ATRIAL NATRIURETIC FACTOR POTENTIATING AND ANTIHYPERTENSIVE ACTIVITY OF SCH-34826 - AN ORALLY ACTIVE NEUTRAL METALLOENDOPEPTIDASE INHIBITOR

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103-125) or -(99-126) and on blood pressure were evaluated in rats. SCH 34826 (10, 30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 μg/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 μg/kg i.v.) as well as the plasma levels achieved after peptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (-35±12 mm Hg), 10 mg/kg p.o. (-30±7 mm Hg), and 90 mg/kg p.o. (-45±6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78±0.6 vs. 1.27±0.3 ml/100 g/3 hr in vehicle-control rats, p<0.05). SCH 34826 (90 mg/kg s.c.) increased plasma levels of atrial natriuretic factor at 1 hour (753±89 vs. 451±79 pg/ml in vehicle-treated rats, p<0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092±1,089 vs. 21±6 pg/100 g/3 hr in vehicle-treated rats, p<0.05) and cyclic guanosine monophosphate (2,121±509 vs. 879±168 pg/1003 hr in vehicle-treated rats, p<0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.