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 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine), were determined in an experimental model of heart failure.


METHODS
The symptoms of heart failure were induced by rapid ventricular pacing for one or three weeks in dogs with surgically implanted catheters for measurement 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 responses in dogs paced for three weeks although baseline glomerular filtration rate was reduced. Because the natriuresis was maintained despite 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 affect 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
Inhibition of neutral endopeptidase in dogs with pacing induced heart failure protected endogenous atrial natriuretic peptide from degradation and stimulated sustained natriuresis, presumably via a tubular mechanism.
Seymour
A A
AA
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
Asaad
M M
MM
Lanoce
V M
VM
Fennell
S A
SA
Cheung
H S
HS
Rogers
W L
WL
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002304:Cardiac Pacing, Artificial; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D014556:Urine
D011480:Protease Inhibitors; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine