ANTIHYPERTENSIVE EFFECTS OF A HIGHLY POTENT AND LONG-ACTING ANGIOTENSIN-II SUBTYPE-1 RECEPTOR ANTAGONIST, (+ -)-1-(CYCLOHEXYLOXYCARBONYLOXY)ETHYL Y-1-[[2'-(1H-TETRAZOL-5-YL)BIPHENYL-4-YL]METHYL]-1 H-BENZIMIDAZOLE-7-CARBOXYLATE (TCV-116), IN VARIOUS HYPERTENSIVE RATS/

The antihypertensive effects of (+/-)-(cyclohexyloxycarbonyloxy)ethyl phenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116), an angio tensin II (All) subtype-1 receptor antagonist, were studied in various hypertensive and normotensive rats, using 2-n-butyl-4-chloro-5-hydrox ymethyl-1- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassiu m salt (losartan) as a reference compound. TCV-116 is a prodrug, which is converted in vivo to the active component, 2-ethoxy-1-[[2'-(1H-tet razol-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 10 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 C V-11974 reduced the blood pressure with an ED(25) of 0.0027 mg/kg. Rep eated 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 corre lated well with the inhibition of angiotensin II-induced contractile r esponses of aortic strips prepared ex vivo after p.o. administration o f TCV-116. Oral TCV-116 had a sustained antihypertensive effect with E D(25) Of 0.03 and 0.23 mg/kg in two-kidney, one-clip and one-kidney, o ne-clip hypertensive rats, respectively, and was much more potent in S HR and renal-hypertensive rats than losartan. Neither TCV-116 nor losa rtan reduced the blood pressure in deoxycorticosterone acetate/salt hy pertensive rats and high doses of TCV-116 (10-100 mg/kg) reduced the b lood pressure slightly (by about 10 mm Hg) in normotensive rats. These results indicate that the antihypertensive effect of TCV- 116 is clos ely related to the activity of the renin-angiotensin system in SHR and renal-hypertensive rats and may be mediated by antagonism of angioten sin II subtype-1 receptors.