Augmentation of the indirect sympathomimetic action of tyramine by cardioactive steroids is a consequence of elevated intracellular sodium

Summary The augmentation by the cardioactive steroid acetylstrophanthidin of neurotransmitter release evoked by tyramine, and the dependence of the augmentation upon Na⁺, has been investigated in dog saphenous vein rings in which monoamine oxidase activity and uptake₂ had been inhibited with pargyline and corticosterone respectively. High extracellular Na⁺ (Na_o; 263 mmol/1) reduced basal efflux of ³H-compounds from the rings and also reduced tyramine-evoked efflux. Low Na_o (25 mmol/1) increased basal efflux of ³H but reduced tyramine-evoked efflux. The increment in basal ³H-efflux caused by low Na_o was cocaine-sensitive. A presumed increase in intracellular Na⁺ (Na_i), produced by preincubating rings with acetylstrophanthidin in normal (143 mmol/1) or high Na_o, augmented ³H-efflux evoked by subsequent incubation with tyramine in normal Na_o Pre-incubating rings with acetylstrophanthidin in low Na_o, conditions which would not be expected to increase Na_i, did not cause augmentation of the subsequent tyramine-evoked ³H-efflux. An increase in Na_i, produced either as above or by pre-incubating rings in high Na_o alone, reduced subsequent neuronal ¹⁴C-tyramine uptake. Low Na_o present only during incubation reduced neuronal ¹⁴C-tyramine uptake, but high Nao present only during incubation did not increase neuronal ¹⁴C-tyramine uptake from that measured in normal Na_o The data are consistent with the following hypotheses: that tyramine uptake is dependent upon the prevailing inwardly directed Na⁺-gradient, that consequent noradrenaline efflux is Na⁺-gradient dependent and that the enhancement by acetylstrophanthidin of tyramine-evoked ³H-efflux is a consequence of the raised Na_i caused by Na⁺,K⁺-ATPase inhibition.Send offprint requests to D. A. Powis