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 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.
Sybertz
E J
EJ
Schering Plough Research, Department of Pharmacology, Bloomfield, New Jersey 07003.
Chiu
P J
PJ
Vemulapalli
S
S
Watkins
R
R
Haslanger
M F
MF
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D004148:Dioxolanes; D004149:Dioxoles; D004151:Dipeptides; C056319:Sch 34826; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP