Enhancement of calcium current during digitalis inotropy in mammalian heart: Positive feed-back regulation by intracellular calcium?

Effects of digitalis compounds on slow inward Ca current (I(si)) and contractile force were examined in ferret ventricular muscle (single sucrose-gap voltage clamp) and calf Purkinje fibres (two micro-electrode voltage clamp). In ventricular muscle, ouabain increased I(si) and inward current tails associated with I(si) conductance. The enhancement of I(si) followed a time course similar to the development of the positive inotropic effect, and it could be observed in the absence of aftercontractions or other signs of toxicity. The response of myocardial I(si) and twitch force to ouabain depended strongly on a previous history of driven action potentials. Veratridine, a toxin that promotes Na entry through tetrodotoxin-sensitive channels, also increased I(si) and twitch force in driven ventricular muscle preparations. The effects of ouabain, action potential stimulation and veratridine are consistent with reported effects of K-poor solutions in indicating that elevation of intracellular Na can lead to enhancement of I(si). Additional experiments suggest that the link between Na(i) and I(si) involves intracellular Ca. When Cs-loaded Purkinje fibres were bathed in solutions containing Sr instead of Ca, enhancement of I(si) by strophanthidin was abolished even though a positive inotropic response persisted. After intracellular injection of Purkinje fibres with EGTA, I(si) no longer increased with strophanthidin, although it remained responsive to adrenaline. Clear-cut increases in I(si) were seen in Cs-loaded Purkinje fibres even at very low concentrations of strophanthidin (20-50 nM), where the occurrence of Na pump inhibition has been questioned. Positive regulation of Ca entry by intracellular Ca may act as a facilitatory mechanism that amplifies myocardial responsiveness to digitalis and other inotropic interventions. Through changes in I(si), small rises in diastolic free Ca might lead to large increases in the activator Ca transient during contraction.