Antihypertensive activity of the non-peptide angiotensin II receptor antagonist, SK&F 108566, in rats and dogs.
The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophene propanoic acid), was examined in rats and dogs. SK&F 108566 produced dose-dependent decreases in blood pressure in renin-dependent hypertensive rats. At 10 mg/kg intraduodenally, mean arterial blood pressure fell from between 150-160 mm Hg to approximately 124 mm Hg. A sustained infusion of SK&F 108566 at 25 micrograms/min intraduodenally normalized blood pressure during 3 days of infusion and for 18 h following cessation of the infusion. Evaluation of the systemic hemodynamic effects of SK&F 108566 in chronically instrumented renin-dependent hypertensive rats demonstrated that the antihypertensive effects of SK&F 108566 were accompanied by a significant increase in cardiac output with little change in stroke volume. In dogs made acutely hypertensive by an intravenous infusion of angiotensin I, SK&F 108566 resulted in dose-dependent decreases in blood pressure. The antihypertensive activity of SK&F 108566 at 10 mg/kg p.o. was maintained for between 13-15 h, a similar duration of action as observed with enalapril (1 mg/kg, p.o.). Administration of DuP 753 (losartan) intravenously caused a small and short-lived fall in blood pressure in the angiotensin I-infused hypertensive dog. However, the active metabolite of losartan, EXP 3174, resulted in a response of longer duration. In dogs made hypertensive by placement of an ameroid constrictor on the left renal artery, SK&F 108566 (10 mg/kg, p.o.) or enalapril (1 mg/kg, p.o.) resulted in antihypertensive responses of at least 12 h duration. The data indicate that SK&F 108566 is a long-acting antihypertensive agent in the rat and dog.
Brooks
D P
DP
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Fredrickson
T A
TA
Weinstock
J
J
Ruffolo
R R
RR
Edwards
R M
RM
Gellai
M
M
D000179:Acrylates / Q000494:pharmacology*; D000803:Angiotensin I / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D013876:Thiophenes; C068373:eprosartan; D000803:Angiotensin I; C066026:losartan carboxylic acid; D019808:Losartan