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Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1-7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1-7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1-7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1-7). The primary product of 125I-Ang-(1-7) metabolism was identified as Ang-(1-5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1-7) to the pentapeptide Ang-(1-5). The ACE inhibitors lisinopril and enalaprilat (1 micromol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1-5) and did not yield other metabolic products. Ang-(1-5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1-7) by ACE revealed a substrate affinity of 0.81 micromol/L and maximal velocity of 0.65 micromols min(-1) mg(-1). The calculated turnover constant for the peptide was 1.8 sec(-1) with a catalytic efficiency (Kcat/Km) of 2200 sec(-1) mmol/L(-1). These findings suggest that increased levels of Ang-(1-7) following ACE inhibition may be due, in part, to decreased metabolism of the peptide.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9453329&dopt=Abstract
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Hypertension. 1998 Feb;31(2):699-705.
Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan.
Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrario CM.
Hypertension Center, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157, USA.
Blockade of angiotensin II (Ang II) function during 8 days of oral therapy with lisinopril (20 mg/kg) and losartan (10 mg/kg) normalized the arterial pressure (112+/-3/70+/-3 mm Hg) and raised the plasma concentrations of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] of 21 male spontaneously hypertensive rats (SHR). Treated animals were then given a 15-minute infusion of either mouse immunoglobulin G1 or a specific monoclonal Ang-(1-7) antibody while their blood pressure and heart rate were recorded continuously in the awake state. The concentrations of Ang II and Ang-(1-7) in arterial blood were determined by radioimmunoassay. Infusion of the Ang-(1-7) antibody caused significant elevations in mean arterial pressure that were sustained for the duration of the infusion and were accompanied by transient bradycardia. Although the hemodynamic effects produced by infusion of the Ang-(1-7) antibody had no effect on plasma levels of Ang II, they caused a twofold rise in the plasma concentrations of Ang-(1-7). A pressor response of similar magnitude and characteristics was obtained in a separate group of SHR treated with the combination of lisinopril and losartan for 8 days during an infusion of [Sar1-Thr8]Ang II. The pressor response induced by the administration of this competitive, non-subtype-selective Ang II receptor blocker was not modified by pretreatment of the rats with an angiotensin type-2 (AT2) receptor blocker (PD123319). Plasma concentrations of Ang II and Ang-(1-7) were not changed by the administration of [Sar1-Thr8]Ang II either in the absence or in the presence of PD123319 pretreatment. These results are the first to indicate an important contribution of Ang-(1-7) in mediating the vasodilator effects caused by combined inhibition of angiotensin-converting enzyme and AT1 receptors. The comparable results obtained by administration of [Sar1-Thr8]Ang II suggest that the vasodepressor effects of Ang-(1-7) during the combined treatment is modulated by a non-AT1/AT2 angiotensin subtype receptor.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9461243&dopt=Abstract
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Cardiovasc Res. 1997 Nov;36(2):236-45.
Changes in collagen phenotypes during progression and regression of cardiac hypertrophy.
Yang CM, Kandaswamy V, Young D, Sen S.
Department of Molecular Cardiology (FF4-09), Cleveland Clinic Foundation, OH 44195, USA.
OBJECTIVE: Excessive deposition of collagen has been implied to be responsible for abnormal stiffness and altered cardiac function during hypertrophy and heart failure. In the present paper we studied the changes in collagen and their phenotypes during development of cardiac hypertrophy in spontaneously hypertensive rats (SHR) compared to age- and sex-matched Wistar Kyoto (WKY). We also studied the changes in collagen after regression of hypertrophy, with antihypertensive therapy with ACE inhibitors, captopril (C) and lisinopril (L). METHOD: Collagen was extracted from the heart tissue by cyanogen bromide (CNBr) digestion. Collagen phenotypes were separated and quantified by SDS-polyacrylamide gel electrophoresis. The transcript levels(mRNA) of collagen phenotypes were determined by Northern analysis. RESULTS: Our studies showed that the ventricular collagen and their phenotypes did not alter in SHR during the first 6 months of progression of hypertrophy when compared to WKY. After 40 weeks, however, in SHR there was an unexpected rise in collagen content and the distribution of collagen phenotype differs compared to WKY, especially during the chronic phase of hypertrophy (65 weeks of age). In WKY during the aging process there was a gradual increase in type III collagen, whereas in SHR it plateaus after 40 weeks of age. Treatment with antihypertensive drugs captopril and lisinopril showed a similar degree of reduction in blood pressure (P < 0.001), regressed hypertrophy (P < 0.001), and reduced collagen, whereas decrease in type I to III ratio was found with captopril only, but not with lisinopril. This decrease in type I to III ratio due to captopril treatment is primarily due to an increase in type III collagen (both protein and transcript level) in SHR. CONCLUSION: Our data showed, for the first time, that during the chronic phase of hypertrophy in SHR there is a gradual reduction in type I to III ratio, primarily due to a lack of increase in type III collagen during chronic phase of hypertrophy. This suggests that quality of collagen is an important factor in determining the degree of cardiac stiffness. Our data also showed that not all ACE inhibitors have similar actions on collagen phenotype production. This suggests that perhaps the mechanism of action of ACE inhibitors on collagen are independent of its effect on angiotensin II formation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9463635&dopt=Abstract
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