Methods for analyzing and interpreting cooperativity in dose-response curves--I. Antagonist effects on angiotensin...

1. Dose-response curves for angiotensins II and III in the rat isolated uterus, portal vein and aorta, in the absence and presence of the antagonist [Sar1Ile8]ANG II, have been analyzed by methods which detect cooperativity. 2. Hanes-Woolf transformations of dose-response data were used to define phases of positive homotropic cooperativity, and this information was applied to the interpretation of Hill plots. 3. The level of positive cooperativity was found to be higher for ANG II (nH = 1.35-2.00) than ANG III (nH = 1.02-1.43) in the three tissues studied. 4. In the presence of the antagonist [Sar1Ile8]ANG II a decrease in the level of cooperativity produced by both agonists was observed, and high concentrations of the antagonist could induce negative cooperativity. 5. These findings have been interpreted on the basis of a 2-site agonist binding mechanism involving receptor dimers, in which angiotensin agonists induce an increase in their own receptor binding affinity, whereas the antagonist [Sar1Ile8]ANG II decreases the affinity of angiotensin receptors for ANG II and ANG III.