Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice

Circulation. 2009 Oct 6;120(14):1345-54. doi: 10.1161/CIRCULATIONAHA.108.846402. Epub 2009 Sep 21.


Background: Neuronal nitric oxide synthase (nNOS) is expressed in cardiomyocytes and plays a role in regulating cardiac function and Ca2+ homeostasis. However, the role of nNOS in cardiac electrophysiology after myocardial infarction (MI) is unclear. We hypothesized that nNOS deficiency increases ventricular arrhythmia and mortality after MI.

Methods and results: MI was induced in wild-type (WT) or nNOS(-/-) mice by ligation of the left coronary artery. Thirty-day mortality was significantly higher in nNOS(-/-) compared with WT mice. Additionally, nNOS(-/-) mice had impaired cardiac function 2 days after MI. Telemetric ECG monitoring showed that compared with WT, nNOS(-/-) mice had significantly more ventricular arrhythmias and were more likely to develop ventricular fibrillation after MI. Treatment with the L-type Ca2+ channel blocker verapamil reduced the incidence of arrhythmia and ventricular fibrillation in nNOS(-/-) mice after MI. To assess the role of nNOS in Ca2+ handling, patch-clamp and Ca2+ fluorescence techniques were used. Ca2+ transients and L-type Ca2+ currents were higher in nNOS(-/-) compared with WT cardiomyocytes. Additionally, nNOS(-/-) cardiomyocytes exhibited significantly higher systolic and diastolic Ca2+ over a range of pacing frequencies. Treatment with the NO donor S-nitroso N-acetyl-penicillamine decreased Ca2+ transients and L-type Ca2+ current in both nNOS(-/-) and WT cardiomyocytes. Furthermore, S-nitrosylation of Ca2+ handling proteins was significantly decreased in nNOS(-/-) myocardium after MI.

Conclusions: Deficiency in nNOS increases ventricular arrhythmia and mortality after MI in mice. The antiarrhythmic effect of nNOS involves inhibition of L-type Ca2+ channel activity and regulation of Ca2+ handling proteins via S-nitrosylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Arrhythmias, Cardiac / etiology*
  • Arrhythmias, Cardiac / mortality
  • Arrhythmias, Cardiac / prevention & control*
  • Calcium / metabolism
  • Calcium Channels, L-Type / physiology
  • Coronary Vessels / pathology
  • Electrocardiography
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monitoring, Physiologic
  • Myocardial Infarction / complications*
  • Myocardial Infarction / prevention & control*
  • Myocardial Ischemia / physiopathology
  • Nitric Oxide Synthase Type I / deficiency
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / metabolism
  • Superoxides / metabolism
  • Telemetry
  • Ventricular Dysfunction, Left / etiology


  • Calcium Channels, L-Type
  • Superoxides
  • Nitric Oxide Synthase Type I
  • Calcium