Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The pathogenetic determinants of sodium retention in IDDM are not fully understood. The aim of this study was to elucidate the action of ANP in 11 IDDM patients with high GFR (greater than or equal to 135 ml.min-1 x 1.73 m-2), referred to here as HF patients; in 10 IDDM patients with normal GFR (greater than 90 and less than 135 ml.min-1 x 1.73 m-2), referred to here as NF patients; and 12 control subjects, here called C subjects, at baseline and during saline infusion administered on the basis of either body weight (2 mmol.kg-1 x 60 min-1; Saline 1) or of ECV (12 mM.ECVL-1 x 90 min-1; Saline 2) during euglycemic insulin-glucose clamp. C subjects and both HF and NF IDDM patients received a second Saline 1 infusion accompanied by ANP infusion (0.02 microgram.kg-1.min-1) at euglycemic levels. HF and NF patients were studied again after 3 mo of treatment with (10 mg/day). Quinapril (CI 906, Malesci, Florence, Italy), an ACE inhibitor without sulfhydryl group. At baseline, both HF and NF IDDM patients had higher plasma ANP concentrations than C subjects (HF, 36 +/- 4, P less than 0.01 and NF, 34 +/- 3, P less than 0.01 vs. C, 19 +/- 3 pg/ml). Plasma ANP and natriuretic response to isotonic volume expansion was impaired both in HF (44 +/- 8 pg/ml, NS vs. base) and NF (40 +/- 7 pg/ml, NS vs. base) compared with C (41 +/- 4 pg/ml, P less than 0.01 vs. base) during Saline 1. On the contrary, plasma ANP response to Saline 2 was similar in HF and NF patients and C subjects, but IDDM patients had still lower urinary sodium excretion rates. The simultaneous administration of ANP and Saline 1 resulted in comparable plasma ANP plateaus in C subjects and HF and NF patients. However, urinary sodium excretion rate was significantly lower in HF and NF patients than in C subjects: HF, 267 +/- 64, P less than 0.01 and NF, 281 +/- 42, P less than 0.01 vs. C, 424 +/- 39 mumol.min-1 x 1.73 m-2. During simultaneous administration of ANP and Saline 1, GFR and FF increased in C subjects, but not in HF and NF patients. HF and NF patients had higher urinary vasodilatory prostanoid excretion rates than C subjects at baseline. Saline infusion did not change urinary excretion rate of prostanoids either in C subjects or IDDM patients (both NF and HF).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of atrial natriuretic peptide in the pathogenesis of sodium retention in IDDM with and without glomerular hyperfiltration. 138 91

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

We investigated the impact of angiotensin I-converting enzyme (ACE) inhibition by enalapril (3 X 2.5 mg p.o.) on the renal action of acute intravenous (i.v.) infusion of atrial natriuretic peptide (1-28-hANP 0.1 micrograms/kg/min for 30 min) in 10 normal subjects. During the control infusion of ANP, urinary sodium excretion rose from 4.5 +/- 0.8 to 11.2 +/- 2.2 mEq/min and urine volume from 32 +/- 14 to 115 +/- 34 ml/30 min. This increment in urinary volume and sodium output during ANP infusion was almost completely reduced by ACE inhibition. ANP plasma levels before and during the infusion and stimulation of urinary cGMP excretion were unaltered by ACE inhibition. However, enalapril treatment reduced systolic blood pressure (SBP) from 112 +/- 3 to 106 +/- 3 mm Hg and diastolic blood pressure (DBP) from 71 +/- 2 to 66 +/- 3 mm Hg. The small rise in glomerular filtration rate (GFR) during the control infusion of ANP was not observed after pretreatment with enalapril. The study demonstrates the importance of the renin-angiotensin system for the natriuretic and diuretic action of ANP in normal humans.
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PMID:Natriuretic action of ANP is blunted by ACE inhibition in humans. 247 23

The hemodynamic parameters (right atrial pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, heart rate, blood pressure) and neurohumoral responses (alpha-ANP, plasma renin activity, aldosterone, angiotensin II) of Captopril, oral ACE inhibitor, and Bunazosin, oral alpha 1-blocker, were investigated in 28 patients with congestive heart failure at rest and after exercise. These data were analysed in both acute and chronic phases. 1) Acute effect. Captopril produced significant improvement of neurohumoral factors at rest and also after exercise. Bunazosin reduced alpha-ANP, but other neurohumoral factors did not change. Bunazosin produced significant hemodynamic improvement both at rest and after exercise. 2) Chronic effect. Captopril produced significant hemodynamic improvement both at rest and after exercise. Improvement of neurohumoral factors in acute phase was also preserved at chronic phase. On Bunazosin, improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors.
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PMID:[The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure]. 257 81

Spontaneously hypertensive rats (SHR) showed lower brain ANP binding density when compared with normotensive Wistar-Kyoto (WKY) rats. In the WKY, angiotensin converting enzyme inhibitor, enalapril (25 mg/kg, p.o. for 14 days), decreased the number of ANP binding sites selectively in the subfornical organ and area postrema. Conversely, enalapril increased ANP binding density in the SHR, but only in the area postrema. Enalapril has central effects on ANP binding sites, specific to the circumventricular organs.
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PMID:Effect of chronic administration of the converting enzyme inhibitor enalapril (MK 421) on brain atrial natriuretic peptide receptors in Wistar-Kyoto and spontaneously hypertensive rats. 285 Aug 34

Removal of iodinated 28-amino acid atrial natriuretic peptide ([125I]ANP) by rabbit lungs was measured by indicator-dilution methods. After bolus injection of 6.5 pmoles of [125I]ANP, 66.9 +/- 2.9% was removed in a single pass through the lungs. Removal was unaltered by a kininase II inhibitor but was reversibly decreased by unlabelled ANP. Thus the lungs can remove ANP from the pulmonary circulation by a mechanism that does not involve hydrolysis by kininase II. Lungs therefore may be involved in regulating systemic concentrations and hence renal and other actions of ANP.
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PMID:Removal of atrial natriuretic peptide by perfused rabbit lungs in situ. 294 98

Atrial natriuretic peptide is rapidly degraded by a soluble, heat labile peptidase isolated from ventricular myocytes. Degradation of [125I]-ANP is antagonized by unlabelled ANP, bradykinin, glucagon, 1,10-phenanthroline, PCMB, EDTA and the bacterial antibiotic bacitracin, but not by phenylmethylsulphonyl fluoride, aprotinin, phosphoramidon, E-64, amastatin or the ACE inhibitor SQ 20881 and bradykinin potentiator C. In addition neither bovine serum albumin nor caesin afforded any protection against degradation. Peptidase activity was optimal at pH values above 8.5. The peptidase is likely to be of intracellular origin and may contribute to the extensive ANP degradative activity found in various ventricular muscle preparations.
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PMID:Degradation of [125I]-atrial natriuretic peptide by a soluble metallopeptidase isolated from rat ventricular myocytes. 296 71

Neurohormonal activation may provide a pathophysiological link between acute myocardial infarction and chronic congestive heart failure, and modulation of neurohormonal activity may be an important therapeutic target in these conditions. Plasma neurohormones were studied in 55 patients with acute myocardial infarction. Angiotensin II, noradrenaline and ANP were elevated in the early phase but tended to normalize during the first week in patients without signs of heart failure. In patients with heart failure angiotensin II and noradrenaline remained elevated for 1 month and ANP for 4-6 months. During head-up tilt, angiotensin II and noradrenaline increased most in patients with heart failure. In patients with a first myocardial infarction there was a positive correlation between sustained neurohormonal activity and infarct size. Almost complete suppression of plasma ACE activity was achieved within 30 min in 48 patients treated with intravenous enalaprilat, initiated within 24 h from the onset of infarction. The drug was tolerated in dosages of 1.0-1.2 mg given over 1-2h. Patients with systolic blood pressure between 100 and 110 mmHg incurred a greater risk of hypotension than those with higher blood pressure at baseline. Tolerance was not worse among patients treated with intravenous diuretics, metoprolol or nitroglycerin. A total of 98 patients were randomized to treatment with enalapril or placebo, initiated within 24 h from onset of infarction and continued for 4-6 months. During treatment there were no significant differences in plasma levels of angiotensin II, aldosterone, ANP or catecholamines between groups. Echocardiographic recordings were performed in 28 patients. Among patients on placebo there was a positive correlation between plasma levels of noradrenaline at days 5-7 and the increase in left ventricular volumes during the study period, and an inverse correlation between plasma aldosterone at days 5-7 and the increase in left ventricular ejection fraction during the study. No such correlation was found among patients on enalapril. ANP levels at 1 month correlated inversely with the left ventricular ejection fraction at the same time. Plasma neurohormones were measured in 223 patients with mild or moderately severe chronic heart failure, randomized to treatment with ramipril or placebo for 3 months. There was wide variation in hormone levels. Noradrenaline and aldosterone correlated inversely with exercise duration at baseline. Noradrenaline correlated positively with the degree of symptoms. Aldosterone and ANP were reduced with ramipril compared with placebo. Noradrenaline was reduced among patients with baseline levels in the highest tertile. Plasma hormones were also measured at peak exercise in 54 patients. Hormonal levels at rest correlated strongly with those at peak exercise.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurohormonal activation in patients with acute myocardial infarction or chronic congestive heart failure. With special reference to treatment with angiotensin converting enzyme inhibitors. 759 49

The coronary vascular effect of atrial natriuretic peptide is controversial: Coronary vasodilator as well as constrictor effects have been reported. The controversy may originate from interference of atrial natriuretic peptide with the renin-angiotensin system and/or tachyphylaxis of the effect of atrial natriuretic peptide. The effect of alpha-human atrial natriuretic peptide bolus application on changes of coronary flow was examined in the isolated, constant-pressure perfused rat heart. Six groups were considered: (1) control group; groups in which the renin-angiotensin system was modulated by pretreatment with continuous infusion of: (2) angiotensin II, (3) the angiotensin converting enzyme inhibitor captopril (4) the angiotensin II receptor blocker saralasin; and groups in which tachyphylaxis was examined by pretreatment with ANP, (5) as continuous infusion and (6) as bolus application. First, in control hearts, dose-response curves were obtained for single ANP dosages of 1-100 nmol. The effect of high dosages (40 and 100 nmol) was biphasic, with an initial vasodilator and subsequent long-lasting vasoconstrictor component. Hearts in which coronary flow was reduced by approximately 18% through continuous angiotensin II infusion showed an enhanced early vasodilator response after ANP administration, whereas the vasoconstrictor effect was no longer observable. Angiotensin converting enzyme inhibition and angiotensin II receptor blockade reduced the vasodilator effect of ANP. In addition, saralasin nearly abolished ANP-induced vasoconstriction, whereas vasoconstriction was unaltered by pretreatment with captopril. Captopril or saralasin alone did not change coronary flow, heart rate and left ventricular developed pressure. In groups (5) and (6). ANP bolus application showed significantly reduced vasomotor activity. We conclude that in the isolated rat heart. ANP has a biphasic effect with early vasodilation and late vasoconstriction. Both effects can be modulated by inhibition of the renin-angiotensin system at different levels indicating that vasomotor ANP effects result from interaction of ANP with the local renin-angiotensin system. ANP effects can be markedly reduced by tachyphylaxis.
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PMID:Interrelation of coronary effects of atrial natriuretic peptide and the renin-angiotensin system in the isolated perfused rat heart. 807 8

The influential studies by Hostetter and associates [103] as well as by others in the last decade have firmly established the association between adaptive increases in renal hemodynamics as well as tubular reabsorption and the progression of renal disease. Many different vasoactive hormones may be involved in such regulatory processes. On the other hand, many investigators have observed that compensatory renal growth, although initially helping to restore functional renal tissue, may be rather harmful in the long-term for renal function, even in the absence of concomitant hemodynamic changes. These apparently separate areas of renal pathophysiology have become united by the identification of the growth regulatory properties of many vasoactive substances. Thus, a perturbation of vasoconstrictors and vasodilatory substances may not only influence vascular tone, glomerular filtration rate and renal plasma flow but also the growth regulation of distinct populations of cells along the nephron. As a generalization, it appears that vasoconstrictors stimulate growth of renal cells (mitogenesis and hypertrophy), whereas vasodilators inhibit the growth response. It can be speculated that similar effects of different hormones may depend on the activation of common second messenger pathway, e.g. the ANG-II-, AVP-, ET-induced mesangial proliferation through the phosphorylation of a common set of target proteins, or the antimitogenic effects of ANP, EDRF and PGE2 through an increase in intracellular cGMP. However, the majority of the growth regulatory effects of vasoactive substances have been studied in relatively artificial cell culture systems. Nevertheless, the well-documented protective effects of ACE inhibitors on renal function in several models include effects on renal growth. The rapid development of new vasoactive drugs like the recently introduced nonpeptide ANG II receptor antagonists may also offer an opportunity to influence renal growth [104]. The mechanisms of the progression of renal disease have become fascinatingly complex, and the next years will most likely witness major achievements in the elucidation of chronic renal pathophysiology on both cellular and molecular levels.
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PMID:Vasoactive substances as regulators of renal growth. 808 63


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