This application is a request for funds to continue studies on the role of adenine nucleotides and adenosine in vascular neuroeffector processes. During recent years there has been a steadily increasing body of evidence indicating that ATP plays a role in sympathetic neurotransmission as a cotransmitter with norepinephrine and as an inhibitory modulator of the nerve stimulation evoked release of transmitter. The neuromodulatory effect may be produced via a prejunctional receptor with which both ATP and adenosine interact. An additional aspect of the potential role of adenine nucleotides and adenosine at the sympathetic vascular neuroeffector junction is that nerves are not the only source of extracellular purines. Endothelial cells appear to be a quantatively important source of ATP and related compounds. The experiments proposed in this application are aimed at gaining a comprehensive understanding of the prejunctional actions of these substances. Thus the hypothesis will be examined that prejunctional purinoceptors on sympathetic nerves represent a class of receptors (p3) that is pharmacologically distinct from known P1 (adenosine) or P2 (ATP) receptors. Experiments are designed not only to define the receptors pharmacologically, but to determine whether these receptors play a physiological role in modulating sympathetic neurotransmitter release and whether under pathological conditions (i.e., hypertension) the modulatory effect is altered. The source of the adenine nucleotides and nucleosides which act on the prejunctional receptors will be probed with a particular emphasis on the role of endothelial cells in this phenomenon. Finally, the mechanisms by which purines act to reduce release of transmitter will also be examined. For these latter studies cell culture models of neurosecretion will be employed including adrenal medullary chromaffin cells and sympathetic neurons with the goal that specific biophysical or biochemical mechanisms of purine action will be identified. Such information is important to the overall understanding of the sympathetic regulation of blood vessel function.
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