Nonpeptide angiotensin II receptor antagonists: insurmountable angiotensin II antagonism of EXP3892 is reversed by the surmountable antagonist DuP 753

Effects of 2-n-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole, potassium salt (DuP 753), a surmountable angiotensin II (AII) receptor antagonist, on the insurmountable AII antagonism induced by 2-n-propyl-4-trifluoromethyl-1-(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxylic acid (EXP3892) were examined. In the rabbit aorta, EXP3892 exhibited selective and insurmountable AII antagonism. DuP 753 at 10(-6) M, added before or after EXP3892, reversed partially the depressed AII maximal response caused by 10(-9) M EXP3892. Repeated washing of the rabbit aorta created with DuP 753 at 10(-6) M or EXP3892 at 10(-9) M did not restore completely the sensitivity to AII for at least 2 hr. In the pithed rat, EXP3892 showed selective and insurmountable AII antagonism. DuP 753 at 0.1 to 3 mg/kg i.v., given before or after EXP3892, reversed the reduced AII-maximal response induced by EXP3892 at 0.1 mg/kg i.v. We propose that DuP 753 by binding to the AII receptor induces conformational changes resulting in a reduction of the affinity of the receptor for coupling factors/transducer proteins, which causes surmountable antagonism. EXP3892 would diminish the binding capacity for coupling factors accounting for insurmountable antagonism. As DuP 753 and EXP3892 compete for the same AII receptor, the reduced AII-maximal response by EXP3892 may be reversed by DuP 753.