SYSTEMIC HEMODYNAMICS, RENAL-FUNCTION AND HORMONAL LEVELS DURING INHIBITION OF NEUTRAL ENDOPEPTIDASE 3.4.24.11 AND ANGIOTENSIN-CONVERTING ENZYME IN CONSCIOUS DOGS WITH PACING-INDUCED HEART-FAILURE

The systemic hemodynamic, renal and hormonal responses to SO 28,603 rc aptomethyl)-1-oxo-3-phenylpropyl]-beta-ala-nine) the selective inhibit or of neutral endopeptidase 3.4.24.11, the angiotensin-converting enzy me inhibitor captopril and their combination were determined in consci ous dogs after 1 or 3 weeks of rapid ventricular pacing. Coadministrat ion of captopril (100 or 10 mumol/kg i.v.) and SQ 28,603 (10 mumol/kg i.v.) significantly reduced mean arterial pressure, systemic vascular resistance and renal vascular resistance and increased cardiac output, stroke volume and renal blood flow in the conscious dogs paced for 1 week. This pattern of hemodynamic improvement was not predicted by the activity of the individual inhibitors. The combination of inhibitors did not significantly increase sodium excretion because of the variabi lity introduced by the depressor activity; however, the pressure-natri uresis curve was steeper and shifted leftward, indicating that sodium excretion was maintained at lower renal perfusion pressures. The incre ases in urinary and plasma levels of cyclic GMP and atrial natriuretic peptide stimulated by SO 28,603 were not affected by captopril. The d ata indicated that the hemodynamic and renal responses produced by SQ 28,603, presumably by elevating atrial natriuretic peptide levels, wer e enhanced by suppression of angiotensin II or that the combination of inhibitors protected other vasodilator/natriuretic peptides from degr adation. Qualitatively similar responses to SQ 28,603, captopril and t he combination of inhibitors were obtained in dogs paced for 3 weeks. In summary, the combined angiotensin-converting enzyme and neutral end opeptidase 3.4.24.11 inhibitors improved systemic hemodynamics and mai ntained renal function in conscious dogs with pacing-induced heart fai lure.