Acetylcholine reversal of isoproterenol-stimulated sodium currents in rabbit ventricular myocytes

J. J. Matsuda, H. C. Lee, E. F. Shibata

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20 Scopus citations

Abstract

We have recently shown that β-adrenergic agonists enhance the cardiac sodium current (I(Na)) in rabbits through dual G-protein regulatory pathways. To determine if muscarinic cholinergic receptor stimulation can also modulate I(Na), we studied the effects of acetylcholine (ACh) and carbachol on I(Na) in enzymatically dispersed rabbit ventricular myocytes. Whole-cell patch- clamp experiments done at room temperature using 20 mM [Na+](o) showed that 100 nM isoproterenol increased I(Na) and accelerated current decay as previously described. ACh (1 μM) or carbachol (1 μM) significantly reversed the stimulatory isoproterenol effects at test potentials throughout the I(Na) activation range and at holding potentials negative to -80 mV. This effect was completely inhibited by atropine (1 μM) and was confirmed by studying single-channel I(Na) from cell-attached patches. When I(Na) was stimulated by forskolin (1 μM), carbachol (1 μM) significantly reversed the effect. The muscarinic-mediated inhibition of I(Na) was inhibited by pertussis toxin (0.1 or 1.0 μg/ml) incubation (12-15 hours), suggesting that the effect was inhibitory G-protein dependent. Further investigation of the ACh inhibitory mechanism revealed that ACh alone had no effect on I(Na) and that when cells were dialyzed with cAMP (5 μM), ACh failed to inhibit I(Na). Furthermore, cGMP failed to inhibit the effect of isoproterenol on I(Na). These data suggest that ACh acts at or proximal to adenylate cyclase stimulation. Thus, rabbit cardiac Na+ channels are regulated by muscarinic agonists in a fashion similar to cardiac Ca2+ channels.

Original languageEnglish (US)
Pages (from-to)517-525
Number of pages9
JournalCirculation research
Volume72
Issue number3
DOIs
StatePublished - 1993

Keywords

  • cardiac myocytes
  • muscarinic receptors
  • sodium channels
  • β-adrenergic receptors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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