This study will examine the function of prejunctional alpha- and beta-adrenoceptors after chronic (sustained or intermittent) elevation of plasma epinephrine (EPI) or norepinephrine (NE) concentrations. We hypothesize that these conditions may change neurotransmitter pools in sympathetic nerves and produce desensitization of prejunctional alpha- and beta-adrenoceptors resulting in significantly altered prejunctional modulation of neurotransmission. Elevation of plasma catecholamine concentrations will be achieved by: 1) administration of NE or EPI via osmotic minipumps at rates which will produce plasma concentrations of 2-40 nM; 2) restraint stress; 3) myocardial infarction; 4) pheochromacytoma. In each of these conditions, stimulus-induced release of neurotransmitter from the isolated perfused rat kidney, heart, and mesenteric vasculature and the influence of prejunctional alpha- and beta-adrenoceptors will be studied in control and treated rats. The experiments will examine how elevation of plasma catecholamine concentration by these conditions has affected: 1) the nature and amount of neurotransmitter in the sympathetic nerve terminals in the selected tissues; 2) the nature and amount of neurotransmitter released from these tissues upon nerve stimulation; 3) the influence of uptake 1 and 2 on neurotransmitter overflow in these tissues; 4) the influence of endogenous neurotransmitter on prejunctional alpha- and beta-adrenoceptors in these tissues; 5) the responsiveness of prejunctional alpha- and beta-adrenoceptor in these tissues to preferential agonists; and 6) the relationship between tissues with regard to the above mentional parameters. Through these studies we will by pharmacological methods characterize the plasma concentrations and durations of exposure required to alter prejunctional adrenoceptor modulation of sympathetic neurotransmission, learn more about the functional interrelationship of prejunctional alpha- and beta-adrenoceptors as well as begin to examine the possible role of these alterations in the pathophysiology of hypertension, MI, stress, and pheochromacytoma.
