The general objective is to elucidate the mechanisms by which local factors influence transmission at adrenergic synapses. Specific investigations will be concerned with (1) characteristics of the inhibitory presynaptic adrenergic and cholinergic receptors on adrenergic nerve terminals, and the mechanisms by which stimulation of these receptors modulates release of the neurotransmitter, norepinephrine; (2) the influx of calcium ions into the adrenergic nerve terminals associated with nerve stimulation and the subsequent release of norepinephrine, and the influence on this influx of frequency of stimulation and of drugs and agents which inhibit or potentiate norepinephrine release; (3) role of intracellular calcium in norepinephrine release; (4) mechanism of action of neuronal blocking agents such as guanethidine and bretylium; (5) the physiological reuse for exocytosis of catecholamine storage vesicles in adrenergic nerve terminals and in the adrenal medulla after they have undergone initial exocytosis. Most experiments will be carried out on perfused organs and isolated organs and tissues, some with sympathetic nerves attached and available for stimulation. Physiological, pharmacological, and biochemical approaches will be employed. Use will be made of radioactive-labeled compounds when appropriate.
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