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 micrograms/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 micrograms/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 less than 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 less than 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 less than 0.05) and cyclic
guanosine monophosphate (2,131 +/- 509 vs. 879 +/- 168 pg/100 g/3 hr in vehicle-treated rats, p less than 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.