In isolated rat islets the alpha 2-adrenergic antagonist phenoxybenzamine was found to be only partially effective at relieving the inhibition of glucose-induced insulin secretion mediated by noradrenaline. Further experiments revealed a direct inhibitory effect of phenoxybenzamine itself on the secretory response to glucose. At concentrations above 1 microM the antagonist inhibited insulin secretion in a dose-dependent manner, with greater than 50% inhibition at 50 microM. The inhibition of secretion developed rapidly in perifused islets, and was not altered when islets were also incubated with idazoxan or benextramine, suggesting that it did not reflect binding of phenoxybenzamine to the alpha 2-receptor. Paradoxically phenoxybenzamine significantly increased the basal secretion rate in the presence of 4 mM glucose. The results demonstrate that phenoxybenzamine can exert direct effects on insulin secretion which are unrelated to its alpha-antagonist properties.