PHARMACOLOGICAL CHARACTERIZATION OF THE NOVEL NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST, BIBR-277

1 The pharmacological profile of BIBR 277, idazol]-1'-yl)methyl]-[1,1' -biphenyl]-2-carboxylic acid, a novel, nonpeptide angiotensin II recep tor antagonist has been investigated by use of receptor binding studie s, enzymatic assays, functional in vitro assays in rabbit aorta as wel l as in vivo experiments in pithed, anaesthetized and conscious rats. 2 BIBR 277 potently interacted with rat AT1 receptors (K(i) 3.7 nm). C ompetitive receptor interaction was shown by radioligand saturation ex periments performed in the presence of BIBR 277. The failure to inhibi t radioligand binding to AT2 sites demonstrates the selectivity of BIB R 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investig ated nor affected the activity of components of the human renin-angiot ensin system, such as plasma renin or serum converting enzyme. 3 In ra bbit aorta, BIBR 277 had no agonistic properties and was shown to be a n insurmountable antagonist of angiotensin II-induced contractions (K( B) 0.33 nm). The antagonistic effect persisted even after several wash -out procedures. However, this interaction was not irreversible since the insurmountable antagonism was concentration-dependently reversed w hen BIBR 277 (0.1 mum) and the surmountable antagonist, losartan (0.1 and 1.0 mum) were incubated simultaneously. The specificity of BIBR 27 7 for the AT1 receptor was further substantiated in this preparation s ince micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline-induced contractions nor acetylcholine-medi ated tissue relaxation. 4 In pithed rats, i.v. administration of BIBR 277 (0.1, 0.3 and 1.0 mg kg-1) shifted the dose-pressor response curve to angiotensin II dose-dependently to the right with ED50 values of 0 .23 mug kg-1 (control) and 1.4 mug kg-1, 4.7 mug kg-1 and 20 mug kg-1, respectively. As observed in the in vitro experiments no agonistic ef fect was detected and the maximum of the blood pressure response to an giotensin II at the highest dose of BIBR 277 was decreased by 29%. 5 I n anaesthetized rats, bolus i.v. administration of 0.1, 0.3 and 1.0 mg kg-1 BIBR 277 attenuated the blood pressure response to bolus i.v. in jections of angiotensin 11 (0.1 mug kg-1). At the highest dose an almo st complete blockade was observed even after 2 h. 6 Single oral admini stration of BIBR 277 (0.3 and 1.0 mg kg-1) to conscious, chronically i nstrumented renovascular hypertensive rats dose-dependently decreased the mean arterial blood pressure by 15 and 30 mmHg, respectively. At t he higher dose a significant antihypertensive effect was maintained fo r more than 24 h. Moreover, consecutive daily dosing of 1 mg kg-1 oral ly resulted in a sustained reduction in blood pressure over the 4 day observation period. 7 It is concluded that BIBR 277 is an effective an d selective angiotensin 11 antagonist with antihypertensive activity a fter oral administration.