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Antihypertensive effects of a highly potent and long-acting angiotensin II subtype-1 receptor antagonist, -1- ethyl 2-ethoxy-1- bipenyl-4-yl-methyl-1H-benzimidazole-7-carboxylate



Antihypertensive effects of a highly potent and long-acting angiotensin II subtype-1 receptor antagonist, -1- ethyl 2-ethoxy-1- bipenyl-4-yl-methyl-1H-benzimidazole-7-carboxylate



Journal of Pharmacology & Experimental Therapeutics 268(3): 1540-1547



The antihypertensive effects of (+-)-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)1H-benzimidazole-7-carboxylate (TCV-116), an angiotensin II (AII) subtype-1 receptor antagonist, were studied in various hypertensive and normotensive rats, using 2-n-butyl-4-chloro-5-hydroxymethyl-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole, potassium salt (losartan) as a reference compound. TCV-1 16 is a prodrug, which is converted in vivo to the active component, 2-ethoxy-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)) methyl)-1H-benzimidazole-7-carboxylic acid (CV-11974). In spontaneously hypertensive rats (SHR) p.o. TCV-116 (0.1 mg/ kg) demonstrated a sustained antihypertensive effect that lasted for more than 1 0 hr and the dose that reduced the blood pressure by an average of 25 mm Hg for 24 hr (ED-25), was 0.68 mg/kg. Intravenous CV-11974 reduced the blood pressure with an ED-25 of 0.0027 mg/kg. Repeated p.o. administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced the blood pressure by 30 to 50 mm Hg over 24 hr without any heart rate changes. The antihypertensive effects of TCV-116 correlated well with the inhibition of angiotensin II-induced contractile responses of aortic strips prepared ex vivo after p.o. administration of TCV-116. Oral TCV-116 had a sustained antihypertensive effect with ED-25 of 0.03 and 0.23 mg/kg in two-kidney, one-clip and one-kidney, one-clip hypertensive rats, respectively, and was much more potent in SHR and renal-hypertensive rats than losartan. Neither TCV-116 nor losartan reduced the blood pressure in deoxycorticosterone acetate/salt hypertensive rats and high doses of TCV-116 (10-100 mg/kg) reduced the blood pressure slightly (by about 10 mm Hg) in normotensive rats. These results indicate that the antihypertensive effect of TCV. 116 is closely related to the activity of the renin-angiotensin system in SHR and renal-hypertensive rats and may be mediated by antagonism of angiotensin II subtype-1 receptors.

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Accession: 030121779

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Antihypertensive effects of a highly potent and long-acting angiotensin II subtype-1 receptor antagonist, (+-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), in various hypertensive rats. Journal of Pharmacology and Experimental Therapeutics 268(3): 1540-1547, 1994

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