Summary
The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E) - α - [[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 μg/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 1, 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.
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Brooks, D.P., Fredrickson, T.A., Weinstock, J. et al. Antihypertensive activity of the non-peptide angiotensin II receptor antagonist, SK&F 108566, in rats and dogs. Naunyn-Schmiedeberg's Arch Pharmacol 345, 673–678 (1992). https://doi.org/10.1007/BF00164582
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DOI: https://doi.org/10.1007/BF00164582