During recent years there has been increasing interest in the possibility that adensoine and adenine nucleotides play a role in adrenergic neurotransmission as cotransmitters with norepinephrine (NE) and/or as modulators of the release of transmitter. The overall objective of this proposal is to define in a comprehensive manner the role of ATP and adenosine in vascular neuroeffector processes. Studies will evaluate the nerve-stimulation induced release of endogenous ATP and related purines (ADP,AMP and adenosine) using HPLC-fluorescent detection, with particular attention to defining the sites from which purines are released (e.g., nerve, muscle, endothelium). The pharmacological effects of ATP and related purines will be evaluated, and compared to neurogenically-induced responses, at several levels of blood vessel organization. These include in vitro blood vessel contractility, vascular smooth muscle membrane potential and biochemically including calcium influx, adenylate cyclase-cAMP and phosphatidylinositol metabolism. These latter studies are designed to seek information about potential second messengers for the purine effects. In addition the modulator effects of purines on the release of NE (measured by HPLC-electrochemical detection) at the vascular neuroeffector junction will be studied with particular emphasis on defining pharmacologically the receptors for purines on sympathetic nerves that mediate an inhibition of NE-release. This will be accomplished by comparing the relative order of potency of a series of adenyl purines, their susceptibility to antagonism by purine-receptor antagonists and manipulation of the pathways for purine metabolism. There is evidence that the ability of purines to reduce NE-release is attenuated in blood vessels from hypertensive rats. This suggests that the loss of this modulatory process may contribute to enhanced sympathetic vasoconstriction. Evidence will be sought to confirm this notion and further determine whether the loss of this prejunctional process extends to sympathetic nerves innervating the heart and other peripheral organs.
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