Mechanism of the positive inotropic responses to bretylium and guanethidine.

Isolated, atropinized, rat atria exhibited positive inotropic responses to bretylium, guanethidine and tyramine. These responses were prevented by treatment of the animal with reserpine, or by addition of dichloroisoprenaline to the organ bath. The positive inotropic effects of these compounds on atria from reserpinized animals were restored by incubation of the tissue with noradrenaline. On the basis of these findings it is concluded that the cardiac stimulation by bretylium, guanethidine and tyramine involves the release of catechol amines. The usually reported increase in sensitivity of the myocardium from reserpinized animals to noradrenaline was not observed. The influence of bretylium and guanethidine on cardiac uptake and release of noradrenaline was also studied with the rat. Guanethidine decreased the concentration of catechol amines and inhibited the uptake of exogenous noradrenaline, while bretylium had no effect on either. The decrease in concentration of cardiac catechol amines produced by guanethidine was prevented by treatment of the animal with bretylium or with 1-phenyl-2-hydrazinopropane (pheniprazine), a monoamine oxidase inhibitor.