Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase

Isao Kubota, Xinqiang Han*, Douglas J. Opel, You Yang Zhao, Ragaven Baliga, Paul Huang, Mark C. Fishman, Richard P. Shannon, Thomas Michel, Ralph A. Kelly

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Nitric oxide generated by cardiac myocytes or delivered by drugs has been shown to regulate cardiac contractile function and has been implicated in suppressing some cardiac arrhythmias, although this remains controversial. We examined the ability of the soluble cardiac glycoside, ouabain, to trigger arrhythmic contractions in ventricular myocytes isolated from mice lacking a functional endothelial nitric oxide synthase gene (eNOS(null)). Arrhythmic activity, defined as aftercontractions, was induced with ouabain (50 μmol/L) and recorded using a video-motion detector in isolated, electrically driven single ventricular myocytes from adult eNOS(null) or from their wild-type (WT) littermates. The rate of ouabain-induced arrhythmic contractions was significantly higher in eNOS(null) myocytes than in WT myocytes. Application of the NO donor S-nitroso-acetylcysteine (SNAC) significantly diminished the frequency of arrhythmic contractions in eNOS(null) myocytes. The antiarrhythmic effect of NO, whether generated by eNOS in WT cells or by SNAC, could be partially reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a specific soluble guanylyl cyclase inhibitor. Ouabain significantly increased intracellular cGMP in WT but not eNOS(null) hearts, and this cGMP response was blocked by ODQ. Since cardiac glycoside-induced aftercontractions are activated by the transient inward current (I(ti)), the role of NO in ouabain (100 μmol/L)-induced I(ti) was examined using the nystatin-perforated patch - clamp technique. The frequency of ouabain-induced I(ti) was significantly higher in eNOS(null) myocytes than in WT myocytes, and this could be suppressed by SNAC. These data demonstrate that NO derived from myocyte eNOS activation suppresses ouabain-induced arrhythmic contractions by a mechanism that might involve activation of guanylyl cyclase and elevation of cGMP. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)1239-1248
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume32
Issue number7
DOIs
StatePublished - Jan 1 2000

Keywords

  • Calcium overload
  • Digitalis glycoside
  • Nitric oxide synthase
  • Transient inward current
  • Triggered arrhythmia
  • cGMP

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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