Membrane current changes associated with digitalis inotropy in mammalian heart muscle

E. Marban, R. W. Tsien

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Abstract

The slow inward calcium current (I(si)) plays an important role in determining the strength of the cardiac contraction. In principle, an increase in this current could contribute to the positive inotropic effect of digitalis, along with other mechanisms. Most of the published evidence is against this possibility. However, enhancement of I(si) by cardiotonic steroids has been reported in frog atrial trabeculae (J. Physiol. Paris 63, 43A) and calf Purkinje fibres (Nature 273, 389). Do cardiac glycosides increase slow inward Ca current in the working myocardium of mammalian heart? We measured I(si) and contraction in ferret papillary muscles in single sucrose-gap voltage-clamp experiments. Exposure to 1μM ouabain, a subtoxic dose for this preparation, produced reversible increases in slow inward current, measured at a test potential near -20 mV. The increase in I(si) was consistently found in either 0.45 or 1.8 mM Ca(o), and was not prevented by blocking β-adrenergic receptors with 1 μM propranolol. Two arguments favor the hypothesis that the increase in I(si) depends on alteration of ionic gradients by ouabain and not on a direct drug-channel interaction. First, the enhancement of I(si) is accentuated by repeated stimualtion during drug exposure, like the positive inotropic effect itself. Second, the effect of ouabain on force and I(si) can be mimicked by veratradine, an agent known to increase sodium entry. One possible interpretation is that a rise in intracellular sodium leads to altered I(si), either by direct modulation, or indirectly, by means of a secondary increase in intracellular calcium.

Original languageEnglish (US)
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume308
Issue numbersuppl
Publication statusPublished - 1979
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

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