INHIBITION OF NEUTRAL ENDOPEPTIDASE 3.4.24.11 IN CONSCIOUS DOGS WITH PACING-INDUCED HEART-FAILURE

Objective: The effects of a selective neutral endopeptidase inhibitor, SQ 28,603 rcaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine), were det ermined in an experimental model of heart failure. Methods: The sympto ms of heart failure were induced by rapid ventricular pacing for one o r three weeks in dogs with surgically implanted catheters for measurem ent of atrial pressures and mean arterial pressure and with ultrasonic flow probes for determination of cardiac output and renal blood flow. Results: Inhibition of neutral endopeptidase by 10, 30, or 100 mumol. kg-1 SQ 28,603 given intravenously increased sodium excretion, cyclic GMP excretion, and plasma concentrations of atrial natriuretic peptide in a dose related manner in conscious dogs paced for one week. SQ 28, 603 (100 mumol.kg-1) stimulated similar natriuretic and cyclic GMP res ponses in dogs paced for three weeks although baseline glomerular filt ration rate was reduced. Because the natriuresis was maintained despit e the smaller filtered sodium load, the increase in fractional sodium excretion was significantly greater after three weeks of pacing (from 0.5(0.2) to 3.7(0.7)%) than after one week of tachycardia (from 0.1(0. 0) to 2.0(0.3)%). By contrast, SQ 28,603 (100 mumol.kg-1) did not affe ct renal, haemodynamic, or hormonal variables in normal conscious dogs where baseline atrial natriuretic peptide (18(3) fmol.ml-1) was lower than in the paced animals (104(10) fmol.ml-1). Conclusions: Inhibitio n of neutral endopeptidase in dogs with pacing induced heart failure p rotected endogenous atrial natriuretic peptide from degradation and st imulated sustained natriuresis, presumably via a tubular mechanism.