Role of the α‐adrenoceptor in regulating noradrenaline overflow by nerve stimulation

Summary 1 . A study of the actions of phenoxybenzamine on transmitter overflow, neuronal and extraneuronal uptake of noradrenaline and in causing α‐adrenoceptor blockade was carried out using the isolated cat nictitating membrane preparation. 2 . Phenoxybenzamine increased transmitter overflow elicited by nerve‐stimulation at 10 Hz in a concentration dependent manner in the range 10−8 to 10−5 g/ml. 3 . Neuronal uptake of [3H]‐noradrenaline was not inhibited by concentrations lower than 10−6 g/ml of phenoxybenzamine. With 10−7 g/ml of phenoxybenzamine a significant increase in transmitter overflow was obtained, although neuronal uptake of noradrenaline was not affected. Higher concentrations of phenoxybenzamine (10−6 and 10−5 g/ml) inhibited the neuronal uptake of noradrenaline and further increased transmitter overflow. 4 . Extraneuronal uptake of [3H]‐noradrenaline was inhibited only with the highest concentration of phenoxybenzamine tested (10−5 g/ml) and therefore appears to be unrelated to the effects on transmitter overflow. 5 . There was a significant correlation between the degree of α‐adrenoceptor block produced by phenoxybenzamine and the increase in transmitter overflow obtained by nerve stimulation. 6 . These results indicate that phenoxybenzamine, in addition to increasing overflow by preventing reuptake of noradrenaline, may increase transmitter release. 7 . The possibility that phenoxybenzamine acts on α‐adrenoceptors in the adrenergic nerve terminal is discussed. These receptors would be involved in a negative feedback mechanism regulating transmitter release.