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PH Bauer, AT Chiu and JC Garrison
Department of Pharmacology, University of Virginia, Charlottesville 22908.
Results obtained with the use of nonpeptide angiotensin II receptor antagonists have suggested the presence of multiple subtypes of angiotensin II receptors in rat adrenal gland. However, the effects of nonpeptide antagonists on second messenger production by angiotensin II have not been investigated. In rat liver, angiotensin II can both activate phospholipase C, generating inositol polyphosphates and raising internal calcium, and inhibit adenylate cyclase. DuP 753 and PD123177, two nonpeptide angiotensin II antagonists, were used to characterize the receptor population in rat liver and to investigate the possibility that different angiotensin II receptor subtypes couple to different second messenger pathways. DuP 753 could completely antagonize the binding of angiotensin II in rat liver membranes, with a K1 of 9.3 x 10(-9) M. PD123177 had no effect on the binding of angiotensin II in rat liver at concentrations between 1 x 10(-9) M and 3 x 10(-5) M, in contrast to its ability to inhibit angiotensin II binding in rat adrenal. At a concentration of 10(-5) M, DuP 753 could inhibit increases in internal free calcium, could prevent production of inositol polyphosphates, and could attenuate inhibition of adenylate cyclase produced by angiotensin II. PD123177 at concentrations between 1 x 10(-9) M and 3 x 10(-5) M was ineffective in all of these assays. The results indicate that DuP 753 can displace the binding of angiotensin II at all receptor sites in rat liver and that this drug can attenuate both of the second messenger events produced by the angiotensin II receptor.
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