EFFECTS OF IRBESARTAN (SR 47436 BMS-186295) ON ANGIOTENSIN-II-INDUCEDPRESSOR-RESPONSES IN THE PITHED RAT - POTENTIAL MECHANISMS OF ACTION/

The effects of two new non-peptide angiotensin receptor antagonists, i rbesartan (SR 47436/BMS-186295, (2-n-butyl-4-spiro-cyclopentane-1 azol -5-yl)biphenyl-4-yl)methyl]2-imidazolin-5-one) and SR 47155A -carboxy) biphenyl-4-yl)methyl]-2-imidazolin-5-one, trifluoroacetate), on angiot ensin II-induced presser responses were studied in the pithed rat in c omparison to losartan, EXP 3174 and [Sar(1),Val(5),Ala(8)]angiotensin II. SR 47155A (1-10 mg/kg i.v.) and losartan (1-10 mg/kg i.v.) shifted dose dependently the dose-response curve of angiotensin II to the rig ht without affecting the maximal response. SR 47436 (0.3-10 mg/kg i.v. ), EXP 3174 (0.03-1 mg/kg i.v.) and [Sar(1),Val(5),Ala(8)]angiotensin II (0.03-1 mg/kg i.v.) induced, at least at high doses, a non-parallel shift to the right of the angiotensin II dose-response curve and this was associated with a reduction of the maximal response. During a 70 min period, the effect of [Sar(1),Val(5),Ala(8)]angiotensin II (1 mg/k g i.v.) on the angiotensin II (0.3 mu g/kg i.v.)-induced presser respo nse was shown to be reversible, the effect of SR 47155A (10 mg/kg i.v, ) was partially reversible and the effect of SR 47436 (3 mg/kg i.v.), EXP 3174 (1 mg/kg i.v.) or losartan (6 mg/kg i.v.) was not reversed at the end of this 70 min period. Administration of SR 47155A (10 mg/kg i.v.) before SR 47436 (1-10 mg/kg i.v.) reversed the reduced angiotens in II-maximal response induced by SR 47436. Administration of SR 47436 (10 mg/kg i.v.) before SR 47155A (1-10 mg/kg i.v.) prevented the full development of the presser response as observed in the absence of SR 47436. In the pithed rat, SR 47436 (30 mg/kg i.v.) and losartan (30 mg /kg i.v.) reduced the change in diastolic blood pressure induced by el ectrical stimulation of the spinal cord only at low stimulation rates. Taken together these results indicate that SR 47436, under in vivo co nditions, is a potent non-peptide angiotensin receptor antagonist. The type of antagonism (partially insurmountable but selective) can be ex plained by different theoretical models which are discussed.