Ouabain-Toxic Canine Purkinje and Ventricular Muscle Fibers

In the "Na lag hypothesis" of cardiac glycoside action, [Ca]i increases through sodium-calcium exchange following block of the sodium-calcium ATPase. This accumulation of [Ca]i has been suggested to be responsible for digitalis-induced delayed afterdepolarizations and arrhythmias. We used standard microelectrode techniques to study the effects of adriamycin, 10-200 fiM, on the canine Purkinje fiber transmembrane potential. Adriamycin, 10 and 50 HM, had no effect on the action potential other than inducing a 28% increase in duration at 50 HM (p < 0.01). Adriamycin, 100 and 200 JIM, further prolonged action potential duration and decreased amplitude and Vn ,̂. We then studied the effects of adriamycin, 50 /XM (a concentration that purportedly blocks sodium-calcium exchange), on ouabain-induced delayed afterdepolarizations and aftercontractions in Purkinje fiber and ventricular muscle. After initially increasing delayed afterdepolarization amplitude in five of nine Purkinje fibers, adriamycin reversibly reduced their amplitude in all nine, by 78%, at a drive cycle length of 500 msec (P < 0.01). Adriamycin, 50 HM, had no effect on calcium ion-induced slow response action potentials, suggesting this concentration does not significantly reduce the slow inward current. In ventricular muscle, adriamycin, 50 MM, did not significantly reduce contraction but did depress aftercontractions (P < 0.025). In sum: in concentrations that have no effect on the AP other than prolonging duration, adriamycin, 50 MM, reversibly depresses ouabain-induced delayed afterdepolarizations and aftercontractions; however, adriamycin, 50 HM, does not depress calcium ion-dependent action potentials. Although the action of adriamycin on delayed afterdepolarizations and aftercontractions is consistent with direct inhibition of the transient inward current and/or an indirect reduction via reduced activity of sodium-calcium exchange, whether either or both of these mechanisms is involved must be defined by further experimentation. (Circ Res 53: 655-662, 1983)