THE MECHANISM OF ACTION OF GUANETHIDINE ON THE ISOLATED MAMMALIAN HEART

¹ Department of Pharmacology and Toxicology, School of Pharmacy, Universidad Central de Venezuela, Caracas, Venezuela

The heartlung preparation of the dog responds to acute injections of reserpine, guanethidine and tyramine with an increase in heart rate which is due to their norepinephrine-releasing effect. The magnitude and time course of the responses are different for each of these agents. In the presence of either cocaine on protriptyline, the response to reserpine is potentiated and its time-response curve becomes steep, whereas the response to tyramine is reduced without a change in its time course. Both cocaine and protniptyline antagonize the response to guanethidine partially, but not completely. The time-response curve for guanethidine becomes flattened in the presence of high doses of either cocaine or protniptyline. These results are consistent with the view that reserpine has its main site of action on a functional compartment of "bound" norepinephnine and is without effect on the reuptake of released norepinephrine, whereas tyramine acts mainly on a functional compartment of "available" norepinephrine and also inhibits the reuptake of released norepinephnine. It is proposed that guanethidine, in addition to impairing the uptake mechanism, releases norepinephrine from both "available" and "bound" compartments.