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

Using nitrendipine to block the smooth muscle contractile effects of angiotensin II, it has been shown that the agonist produces a dose-related inhibitory effect on the electrically stimulated, longitudinal smooth muscle, myenteric plexus preparation from the guinea-pig. In the absence of stimulation, there is no detectable direct relaxant effect of angiotensin II on the preparation, even when it is partially contracted with carbachol, leading to the conclusion that the inhibitory effects of angiotensin are mediated via prejunctional receptors on the neuron. A number of angiotensin antagonists, including DUP753, saralasin, SKBI08566 and several nonpeptide antagonists synthesized at ZENECA, have been investigated vs (1) the inhibitory effects of angiotensin II and (2) the direct contractile effects produced in unstimulated tissues in the absence of nitrendipine. A correlation curve comparing the results from the two sets of experiments gave a slope of 1.05 and a correlation coefficient of 0.99, providing very strong evidence that the two receptor systems are pharmacologically identical. The antagonists were further evaluated vs angiotensin II in the rat fundic strip in order to (1) determine whether there was any species variation in the receptor systems and (2) provide an example of a smooth muscle preparation uncomplicated by indirect effects of transmitters released by angiotensin, as has been reported in the guinea-pig ileum. An excellent correlation was obtained between the K(e) values in the fundus and the guinea-pig ileum, indicating no difference in receptors between species or between neurons and smooth muscle.