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. W e describe biochemical and pharmacological profiles of a novel NEP inh ibitor, SCH 42354 thyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine a nd its orally active ethylester prodrug, SCH 42495. SCH 42354 selectiv ely 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 exp anded rats were higher in SCH 42495-treated rats. Diuretic and natriur etic effects of ANF were increased in rats treated with SCH 42495. Ora l doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reducti ons 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 ex cretion, or plasma ANF. SCH 42495 produced significant elevation of ur inary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 4249 5 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitu de similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral do se 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 inhibi tion. 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 inhi bition.