Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277.

1. The pharmacological profile of BIBR 277, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl ]- [1,1'-biphenyl]-2-carboxylic acid, a novel, nonpeptide angiotensin II receptor antagonist has been investigated by use of receptor binding studies, enzymatic assays, functional in vitro assays in rabbit aorta as well as in vivo experiments in pithed, anaesthetized and conscious rats. 2. BIBR 277 potently interacted with rat AT1 receptors (Ki 3.7 nM). Competitive receptor interaction was shown by radioligand saturation experiments performed in the presence of BIBR 277. The failure to inhibit radioligand binding to AT2 sites demonstrates the selectivity of BIBR 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investigated nor affected the activity of components of the human renin-angiotensin system, such as plasma renin or serum converting enzyme. 3. In rabbit aorta, BIBR 277 had no agonistic properties and was shown to be an insurmountable antagonist of angiotensin II-induced contractions (KB 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 when BIBR 277 (0.1 microM) and the surmountable antagonist, losartan (0.1 and 1.0 microM) were incubated simultaneously. The specificity of BIBR 277 for the AT1 receptor was further substantiated in this preparation since micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline-induced contractions nor acetylcholine-mediated 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 microg kg-1 (control)and 1.4 microg kg-1, 4.7 microg kg-1 and 20 microg kg-1, respectively. As observed in the in vitro experiments no agonistic effect was detected and the maximum of the blood pressure response to angiotensin II at the highest dose of BIBR 277 was decreased by 29%.5. In 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. injections of angiotensin 11 (0.1 microg kg-1). At the highest dose an almost complete blockade was observed even after 2 h.6. Single oral administration of BIBR 277 (0.3 and 1.0 mg kg-1) to conscious, chronically instrumented renovascular hypertensive rats dose-dependently decreased the mean arterial blood pressure by 15 and 30 mmHg, respectively. At the higher dose a significant antihypertensive effect was maintained for more than 24 h. Moreover, consecutive daily dosing of 1 mg kg-1 orally resulted in a sustained reduction in blood pressure over the 4 day observation period.7. It is concluded that BIBR 277 is an effective and selective angiotensin II antagonist with antihypertensive activity after oral administration.