DISCOVERY AND CHARACTERIZATION OF AN INHIBITORY ANGIOTENSIN RECEPTOR IN THE GUINEA-PIG ILEUM

Using nitrendipine to block the smooth muscle contractile effects of a ngiotensin II, it has been shown that the agonist produces a dose-rela ted inhibitory effect on the electrically stimulated, longitudinal smo oth muscle, myenteric plexus preparation from the guinea-pig. In the a bsence of stimulation, there is no detectable direct relaxant effect o f angiotensin II on the preparation, even when it is partially contrac ted with carbachol, leading to the conclusion that the inhibitory effe cts of angiotensin are mediated via prejunctional receptors on the neu ron. A number of angiotensin antagonists, including DUP753, saralasin, SKBI08566 and several nonpeptide antagonists synthesized at ZENECA, h ave been investigated vs (1) the inhibitory effects of angiotensin II and (2) the direct contractile effects produced in unstimulated tissue s in the absence of nitrendipine. A correlation curve comparing the re sults from the two sets of experiments gave a slope of 1.05 and a corr elation coefficient of 0.99, providing very strong evidence that the t wo receptor systems are pharmacologically identical. The antagonists w ere further evaluated vs angiotensin II in the rat fundic strip in ord er to (1) determine whether there was any species variation in the rec eptor systems and (2) provide an example of a smooth muscle preparatio n uncomplicated by indirect effects of transmitters released by angiot ensin, as has been reported in the guinea-pig ileum. An excellent corr elation was obtained between the K(e) values in the fundus and the gui nea-pig ileum, indicating no difference in receptors between species o r between neurons and smooth muscle.