ROLE OF THE ALPHA-ADRENOCEPTOR IN REGULATING NORADRENALINE OVERFLOW BY NERVE-STIMULATION (REPRINTED FROM BRIT J PHARMACOL, VOL 44, PG 672-688, 1972)

1. A study of the actions of phenoxybenzamine on transmitter overflow, neuronal and extraneuronal uptake of noradrenaline and in causing alp ha-adrenoceptor blockade was carried out using the isolated cat nictit ating membrane preparation. 2. Phenoxybenzamine increased transmitter overflow elicited by nerve-stimulation at 10 Hz in a concentration dep endent manner in the range 10(-8) to 10(-5) g/ml. 3. Neuronal uptake o f [H-3]-noradrenaline was not inhibited by concentrations lower than 1 0(-6) g/ml of phenoxybenzamine. With 10(-7) g/ml of phenoxybenzamine a significant increase in transmitter overflow was obtained, although n euronal uptake of noradrenaline was not affected. Higher concentration s of phenoxybenzamine (10(-6) and 10(-5) g/ml) inhibited the neuronal uptake of noradrenaline and further increased transmitter overflow. 4. Extraneuronal uptake of [H-3]-noradrenaline was inhibited only with t he highest concentration of phenoxybenzamine tested (10(-5) g/ml) and therefore appears to be unrelated to the effects on transmitter overfl ow. 5. There was a significant correlation between the degree of alpha -adrenoceptor block produced by phenoxybenzamine and the increase in t ransmitter overflow obtained by nerve stimulation. 6. These results in dicate that phenoxybenzamine, in addition to increasing overflow by pr eventing reuptake of noradrenaline, may increase transmitter release. 7. The possibility that phenoxybenzamine acts on alpha-adrenoceptors i n the adrenergic nerve terminal is discussed. These receptors would be involved in a negative feedback mechanism regulating transmitter rele ase.