There is an increasing appreciation for the importance of """"""""post- receptor"""""""" mediators of functional response to Ang II in systemic and renal vasculature. Marked potentiation in vasoconstriction accompanies modest increments in circulating Ang II which eventually leads to hypertension and enhanced vasoconstriction to other agents as well as Ang II. Recent studies from this laboratory revealed increased Ang II binding to smooth muscle and glomerulus that was not sufficient to account for enhanced contraction observed. An evaluation of pro-contractile modulators revealed enhanced Ang II-induced decrements in cAMP and increased phospholipase C activity. More importantly, there were alterations in prostaglandin-induced adenylate cyclase activity, in support of generalized dysfunction of receptor- effector coupling. G-proteins or guanine nucleotide binding proteins are coupling proteins that link the receptor to intracellular messengers. G-proteins can alter binding as well as intracellular mediators of signal transduction. These recent observations support the hypothesis that on abnormality in G- proteins may be responsible for altered systemic and renal vascular reactivity that can not be attributed solely to changes in Ang II binding. The hypothesis will be tested by 1) evaluating the influence of pharmacologic modulators of G proteins function on binding, intracellular mediators and contraction; 2) quantitating G proteins by SDS/PAGE employing immunotransfer blotting and specific antisera to subunits of G proteins; and 3) reconstructing the environment, in vitro, employing smooth muscle and mesangial cells in tissue culture and various vasoactive agents. These studies will compare vascular smooth muscle and glomeruli from control rats and after subpressor Ang II infusion, sodium and potassium depletion, all examples of discordance of binding and contractile responses. These studies have the potential for expanding our knowledge about post-binding modulators of vasoactive agents. They may provide significant insight into mechanisms of Ang II-induced hypertension and other alterations of vasoreactivity.

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National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Case Western Reserve University
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