The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function

Julio Altamirano, Yanxia Li, Jaime Desantiago, Valentino Piacentino, Steven R. Houser, Donald M Bers

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Glycoside-induced cardiac inotropy has traditionally been attributed to direct Na+-K+-ATPase inhibition, causing increased intracellular [Na+]and consequent Ca2+ gain via the Na+-Ca2+ exchanger (NCX). However, recent studies suggested alternative mechanisms of glycoside-induced inotropy: (1) direct activation of sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors; RyRs); (2) increased Ca2+ selectivity of Na+ channels (slip-mode conductance); and (3) other signal transduction pathways. None of these proposed mechanisms requires NCX or an altered [Na+] gradient. Here we tested the ability of ouabain (OUA, 3 μM), digoxin (DIG, 20 μM) or acetylstrophanthidin (ACS, 4 μM) to alter Ca2+ transients in completely Na+-free conditions in intact ferret and cat ventricular myocytes. We also tested whether OUA directly activates RyRs in permeabilized cat myocytes (measuring Ca2+ sparks by confocal microscopy). In intact ferret myocytes (stimulated at 0.2 Hz), DIG and ACS enhanced Ca2+ transients and cell shortening during twitches, as expected. However, prior depletion of [Na+ ] i (in Na+-free, Ca2+-free solution) and in Na+-free solution (replaced by Li+) the inotropic effects of DIG and ACS were completely prevented. In voltage-clamped cat myocytes, OUA increased Ca2+ transients by 48 ± 4% but OUA had no effect in Na+-depleted cells (replaced by N-methyl-D-glucamine). In permeabilized cat myocytes, OUA did not change Ca2+spark frequency, amplitude or spatial spread (although spark duration was slightly prolonged). We conclude that the acute inotropic effects of DIG, ACS and OUA (and the effects on RyRs) depend on the presence of Na+ and a functional NCX in ferret and cat myocytes (rather than alternate Na+-independent mechanisms).

Original languageEnglish (US)
Pages (from-to)845-854
Number of pages10
JournalJournal of Physiology
Volume575
Issue number3
DOIs
StatePublished - Sep 2006
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

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