application) This application is a request for funds to continue studies on the role of adenine nucleotides and nucleosides, especially ATP, in sympathetic neuroeffector processes. During recent years there has been a steadily increasing body of evidence indicating that ATP plays an important role in sympathetic neurotransmission with norepinephrine (NE). Based partially on an analogy with adrenal chromaffin cells, it is a common view that ATP and NE are stored and released in parallel from postganglionic sympathetic axons. However, recent work in the PI's laboratory indicates that release of these cotransmitters is temporally distinct. The first specific aim derives from these observations and examines the hypothesis that the differential release of the sympathetic nerve cotransmitters ATP and NE is coupled to calcium entry through two different channels. An extension of this hypothesis is that there may be subtypes of prejunctional alpha2-adrenoceptors that influence calcium entry via different calcium channels and thereby differentially influence the release of the cotransmitters. These studies will involve experiments to determine the time-course of the release of the transmitters in response to sympathetic nerve stimulation in several vascular and nonvascular neuroeffector preparations as well as with PC12 cells and to evaluate the effects on cotransmitter release of calcium channel antagonists and drugs that act on prejunctional modulatory receptors. The second specific aim of this proposal is directed at a better understanding of how transmitter ATP is inactivated. Preliminary studies indicate that the metabolism of extracellular ATP is markedly accelerated when the nerves are stimulated. This observation will be pursued by examining the hypothesis that the metabolism of ATP occurs via the action of an enzyme system whose activity is linked to nerve stimulations. Additional preliminary evidence that there is an ATPase (activity) that is released extracellularly upon nerve stimulation will be pursued by attempting to characterize the substance that exhibits this ATPase activity.
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