Analysis of the inhibitory effects of DuP 753 and EXP 3174 on responses to angiotensin II in the feline hindquarters vascular bed

The effects of DuP 753 and EXP 3174, nonpeptide angiotensin II type 1 antagonists, on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Responses to the peptide were stable with respect to time, did not exhibit tachyphylaxis, and 2-n-butyl-4- chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]methyl]imidazole (DuP 753) in doses of 1 and 2.5 mg/kg decreased vasoconstrictor responses to angiotensin II in a competitive manner, with a longer duration of action at the higher dose. DuP 753 had no significant effect on vasoconstrictor responses to vasopressin, norepinephrine, neuropeptide Y or 11α,6α-epoxymethano-9α,11α-dideoxy-prostaglandin F(2α), on biphasic responses to endothelin-1, or on vasodilator responses to acetylcholine. 2-n-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]imidazole-5-carboxylic acid (EXP 3174) also decreased responses to angiotensin II without altering responses to norepinephrine, vasopressin, U46619 or endothelin-1. The inhibitory effect of EXP 3174 was surmountable; however, large doses of angiotensin II were required, and the blockade was long in duration. The effects of DuP 753 and EXP 3174 on responses to angiotensin II and angiotensin III were similar, and when EXP 3174 was administered in doses of 0.1 and 0.05 mg/kg i.v., the blockade was overcome and the dose-response curves for angiotensin II were shifted to the right in a parallel manner. When the inhibitory effects of DuP 753 were monitored at short time intervals, a biphasic pattern of inhibition of the response to angiotensin II was not observed. These results suggest that DuP 753 and EXP 3174 are potent selective angiotensin II receptor antagonists with little agonistic activity in the hindquarters vascular bed of the cat, and that DuP 753 is not metabolized to a more active compound in the cat.