Atrial natriuretic factor potentiating and hemodynamic effects of SCH 42495, a new, neutral metalloendopeptidase inhibitor.
Neutral metalloendopeptidase (NEP) inhibitors delay atrial natriuretic factor (ANF) catabolism and potentiate biological responses to ANF. We describe biochemical and pharmacological profiles of a novel NEP inhibitor, SCH 42354 (N-[2(S)-(mercaptomethyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine and its orally active ethylester prodrug, SCH 42495. SCH 42354 selectively inhibited hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nmol/L, respectively) in vitro. Plasma levels of exogenous ANF were augmented and ANF clearance from plasma was delayed by oral SCH 42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats were higher in SCH 42495-treated rats. Diuretic and natriuretic effects of ANF were increased in rats treated with SCH 42495. Oral doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reductions in blood pressure in DOCA-Na hypertensive rats of 22 +/- 6, 43 +/- 7, and 62 +/- 12 mm Hg, respectively, which were not associated with increases in heart rate. These doses did not alter urine flow, salt excretion, or plasma ANF. SCH 42495 produced significant elevation of urinary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 42495 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of SCH 42495 significantly decreased cardiac output and did not lower systemic vascular resistance, a profile similar to that of ANF. The hypotensive response to SCH 42495 was not ascribable to ACE inhibition. Pithed rat preparations revealed no interaction of the drug with autonomic cardiovascular function. The antihypertensive effect of SCH 42495 likely results from potentiation of endogenous ANF via NEP inhibition.
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539.
R W
RW
Watkins
S
S
Vemulapalli
P J
PJ
Chiu
C
C
Foster
E M
EM
Smith
B
B
Neustadt
M
M
Haslanger
E J
EJ
Sybertz
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects; D001920:Bradykinin / Q000037:antagonists & inhibitors; D003900:Desoxycorticosterone; D004357:Drug Synergism; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics; D007668:Kidney / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D012965:Sodium Chloride
D000959:Antihypertensive Agents; C086374:CGS 26129; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D009320:Atrial Natriuretic Factor; D008715:Methionine; D008666:Metalloendopeptidases; D001920:Bradykinin