Renin release into the circulation results in the production of several potent biologically active agents, the angiotensins. The most potent of these are angiotensins II and III which differ by the absence of an aspartyl residue on the amino terminus of angiotensin III. The role(s) of these agents in physiological and pathological conditions is unresolved, primarily because specific antagonists and/or receptors have not been identified for either angiotensin II or III. The possibility that the rabbit vas deferens contains such specific receptors is likely, as is detailed in Preliminary Results. The project will test if selective receptors to angiotensin II or III are present in the rabbit vas deferens. The presence of specific angiotensin II or III receptors will be identified by the following: 1) mechanism(s) by which the angiotensins inhibit electrically-induced nonadrenergic contractions; 2) radioligand binding studies; and 3) angiotensin antagonists. Two potential mechanisms are hypothesized for inhibitory effects of the angiotensins and they are that angiotensins: 1) enhance neural release of norepinephrine which depresses nonadrenergic contractions via an adrenergic receptor; and 2) enhance prostaglandin (PG) synthesis which depresses nonadrenergic contractions. The involvement of norepinephrine in mediating angiotensin-induced inhibition of the nonadrenergic contraction or stimulation of PG synthesis will be assessed with adrenergic receptor antagonists, norepinephrine depleting agents and denervation. PGE2 production in response to the angiotensins will be measured by radioimmunoassay. Radioligand binding studies will test if angiotensins II and III bind to identical sites and if the binding is saturable, reversible, specific and proportional to biological activity. Angiotensin receptor antagonists which are suspected of preferentially antagonizing actions of either angiotensin II or III will be tested for specificity in blocking angiotensin II or III effects in the vas deferens. The most significant aspect of this study would be the identification of an angiotensin III-selective receptor in the vas deferens. A long-term beneficial effect of this work is the potential identification of angiotensin-specific antagonists. Such specific antagonists are necessary to evaluate the biological importance of individual angiotensins.
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