The process by which adenosine receptor agonists inhibit the evoked release of acetylcholine (ACh) was studied at motor nerve endings to frog skeletal muscle. Adenosine and 2‐chloroadenosine were employed as agonists. Each agonist reduced the mean number of ACh packets released synchronously in response to a nerve impulse (m). Adenosine was from one to two orders of magnitude less potent than 2‐chloroadenosine as an inhibitor of this release. Focally recorded nerve terminal action potentials were unaffected by either adenosine receptor agonist. In normal Ca (1.8 mM), addition of sufficient Mg to reduce m to less than half the control value did not alter the degree of inhibition produced by adenosine receptor agonists. ACh release evoked by methods that do not require Ca entry through Ca channels (Ca‐containing liposomes, La) was inhibited by either 2‐chloroadenosine or adenosine. In Ca‐free solutions containing Ba, the magnitude of neurally evoked asynchronous ACh release (miniature end‐plate potential frequency = m.e.p.p.f) was depressed by either adenosine receptor agonist without change in the rate constant of decay of m.e.p.p.f; the m.e.p.p.f decay is thought to reflect the rate of clearance of Ba from regions of ACh release. Agents which displace Ca from storage sites and also inhibit phosphodiesterases increased m.e.p.p.f in the virtual absence of extracellular Ca and increased the level of inhibition produced by adenosine receptor agonists. RMI 12,330A (7 X 10(‐6) to 7 X 10(‐5) M), an adenylate cyclase inhibitor, occluded the effects of adenosine receptor agonists on ACh release. The results are consistent with the hypothesis that activation of extracellular adenosine receptors on adenylate cyclase inhibits evoked ACh release by reducing the affinity for Ca of an intracellular component of the secretory apparatus.
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