Atrial Natriuretic Factor-Potentiating and Antihypertensive Activity of SCH 34826: An Orally Active Neutral Metalloendopeptidase Inhibitor

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 1990-02, Vol.15 (2), p.152-161
• Main Authors: Sybertz, Edmund J, Chiu, Peter J.S, Vemulapalli, Subbarao, Watkins, Robert, Haslanger, Martin F
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Atrial Natriuretic Factor - metabolism; Atrial Natriuretic Factor - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Cyclic GMP - metabolism; Dioxolanes - pharmacology; Dioxoles - pharmacology; Dipeptides - pharmacology; Drug Synergism; Hemodynamics - drug effects; Hypertension - physiopathology; Kidney - drug effects; Male; Medical sciences; Neprilysin - antagonists & inhibitors; Pharmacology. Drug treatments; Rats; Rats, Inbred SHR
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.hyp.15.2.152

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 /tg/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 /tg/kg i.v.) as well as the plasma levels achieved after pcptide 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. l27±03 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 (2,131 ±509 vs. 879±168 pg/100 g/3 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.