Renal and Depressor Activities of Inhibitors of Neutral Endopeptidase and Angiotensin Converting Enzyme in Monkeys Infused with Angiotensin II

Abstract

In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.

Regulation of 11β-hydroxysteroid dehydrogenase type 2 by diuretics and the renin–angiotensin–aldosterone axis

“…Studies have shown that intrarenal infusions of ACEI increase renal sodium excretion independent of circulating concentrations of ANG II [33,34], in keeping with data from Navis et al [17]. Our data suggest that this effect may be mediated by increased conversion of cortisol to cortisone, via a direct action on 11β-HSD2.…”

Dual Metalloprotease Inhibitors: Mercaptoacetyl-Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

“…The constant infusion of AII masked the effect of ACE inhibition by suppressing renin release and replacing angiotensin II so that a clearer measure of in vivo inhibition of NEP would be obtained. 19 As anticipated, 0.1-3 µmol/kg doses of 1a potentiated urinary sodium, urinary ANP, and urinary cGMP excretion (Figure 5). The responses were dose related except for ANP since the time course of the experiment did not allow ANP levels to return to baseline and thus the full ANP response to the drug was not obtained.…”

“…In order to better assess the NEP inhibitory component on renal parameters, 1a was administered to cynomolgus monkeys infused with saline and 30 ng/min of AII and subsequently challenged with a bolus dose of human-ANP. The constant infusion of AII masked the effect of ACE inhibition by suppressing renin release and replacing angiotensin II so that a clearer measure of in vivo inhibition of NEP would be obtained . As anticipated, 0.1−3 μmol/kg doses of 1a potentiated urinary sodium, urinary ANP, and urinary cGMP excretion (Figure ).…”

Role of the Natriuretic Peptide System in Cardiorenal Protection

“…87 However, blocking the RAAS with the ACE inhibitor captopril while inhibiting NEP (Figure 3) has been shown to be effective in reducing BP in rat and primate models of hypertension. [88][89][90] Likewise, NEP inhibition alone has been ineffective in animal and human heart failure. In a rat model of heart failure produced by myocardial infarction, no differences were found in cardiac hemodynamics or cardiac hypertrophy produced by candoxatril or placebo.…”