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 SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine) the selective inhibitor of neutral endopeptidase 3.4.24.11, the angiotensin-converting enzyme inhibitor captopril and their combination were determined in conscious dogs after 1 or 3 weeks of rapid ventricular pacing. Coadministration 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 variability introduced by the depressor activity; however, the pressure-natriuresis curve was steeper and shifted leftward, indicating that sodium excretion was maintained at lower renal perfusion pressures. The increases in urinary and plasma levels of cyclic GMP and atrial natriuretic peptide stimulated by SQ 28,603 were not affected by captopril. The data indicated that the hemodynamic and renal responses produced by SQ 28,603, presumably by elevating atrial natriuretic peptide levels, were enhanced by suppression of angiotensin II or that the combination of inhibitors protected other vasodilator/natriuretic peptides from degradation. Qualitatively similar responses to SQ 28,603, captopril and the combination of inhibitors were obtained in dogs paced for 3 weeks. In summary, the combined angiotensin-converting enzyme and neutral endopeptidase 3.4.24.11 inhibitors improved systemic hemodynamics and maintained renal function in conscious dogs with pacing-induced heart failure.
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
A A
AA
Seymour
M M
MM
Asaad
V M
VM
Lanoce
K M
KM
Langenbacher
S A
SA
Fennell
W L
WL
Rogers
D000409:Alanine / Q000031:analogs & derivatives*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002216:Captopril / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D002216:Captopril; D012083:Renin; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine