Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of atrial natriuretic factor (ANF) and the renin-angiotensin system as well as the effects of losartan in rats with aortocaval (AC) shunts. Right atrial and left ventricular end-diastolic pressures (LVEDP) were higher and mean arterial blood pressure (MAP) was lower in AC shunt animals than in their controls. AC shunt rats presented marked cardiac hypertrophy, decreased right atrial ANF concentration, and increased ventricular ANF content and concentration. Plasma ANF levels were elevated, and hematocrit was lower in AC shunt animals than in controls. Captopril or losartan treatment decreased MAP and returned LVEDP to sham-operated control values. A clear regression of cardiac hypertrophy was evident in both treated AC shunt groups, with plasma ANF levels tending to follow those in sham-operated rats. Plasma COOH-terminal ANF levels were decreased and urinary volume and hematocrit were increased in losartan-treated AC shunt animals. We conclude that chronic angiotensin converting enzyme inhibition and angiotension II receptor antagonism improved hemodynamic conditions, diminished water retention, reversed cardiac hypertrophy, and restored plasma and tissue ANF to more "normal" levels in rats with moderate high-output heart failure.
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PMID:Chronic captopril and losartan (DuP 753) administration in rats with high-output heart failure. 141 10

The effects of two oral doses of zabicipril, a new angiotensin converting enzyme inhibitor, on systemic (arterial pressure, heart rate, and cardiac output) hemodynamic parameters and regional (brachial, carotid and femoral arteries' diameters and flows) hemodynamic parameters and on biologic (plasma-converting enzyme and renin activities, catecholamines, and atrial natriuretic factor) parameters were noninvasively investigated and compared with those of a placebo in a double-blind crossover study performed in six healthy male volunteers. Although it did not affect the systemic hemodynamic parameters, zabicipril induced a strong peripheral vasodilation, significantly reducing brachial, carotid, and femoral resistances and increasing the corresponding blood flows from 3 or 4 1/2 hours to 9 hours. This vasodilation affected only the arterioles, not the large arteries, and resulted in a redistribution of cardiac output toward the three regional vascular beds. Zabicipril induced an early, potent, and long-lasting converting enzyme inhibition. Furthermore, zabicipril did not affect plasma catecholamines and atrial natriuretic factor.
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PMID:Systemic and regional hemodynamic effects of zabicipril in healthy volunteers. 153 52

The atrial natriuretic factor (ANF) is secreted by the atria in mild and moderate cardiac failure but, during the evolution of the cardiac failure, the ventricles are also recruited and secrete ANF. In order to investigate the relation between plasma ANF and Doppler echocardiographic parameters of severe cardiac failure, the concentrations were measured simultaneously in 20 patients with NYHA Class III and IV cardiac failure (10 due to ischaemic and 10 due to primary dilated cardiomyopathy) despite optimal medical treatment including an angiotensin converting enzyme inhibitor. Overall, there was a weak negative correlation between the plasma ANF concentrations and the decrease in right ventricular surface area (r = -0.58, p less than 0.005, n = 20 patients). This relation was highly significant in ischaemic cardiomyopathy (r = -0.81, p less than 0.002, n = 10 patients) and not significant in primary dilated cardiomyopathy (r = -0.29, NS, n = 10 patients). No relationship was observed between plasma ANF and other echocardiographic parameters (atrial surface area, right and left ventricular dimensions, left ventricular ejection fraction and mass) or with Doppler aortic indices (acceleration, maximum and mean velocities, aortic velocity-time integrals). However, plasma ANF was related to the velocity of mitral regurgitant jets (r = -0.70, p less than 0.01) which is dependent on left ventricular pump function. These results show that plasma ANF concentrations are only related to right ventricular systolic function and the velocity of mitral regurgitation in patients with severe cardiac failure.
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PMID:[Correlations between plasma concentrations of atrial natriuretic factor and right ventricular function in patients with severe cardiac failure]. 153 2

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double-blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run-in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l-1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l-1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active dose was significantly greater on AP than AA (P = 0.005). The increased sensitivity to inhibition during once daily administration was reflected in mean arterial pressure. The pre-dose standing pressure was less on AP than on PP (P less than 0.05), and the change in postural fall (pre-dose minus 2 h post), was greater (P = 0.004), but AA and PP were similar in these respects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients. 153 21

The activation or interruption of the responses induced by regulatory peptides are ensured by ectoenzymes, the most important of them belonging to the group of zinc metallopeptidases. Thus angiotensin converting enzyme (ACE) forms the hypertensive peptide angiotensin II from its inactive precursor AI. This also the case for aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP, CALLA) which together inactivate the endogenous opioid peptides, enkephalins, whereas only NEP is involved in the metabolism of the atrial natriuretic factor (ANP) at the kidney and vascular levels. The pharmacological effects resulting from the inhibition of these enzymatic processes will appear only in tissues where the peptide substrate is tonically or phasically released. This promising approach is expected to avoid, or at least to minimize, the side effects resulting from excessive and ubiquitous stimulation of peptide receptors by exogenously administered agonists or antagonists. The essential amino acids known to be present in the active site of the bacterial endopeptidase thermolysin from crystallographic studies, have also been found in NEP by using a new program of sequence comparison associated with mutagenesis experiments. Several classes of selective inhibitors of NEP, APN and ACE have been rationally designed by taking into account the structural differences in the active site of these peptidases. Thus, the retro-inversion of the amide bond of the NEP inhibitor thiorphan resulted in the elimination of a residual interaction with ACE. Moreover, we have proposed to associate inhibitory potencies towards two peptidases in the same compound. Thus kelatorphan HONH-CO-CH2-CH(CH2 phi)-CONH-CH(CH3)-COOH and other systemically-active mixed NEP/APN inhibitors were shown capable of completely blocking enkephalin metabolism in vivo. This concept has been extended to mixed NEP/ACE inhibitors with compounds such as HS-CH2-CH(CH2 phi)-CONH-CH(CH2R)-COOH where R = CH-(CH3)2 (ES 34) or -OCH2 phi (ES 37). Only mixed inhibitors of NEP and APN are able to produce potent analgesia after intracerebroventricular or systemic administration without the major side effects of morphine (tolerance and dependence). Thiorphan or its prodrugs acetorphan or sinorphan lead to a increase in natriuresis and diuresis by protection of ANP degradation, but without any significant antihypertensive effect. Contrastingly mixed NEP/ACE inhibitors such as ES34 induce decreases in blood pressure higher than those that produced by the association of selective NEP and ACE inhibitors.
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PMID:[New approach in the research of analgesics and antihypertensive agents]. 184 70

Vasoactive hormones acting as endocrine, neuroendocrine, or local hormonal systems (intracrine, autocrine, and paracrine) are an important component of the many factors that regulate blood pressure. Hypertension may be the result of an alteration in the balance between vasodepressor and vasopressor hormonal systems. Changes in this balance could be due to genetic factors such as mutations in one of the genes of the vasoactive system or environmental factors that alter the synthesis and release of one or more vasoactive hormones. Endocrine and neuroendocrine vasopressor hormonal systems, such as the renin-angiotensin system and catecholamines, play a well-established and important role in the regulation of blood pressure and the pathogenesis of some secondary forms of hypertension. The blockade of such systems has already resulted in effective antihypertensive treatment. The role of local hormonal systems is less well established; however, recent evidence suggests they also play an important role in the regulation of blood pressure and the pathogenesis of hypertension. Some vasopressor hormonal systems, such as the renin-angiotensin system, can act as both endocrine or local hormonal systems. Work using transgenic rats harboring the mouse Ren-2 gene has conclusively demonstrated that the renin-angiotensin system, acting as a local hormonal system, has the capability to cause severe hypertension. Whether this model of experimental hypertension mimics any type of human hypertension is not known. Vasodepressor hormones such as kinins, prostaglandins, and endothelium-derived relaxing factor (EDRF) act mainly as local hormonal systems, with the notable exception of atrial natriuretic factor, which may act as both an endocrine and a local hormone. The tissue kallikrein-kinin system, acting either directly or via paracrine eicosanoids or EDRF, participates in local regulation of the circulation, renal function, and the acute antihypertensive effect of angiotensin converting enzyme inhibitors. A restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family of a strain of spontaneously hypertensive rats (SHR) from normotensive Brown Norway rats has been identified. In a set of 32 recombinant inbred strains derived from these SHR and Brown Norway strains, the RFLP marking the kallikrein gene family of SHR cosegregated with an increase in blood pressure. Also, in a study of Utah families it was found that a dominant-allele kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. In conclusion, vasopressor and vasodepressor hormones, acting not only as endocrine but also as local hormones, play an important role in the regulation of blood pressure and the pathogenesis of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. 188 59

Congestive heart failure (CHF) is characterized by activation of (i) vasopressor and antinatriuretic influences (ii) and by counter-activation of vasodilator natriuretic systems. The former comprise the sympathoadrenal, renin-angiotensin-aldosterone and arginine vasopressin systems, and possibly endothelin and withdrawal of endothelium dependent relaxing factor respectively. The latter include the prostaglandins (PGE-2, PGI-2), dopamine and atrial natriuretic factor. The response of the kidney to chronic heart failure, i.e. vasoconstriction and antinatriuresis, resembles the renal reaction to volume depletion. The adverse renal effects of ACE inhibitors in some patients with advanced congestive heart failure may be explained by lowering of renal perfusion pressure and dependence of glomerular filtration rate on angiotensin II.
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PMID:The kidney in congestive heart failure. 191 36

1. We have studied the effects of low dose infusions of atrial natriuretic factor (human ANF (99-126), 1.95 pmol/min per kg) on angiotensin converting enzyme (ACE) inhibitor-induced haemodynamic and hormonal changes in healthy subjects. 2. ACE inhibitor (captopril 25 mg, administered orally) was given against a background infusion of physiological saline (placebo day) or ANF (experimental day). 3. Compared with the placebo observations, ANF enhanced the fall in plasma aldosterone concentrations induced by captopril (P less than 0.05). 4. The rise of plasma renin activity following administration of ACE inhibitor which was observed during placebo infusion was abolished by ANF (P less than 0.05). 5. The responses of systemic blood pressure and heart rate to the converting enzyme inhibition were not affected by the infusion of ANF. 6. These results suggest that variations in endogenous circulating ANF may influence, in part, the response of these hormonal levels during ACE inhibition.
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PMID:Effects of low dose infusion of atrial natriuretic factor on acute inhibition of angiotensin converting enzyme in normal man. 214 Sep 61

The aim of this study was to assess the influence of atrial natriuretic factor (ANF) on arterial baroreflex chronotropic responses and to investigate whether this effect of ANF is affected by angiotensin converting enzyme inhibition (CEI). For this purpose, in 13 normal volunteers, the reflex chronotropic responses to arterial baroreceptor stimulation (phenylephrine, 25-100 micrograms i.v.) or deactivation (nitroglycerin, 25-100 micrograms i.v.) were evaluated in control conditions and during the steady-state phase of a sustained infusion of ANF (50 ng/kg/min) or placebo, before and during prolonged treatment with the converting enzyme inhibitor enalapril (20 mg p.o. for 5 days). ANF infusion, which raised plasma ANF levels from 48 +/- 19 to 1,765 +/- 203 pg/ml, was associated with a slight decrease in systemic blood pressure and no change in heart rate. In addition, it caused a significant increase of the regression slope obtained with phenylephrine (from 11.3 +/- 2 to 18.5 +/- 2 msec/mm Hg) and a significant reduction of slope of the nitroglycerin-produced regression line (from 9.3 +/- 1 to 5.6 +/- 0.6 msec/mm Hg). After sustained CEI, which raised plasma renin activity from 1.4 +/- 0.4 to 19.9 +/- 5 ng/ml/hr, ANF infusion induced an increase in plasma ANF levels and a reduction in blood pressure comparable to those observed in control conditions. During CEI, however, ANF infusion had no significant effect on the chronotropic baroreflex responses produced by phenylephrine or nitroglycerin. Chronotropic and pressor responses to cold exposure were unchanged after CEI and during ANF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Converting enzyme inhibition prevents the effects of atrial natriuretic factor on baroreflex responses in humans. 214

1. The pharmacokinetics and pharmacodynamics of quinapril and its active metabolite quinaprilat were studied in 20 subjects with renal function varying from normal to severe renal failure, during the approach to and at steady-state, and for 72 h after cessation of quinapril 20 mg orally for 7 days. 2. The apparent oral plasma clearance of quinaprilat (dose of quinapril equivalent/AUC of quinaprilat) was directly related to creatinine clearance (CLCr). The predicted apparent oral clearance of quinaprilat was zero when CLCr was zero, suggesting minimal extrarenal elimination. 3. Peak and trough concentrations of quinaprilat, and its apparent elimination half-life, varied inversely with CLCr. 4. Trough concentrations of quinaprilat showed no accumulation between 2 and 7 days, even in severe renal impairment. 5. There was a weak relationship between the oral plasma clearance of quinapril and CLCr. 6. ACE inhibition was marked and prolonged in all subjects, with 50% inhibition at 2.7 +/- 1.9% ng ml-1 of quinaprilat. The time for which ACE inhibition was greater than 90% was related inversely to CLCr. 7. Aldosterone concentrations and plasma renin activity responded in a predictable way, but with no clear relationship To CLCr. 8. Atrial natriuretic peptide concentrations were not affected by quinapril administration. 9. Glomerular filtration rate, as measured by Tc99mDTPA clearance, was not affected by quinapril administration. 10. Blood pressure at steady-state decreased significantly in the subjects with hypertension. The changes in blood pressure were not related to renal function. 11. These results suggest that the dosage rate of quinapril may have to be altered in renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacokinetics and pharmacodynamics of quinapril and quinaprilat in renal impairment. 214 94


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