15931314.xx.x">
<answer instance="15931314.xx.x" senseid="C0022709"/>
<context>
Tracheopathia osteochondroplastica. The case of a male, 61 years of age, presenting with occasional hemoptysis and shortness of breath (duration of 1 year) is reported. Congestive heart failure was presumed and supported by chest x-ray and echocardiography. The patient improved with diuretic and <head> ACE</head> inhibitor therapy, but continued to experience cough and occasional hemoptysis. Bronchoscopy revealed numerous firm nodular projections within the trachea with distribution along the cartilaginous rings. Tracheopathia osteochondroplastica (TPO) was diagnosed. TPO is an uncommon, benign, but slowly progressive disease of unknown etiology. It is characterized by endoluminal projection of cartilaginous and bony nodules arising in the submucosa of the trachea. Involvement may extend to lobar or segmental bronchi. TPO should be considered in cases where cough, dyspnea, persistent pulmonary infection, hoarseness, or recurrent hemoptysis remain after appropriate treatment of other presumptive underlying causes.
</context>
</instance>
<instance id="10968199.xx.x">
<answer instance="10968199.xx.x" senseid="C0022709"/>
<context>
Comparison of the antihypertensive effects of the new angiotensin II (AT1) receptor antagonist candesartan cilexetil (TCV-116) and the angiotensin converting enzyme inhibitor enalapril in rats. Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an <head> ACE</head> inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.
</context>
</instance>
<instance id="9218183.xx.x">
<answer instance="9218183.xx.x" senseid="C0022709"/>
<context>
Role of kinins and angiotensin II in the vasodilating action of angiotensin converting enzyme inhibition in rat renal vessels. OBJECTIVE: To assess directly the vasodilating effects of <head> ACE</head> inhibition in different renal vessels and to determine the role of kinins and angiotensin II (ANGII) therein. METHODS: Lumen diameters of different vessels and glomerular blood flows were measured in cortical and juxtamedullary glomeruli by in-vivo microscopy in the split hydronephrotic kidney of anesthetized female Wistar rats. RESULTS: Injection of the ACE inhibitor quinapril at a dose of 0.9 mg/kg intravenously, which blocks conversion of locally applied angiotensin I (1 mumol/l), increased glomerular blood flows by 39 +/- 6 and 18 +/- 4% in cortical and juxtamedullary glomeruli, respectively, due to vasodilatation in all renal vessels. The most pronounced vasodilatation was observed in interlobular arteries (19 +/- 2%) and in cortical afferent arterioles (16 +/- 3%). Pretreatment of the hydronephrotic kidney by local application of 40 nmol/l Hoe140, a bradykinin B2 receptor antagonist, or 3 mumol/l valsartan, an ANGII type 1 receptor antagonist, attenuated the vasodilatation in response to quinapril. ANGII receptor blockade affected only weakly, whereas bradykinin receptor blockade blunted markedly, the quinapril-induced vasodilatation, suggesting that kinins play an important role in our experimental model. Administration of valsartan, which abrogated the renal vasoconstriction induced by 10 nmol/l ANGII completely, caused vasodilation of magnitude similar to that caused by administration of quinapril. Yet, the vasodilatation induced by the combination of valsartan and quinapril was significantly larger than that induced by administration of quinapril alone in interlobular arteries, afferent arterioles, and cortical efferent arterioles. CONCLUSIONS: Our results indicate that kinins and ANGII can contribute to the renal vasodilatation in response to ACE inhibitors, but ACE inhibitors appear to have only minor effects on ANGII levels in those renal vessels, which are the well-known sites of renin expression.
</context>
</instance>
<instance id="227219.xx.x">
<answer instance="227219.xx.x" senseid="C0022709"/>
<context>
Angiotensin converting enzyem ( <head> ACE</head> ) - a blood chemistry parameter in the diagnosis of sarcoidosis. Serum ACE activity was studied in 50 patients with sarcoidosis (39 active, 11 inactive sarcoidosis), as well as in 50 control patients (34 chronic lung diseases, 9 Hodgkin-disease, 7 rheumatoid arthritis). There is a significant difference (p less than 0.001) of ACE-activity between sarcoidosis patients and controls, and between active (without steroid treatment) and inactive sarcoidosis. Steroid treatment apparently lowers ACE-activity in sarcoidosis, however, without evidence for clinical improvement. Increased ACE-activity was also found in a patient with primary biliary cirrhosis.
</context>
</instance>
<instance id="8937465.xx.x">
<answer instance="8937465.xx.x" senseid="C0022709"/>
<context>
Alleviation of paraquat-induced lung injury by pretreatment with bifunctional liposomes containing alpha-tocopherol and glutathione. Reactive oxygen species are known to play a key role in the development of acute lung injury, and such injury can be alleviated by pretreating the lung with a suitable antioxidant preparation. In this study, we evaluated and compared the antioxidant efficacy of two liposomal preparations: liposomes containing only alpha-tocopherol versus bifunctional liposomes containing both alpha-tocopherol and glutathione (GSH). alpha-Tocopherol liposomes (2 mg alpha-tocopherol/animal) or liposomes containing both alpha-tocopherol and GSH (2 mg alpha-tocopherol and 10 mumol GSH/animal) were intratracheally instilled into the lungs of rats 30 min prior to a challenge with paraquat dichloride (30 mg/kg, i.p.); animals were killed 24 hr post-paraquat challenge. Lungs of paraquat-challenged animals were damaged extensively as evidenced by increases in lung weight, indicative of edema, and decreases in lung activities of <head> ACE</head> and alkaline phosphatase (AKP), indicative of endothelial and alveolar type II epithelial cell injuries, respectively. While the pretreatment of rats with alpha-tocopherol liposomes or liposomes containing both alpha-tocopherol and GSH significantly attenuated paraquat-induced changes in lung ACE activity to more or less the same extent, the bifunctional liposomal preparation conferred additional protection to alveolar type II epithelial cells, as evidenced by a significantly higher pulmonary AKP activity. Our results also showed that both liposomal preparations failed to ameliorate paraquat-induced lung edema despite a significant protection of pulmonary endothelial cells, suggesting that paraquat-induced edema formation may be independent of endothelial cell damage. In conclusion, liposome-associated antioxidants can protect the lung against an oxidant challenge, and the extent of protection appears to be related to the characteristics of each antioxidant formulation.
</context>
</instance>
<instance id="8592247.xx.x">
<answer instance="8592247.xx.x" senseid="C0022709"/>
<context>
Putative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors. BACKGROUND: A dry cough is the most common adverse effect of <head> ACE</head> inhibitors, even if it is not particularly serious. Controlled studies have suggested that the incidence may eventually be as high as 20% and the problem seems to occur much more often in women. MECHANISM OF ACE INHIBITOR COUGH: The mechanism of the cough associated with ACE inhibitor treatment is unrelated to inhibition of the renin-angiotensin system because treatment with angiotensin receptor blockers and renin inhibitors has not caused similar problems. Other substrates of ACE have been implicated, and the side effect has been linked in particular to an accumulation of bradykinin or tachykinins in the airways with consequent stimulation of vagal afferents that subserve the cough reflex, particularly the non-myelinated or C fibres. Some of the effects of bradykinin in particular may be due to secondary activation of prostaglandins (PG), especially PGE2 and PGI2. Anecdotal evidence that cyclooxygenase inhibitors prevent the cough has not been sustained in well controlled clinical trials, but recent evidence suggests that inhaled cromoglycate may have a significant inhibitory effect. The mechanism of action of cromoglycate is not well understood but evidence of inhibition of local neural reflexes has been inferred, mostly from animal studies. The observation seems unlikely to have much practical benefit for it is difficult to envisage routine use of an inhaled agent to prevent a drug side effect. The question of whether ACE inhibitors are safe in patients with asthma is still open, and most rechallenge studies have shown little effect on lung function. Data from one large-scale surveillance study suggest that a few individuals may experience dyspnoea and wheezing but no causal relationship has been established. CONCLUSION: Delineation of the mechanism of the ACE inhibitor cough may lead to a better understanding of the mechanism of cough in inflammatory airways disease.
</context>
</instance>
<instance id="7731158.xx.x">
<answer instance="7731158.xx.x" senseid="C0022709"/>
<context>
Efficacy of intrarenal <head> ACE</head> -inhibition estimated from the renal response to angiotensin I and II in humans. Recent studies on the nature of the renin-angiotensin system (RAS) in animals have led to the concept that systemic and intrarenal RAS can be influenced to different degrees by ACE inhibitors. Assessment of efficacy of intrarenal ACE inhibition by ACE inhibitors in humans is necessarily indirect and has not been reported. We therefore monitored the renal response to acute angiotensin (Ang) I infusion in volunteers taking 20 mg enalapril twice daily, and related the responses to the obtained increments in plasma Ang II levels. Ang I infusion rates of 4, 8, 16, and 32 pmol/kg/min caused gradual increments in plasma Ang I (maximal change from 26 +/- 18 to 578 +/- 120 pmol/liter, P < 0.05) and, despite treatment with enalapril, also of Ang II (from 3 +/- 1 to 29 +/- 5 pmol/liter, P < 0.05). This was associated with large reductions in renal plasma flow (paraaminohippurate clearance), filtration fraction, maximal urine flow, sodium excretion, lithium and uric acid clearance, and increments in mean arterial pressure and plasma aldosterone (P < 0.05 for each variable). Strong correlations existed between the changes in either variable and the increment in plasma Ang II. Infusions of Ang II at 1 and 4 pmol/kg/min in the same subjects caused comparable increments in plasma Ang II and had similar physiological effects as found during the Ang I infusion. Analysis of covariance of the changes in plasma Ang II and each of the measured variables revealed no differences between Ang I and Ang II infusions.(ABSTRACT TRUNCATED AT 250 WORDS)
</context>
</instance>
<instance id="2466391.xx.x">
<answer instance="2466391.xx.x" senseid="C0022709"/>
<context>
New aspects on inflammatory reactions and cough following inhibiton of angiotensin converting enzyme. The first inhibitor of <head> ACE</head> was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".
</context>
</instance>
<instance id="1377114.xx.x">
<answer instance="1377114.xx.x" senseid="C0022709"/>
<context>
Recent advances in pharmacological management of hypertension in diabetic patients with nephropathy. Effects of antihypertensive drugs on kidney function and insulin sensitivity. Hypertension is often seen in Type 1 and Type 2 diabetic patients, particularly in those with nephropathy, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of antihypertensive drugs on kidney function and insulin sensitivity in diabetic patients are of great clinical importance. Successful antihypertensive treatment has been shown to slow the progression of diabetic nephropathy. Several results from short term studies have suggested that <head> ACE</head> inhibitors may be advantageous over other conventional antihypertensive agents in reducing albuminuria in both hypertensive and normotensive diabetics with microalbuminuria or persistent proteinuria. However, the decline in glomerular filtration rate during ACE inhibitor treatment is comparable to that during effective treatment with conventional antihypertensive drugs in hypertensive Type 1 diabetic patients with overt nephropathy. Whether ACE inhibitors possess a specific effect in preventing the development of diabetic nephropathy remains to be seen in properly designed long term studies. Although calcium antagonists may preserve kidney function or possess a renoprotective effect in hypertensive Type 2 diabetics with nephropathy, firm evidence supporting this contention seems to be lacking and also requires long term evaluation. Increasing attention is being directed toward the effect of antihypertensive drugs on insulin sensitivity in diabetic patients: ACE inhibitors and alpha 1-adrenoceptor blocking agents have been shown to improve this sensitivity. Despite the widespread involvement of calcium in hormone secretion and action, calcium antagonists appear to have little effects on the glucoregulatory and calcium-regulatory hormones within the drug dosages used in clinical practice. Several clinical variables, such as the presence or absence of hypertension, overt nephropathy and microalbuminuria, or a combination of variables should be accounted for when evaluating critically the cumulative data on the effects of antihypertensive drugs on kidney function and albuminuria in the variety of diabetic patient groups. Understanding the pharmacokinetic and pharmacodynamic characteristics of antihypertensive drugs will be of clinical importance in diabetic patients with advanced nephropathy (glomerular filtration rate of less than 30 ml/min) and/or other complications, such as impaired gastric motility or gastroparesis, and will thereby lead to a more rational management of hypertension in those patients.
</context>
</instance>
<instance id="1712266.xx.x">
<answer instance="1712266.xx.x" senseid="C0022709"/>
<context>
Clinical pharmacodynamic studies with cilazapril and a combination of cilazapril and propranolol. We evaluated the degree of inhibition of <head> ACE</head> , principally by cilazapril, by assessing the blood pressure response to a continuous infusion of increasing doses of angiotensin I, and assessed the possible pharmacokinetic and pharmacodynamic interactions between cilazapril and propranolol in healthy volunteers and patients with mild to severe essential hypertension. The specificity of the angiotensin I infusion method was verified when a single dose of cilazapril 30mg antagonised the increase in diastolic blood pressure induced by angiotensin I but did not influence the response to angiotensin II. Using this method, we showed that single oral doses of cilazapril 4 mg, captopril 25 mg and enalapril 10mg shifted the angiotensin I dose-effect curve to the right and determined a pharmacological half-life of about 4 hours for cilazapril. Increasing single oral doses (1.25, 3.75, 10 and 30mg) of cilazapril reduced diastolic blood pressure dose-dependently and shifted the angiotensin I dose-response curves to the right. The dose representing 50% inhibition of ACE activity (apparent Ki-dose) was about 0.6mg, 3 hours after cilazapril administration. Cilazapril and propranolol did not exhibit any clinically significant pharmacokinetic interaction in healthy volunteers; each drug reduced diastolic and systolic blood pressure by about 7 mm Hg, and this was doubled by the combination. Cilazapril had no significant effect on heart rate, in patients with essential hypertension whereas both propranolol and the combination of cilazapril and propranolol reduced it. Monotherapy with each drug reduced blood pressure, and combined administration enhanced the antihypertensive effect.(ABSTRACT TRUNCATED AT 250 WORDS)
</context>
</instance>
<instance id="15283769.xx.x">
<answer instance="15283769.xx.x" senseid="C0022709"/>
<context>
Cyclooxygenase-2 and the renal renin-angiotensin system. In the kidney, cyclooxygenase-2 (COX-2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na(+)/K(+)/2Cl(-) cotransport, and administration of non-specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, <head> ACE</head> inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX-2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX-2 expression. In AT1 receptor knockout mice, COX-2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX-2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX-2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX-2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX-2 inhibitor but not a COX-1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low-salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX-2-selective inhibitors. In mice with genetic deletion of COX-2, ACE inhibitors or low-salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX-1 null mice there were no significant differences in either the basal or ACE inhibitor-stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX-2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX-2 derived prostaglandins and the renin-angiotensin system may underlie physiological and pathophysiological regulation of renal function.
</context>
</instance>
<instance id="3038422.xx.x">
<answer instance="3038422.xx.x" senseid="C0022709"/>
<context>
Comparison of sublingual and oral captopril in hypertension. The use of sublingual captopril has been recently suggested in hypertensive crisis on the assumption of a faster absorption and thus a more rapid effect on blood pressure than with the oral route. To verify this hypothesis we have compared the hypotensive effect of oral and sublingual captopril in 40 essential hypertensives who were randomly allocated to either route of administration. Captopril was administered orally dissolved in water or allowed to dissolve under the tongue. After 5, 10, 20, 30, 40, 60 and 90 minutes blood pressure, Plasma Renin Activity (PRA) and <head> ACE</head> were measured. No significant differences were found between the two groups in the time course of blood pressure decrease, PRA increase and ACE inhibition. The changes of the parameters studied was superimposable irrespective of the route of administration thus not supporting the hypothesis that sublingual captopril might be absorbed more rapidly.
</context>
</instance>
<instance id="6089307.xx.x">
<answer instance="6089307.xx.x" senseid="C0022709"/>
<context>
Enalapril and lisinopril in renovascular hypertension--antihypertensive and hormonal effects of two new angiotensin-converting-enzyme ( <head> ACE</head> ) inhibitors. A preliminary report. We assessed the antihypertensive and hormonal effects of two new ACE inhibitors, enalapril (MK-421) and lisinopril (MK-521) in 22 patients with renovascular hypertension. All patients had angiographically verified renal artery lesions, 3 had bilateral renal artery stenosis and one a stenosis in a single kidney, and the rest had unilateral renal artery stenosis. After placebo treatment for 3 days in hospital, increasing doses from 5 to 40 mg daily, of both ACE-inhibitors were given. Both drugs induced a significant fall in blood pressure (BP). Significant BP reductions were seen after 2 h with a maximum fall for the enalapril group at a dose of 40 mg 4 h after drug intake (mean supine BP decrease - 31/24 mm Hg, standing - 29/16 mmHg). The corresponding maximal BP reductions were for the lisinopril group at a dose of 40 mg o.d. at 6 h: mean supine BP fall - 25/28 mmHg and standing - 33/31 mm Hg. Both drugs significantly inhibited serum ACE to about 5 to 10% of initial values and with a duration for more than 24 h. Both drugs also caused a decrease in plasma-AII levels and also in plasma aldosterone concentrations. There were not toxic effects and no serious side effects. Careful monitoring of biochemical variables showed no significant changes. We conclude that both enalapril and lisinopril are effective and very safe agents for the treatment of renovascular hypertension and with a long duration of action and with very good tolerance.
</context>
</instance>
<instance id="1403231.xx.x">
<answer instance="1403231.xx.x" senseid="C0022709"/>
<context>
The dose-response relationship with angiotensin converting enzyme inhibitors: effects on blood pressure and biochemical parameters. CURRENT USAGE: Plasma <head> ACE</head> inhibition and dose-response relationships during blood pressure reductions were compared for several marketed ACE inhibitor compounds. Both peak and trough responses are considered and contrasted. The presently recommended antihypertensive doses of enalapril, lisinopril, perindopril and ramipril appear to lie within the linear range of the antihypertensive dose-response relationship. For benazepril and captopril, the recommended doses may be in the flat, upper part of the relationship. RECOMMENDATIONS: The recommended doses for initiating antihypertensive therapy may still be excessive in patients at risk of heightened pharmacodynamic responses. Further studies are required to clarify the dose-response relationship for all of these compounds.
</context>
</instance>
<instance id="1711445.xx.x">
<answer instance="1711445.xx.x" senseid="C0022709"/>
<context>
Quinapril. A review of its pharmacological properties, and therapeutic efficacy in cardiovascular disorders. Quinapril is a monoethyl ester which is hydrolysed after absorption to form an active metabolite, quinaprilat, which is a more potent <head> ACE</head> inhibitor than the parent drug. Quinaprilat has a short elimination half-life but a potent binding affinity for ACE which enables once daily administration. Data from clinical studies indicate that quinapril 10 to 40 mg daily, given as a single dose, is an effective antihypertensive agent, suitable as monotherapy for reducing high blood pressure and maintaining satisfactory control during long term treatment of mild to severe hypertension. Dosages of 80 mg daily have been used in some patients. Concomitant diuretic therapy usually elicits a response in patients who fail to respond adequately to monotherapy. Initial studies suggest that quinapril also has a role in the treatment of mild to severe congestive heart failure. In the few long term studies conducted the beneficial acute haemodynamic effects were maintained during long term treatment and were accompanied by symptomatic and functional improvement. The majority of these patients responded to twice daily administration. Adverse effects associated with the antihypertensive action of quinapril are generally mild, well tolerated and are similar to those of other ACE inhibitors. Thus, quinapril appears to be a useful alternative ACE inhibitor for the treatment of mild to severe hypertension and congestive heart failure.
</context>
</instance>
<instance id="17408935.xx.x">
<answer instance="17408935.xx.x" senseid="C0022709"/>
<context>
Angiotensin converting enzyme inhibitor captopril modifies conditioned place preference induced by morphine and morphine withdrawal signs in rats. Angiotensin II and <head> ACE</head> inhibitors have analgesic, anticonvulsant and antidepressive effects and in some cases they can antagonize morphine. In the present study effects of angiotensin II and ACE inhibitor captopril administered intracerobroventricularily (icv) on conditioned place preference induced by morphine as well as on morphine withdrawal signs has been evaluated in rats. Icv canullas were implanted in anesthetized male rats. Rats were allowed to recover from the surgery and conditioned place preference was induced by morphine, and the time spent in morphine compartment was compared in saline, morphine, captopril and Ang II groups. Morphine withdrawal signs were compared in three other groups of rats: morphine alone, captopril+morphine and Ang II+morphine 4 days after morphine injections (three times in each day) with naloxone injection on 4th day. Results with rats conditioned place preference induced by morphine showed that icv captopril decreased significantly the time in morphine compartment (P<0.01) while Ang II had no effect. In morphine dependent rats captopril decreased some withdrawal signs after naloxone precipitation (P<0.05 and P<0.01). Ang II administration augmented some of withdrawal signs than in the morphine group (P<0.01 and P<0.001). In conclusion captopril reduced conditioned place preference induced by morphine and some withdrawal signs in morphine dependent rats.
</context>
</instance>
<instance id="2693657.xx.x">
<answer instance="2693657.xx.x" senseid="C0022709"/>
<context>
Effects of angiotensin converting enzyme inhibitors on the progression of renal failure and proteinuria in humans. We studied the long-term effect of an <head> ACE</head> inhibitor, captopril, on the progression of chronic renal failure and on the rate of urinary protein excretion. When compared with standard triple therapy, captopril slowed the progression of renal failure. Captopril was also able to reduce the proteinuria of non-diabetic glomerular origin. This reduction was not dependent on the presence or absence of arterial hypertension but was limited by the presence of low serum albumin levels, and only occurred in patients with proteinuria in excess of 3 g/24 h.
</context>
</instance>
<instance id="10888303.xx.x">
<answer instance="10888303.xx.x" senseid="C0022709"/>
<context>
Differential recognition of <head> ACE</head> inhibitors in Xenopus laevis oocytes expressing rat PEPT1 and PEPT2. PURPOSE: To examine the mechanism of inhibition of glycylsarcosine (GlySar) transport by quinapril and enalapril, and whether or not ACE inhibitors are transported by PEPT2 as well as by PEPT1. METHODS: Xenopus laevis oocytes were cRNA-injected with rat PEPT1 or PEPT2 and the transport kinetics of radiolabeled GlySar were studied in the absence and presence of quinapril and enalapril. The two-microelectrode voltage-clamp technique was also performed to probe the electrogenic uptake of captopril, quinapril and enalapril. RESULTS: Kinetic analyses demonstrated that quinapril inhibited the uptake of GlySar in a noncompetitive manner in Xenopus oocytes injected with PEPT1 or PEPT2 (Ki = 0.8 or 0.4 mM, respectively). In contrast, a competitive interaction was observed between GlySar and enalapril (Ki = 10.8 mM for PEPT1 or 4.3 mM for PEPT2). Most significantly, captopril and enalapril, but not quinapril, induced inwardly-directed currents in both PEPT1- and PEPT2-expressed oocytes. CONCLUSIONS: These results are unique in providing direct evidence for the substrate recognition and transport of some ACE inhibitors by the high- and low-affinity oligopeptide transporters. Our findings point to differences between PEPT1 and PEPT2 in their affinity to, rather than in their specificity for, ACE inhibitors.
</context>
</instance>
<instance id="8205376.xx.x">
<answer instance="8205376.xx.x" senseid="C0022709"/>
<context>
Enalapril pharmacokinetics and <head> ACE</head> inhibition, following single and chronic oral dosing. Twelve normal volunteers were given 10 mg enalapril maleate by single and 2 weeks multiple dose administration, and blood samples were collected for the determination of enalaprilat concentration and ACE activity. The mean terminal elimination half-life following a single administration of 10 mg enalapril, was 27 hours. The inhibition of ACE activity paralleled enalaprilat concentrations following both single and multiple dosing and the time of maximum inhibition of ACE activity was associated on both occasions with maximum concentration of enalaprilat. Emax modelling of enalaprilat concentration and ACE activity gave comparable values of Emax for both methods of administration. An accumulation factor of 1.7 was calculated from the area under the concentration time curve (AUC) of enalaprilat within a dosing interval at steady-state and the total AUC following single administration of enalapril. There were no significant differences between males and females in the accumulation factor, half-life and AUCinf.
</context>
</instance>
<instance id="10816725.xx.x">
<answer instance="10816725.xx.x" senseid="C0022709"/>
<context>
The renin-angiotensin system and progression of kidney disease. CONSTRICTIVE ACTIVITY OF THE RAS AND DEVELOPMENT OF RENAL DISEASES: Several studies have suggested that the constitutive level of activity of the renin-angiotensin system (RAS), and especially of <head> ACE</head> which plays an important role in the kidney in determining intrarenal angiotensin and kinin concentrations, is genetically determined and linked to the risk of developing several vascular diseases, including diabetic nephropathy, and to the risk of renal function deterioration in glomerular diseases of several origins. INHIBITION OF THE RAS AND PROGRESSION OF RENAL DISEASES: Large controlled clinical trials have shown over the past years that inhibition of ACE has a beneficial effect and protects against degradation of renal function in type I diabetes with microalbuminuria and also in renal diseases of several origins. PATHOPHYSIOLOGY: All these observations taken together suggest that activation of the RAS, which is necessary in certain circumstances to maintain glomerular filtration and tissue perfusion, can have a long-term deleterious effect on the heart, vessels, and kidneys, especially through glomerular hypertension which can lead to glomerulosclerosis. They support the use of ACE inhibitors, within the indications deduced from analyses of the large clinical trials, for protecting renal function in kidney diseases.
</context>
</instance>
<instance id="10934839.xx.x">
<answer instance="10934839.xx.x" senseid="C0022709"/>
<context>
Trandolapril in the prevention of the sequelae of left ventricular systolic dysfunction after acute myocardial infarct. Left ventricle systolic dysfunction and congestive heart failure after AMI are still a great problem in cardiology. Introduction of <head> ACE</head> inhibitors after AMI has been a new step in therapy of the left ventricle systolic disfunction. Some long term studies have proved influence of ACE inhibitors on reduction of mortality, severe congestive heart failure (CHF), and reinfarction. The importance of administration of a remedy once daily has been emphasized, and the pharmacokinetics and pharmacodynamics of trandolapril in the left ventricle dysfunction and CHF has been described. TRACE study proved influence of long-term once daily administration of trandolapril on significant reduction of total and cardiovascular mortality, reduction of sudden death, reduction of severe and resistant CHF and reduction or relay of reinfarction. A good risk/benefit ratio has been found.
</context>
</instance>
<instance id="2402813.xx.x">
<answer instance="2402813.xx.x" senseid="C0022709"/>
<context>
Side effects in 28 patients treated with angiotensin converting enzyme <head>ACE</head> inhibitor in arterial hypertension in general practice. ACE-inhibitors have long been considerACEside-effects. Their use in clinical practice has shown that a considerable number of patients develop a dry, non-productive cough, resistant to treatment. The cause is hitherto unknown, but ACE-inhibition has been proved to alter the cough reflex. Non-smokers seem to cough more often than smokers, and females more often than males. Registration of side-effects in 28 patients treated for arterial hypertension in general practice in the years 1985-1988 is presented.
</context>
</instance>
</lexelt>
</corpus>
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