Enhancement of calcium current during digitalis inotrophy in mammalian heart: positive feed‐back regulation by intracellular calcium?

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Abstract
Effects of digitalis compounds on slow inward CA current (Isi) and contractile force were examined in ferret ventricular muscle (single sucrose-gap voltage clamp) and calf Purkinje fibers (2 microelectrode voltage clamp). In ventricular muscle, ouabain increased Isi and inward current tails associated with Isi conductance. The enhancement of Isi followed a time course similar to the development of the positive inotropic effect, and it was observed in the absence of aftercontractions or other signs of toxicity. The response of myocardial Isi 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 Isi 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 Isi. Additional experiments suggest that the link between Nai and Isi involves intracellular Ca. When Cs-loaded Purkinje fibers were bathed in solutions containing Sr instead of Ca, enhancement of Isi by strophanthidin was abolished, even though a positive inotropic response persisted. After intracellular injection of Purkinje fibers with EGTA [ethyleneglycol-bis(.beta.-aminoethylether)-N,N,N'',N''-tetraacetic acid], Isi no longer increased with strophanthidin, although it remained responsive to adrenaline [epinephrine]. Clear-cut increases in Isi were seen in Cs-loaded Purkinje fibers even at very low concentrations of strophanthidin (20-50 nM), at which the occurrence of Na pump inhibition has been questioned. Positive regulation of Ca entry by intracellular Ca may act as a facilitory mechanism that amplifies myocardial responsiveness to digitalis and other inotropic interventions. Through changes in Isi, small rises in diastolic free Ca might lead to large increases in the activator Ca transient during contraction.

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