INTERACTION OF PHENOXYBENZAMINE WITH GUANETHIDINE AND BRETYLIUM AT THE SYMPATHETIC NERVE ENDINGS OF THE ISOLATED PERFUSED SPLEEN OF THE CAT

¹ Department of Experimental Medicine, F. Hoffmann-La Roche & Company Ltd., Basle, Switzerland

The interaction of phenoxybenzamine with bretylium and guanethidine on postganglionic sympathetic transmission was studied in the isolated perfused cat spleen. Guanethidine decreased splenic contraction and norepinephrine output resulting from sympathetic stimulation in a dose-dependent manner. In contrast, bretylium, before blocking the liberation of norepinephrine, markedly increased the norepinephrine output after nerve stimulation and led to a corresponding increase in the response of the effector organ. It cannot yet be clearly determined to what extent this initial increase of norepinephrine output is caused by an increase in the amount of norepinephrine liberated (short-lasting facilitation preceding blockade) or by an inhibition of norepinephrine inactivation. Phenoxybenzamine, which itself increased the norepinephrine output, prevented the initial increase and subsequent decrease of this output caused by bretylium as well as the decrease caused by guanethidine. Once the postganglionic blocking effect by guanethidine or bretylium was established, it could not be reversed by phenoxybenzamine. It is suggested that phenoxybenzamine occupies the sites responsible for norepinephrine uptake and thereby prevents uptake and reuptake of norepinephrine, resulting in an increased norepinephrine output. In addition it inhibits the access of guanethidine and bretylium to sites responsible for the blocking effect on norepinephrine liberation.