title: Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A5C1.
authors.forename: Dylan E
authors.initials: DE
authors.lastname: Burger
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Fu-Li
authors.initials: FL
authors.lastname: Xiang
authors.forename: Lamis
authors.initials: L
authors.lastname: Hammoud
authors.forename: Mao
authors.initials: M
authors.lastname: Jiang
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Jones
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sims
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D003331:Coronary Vessels / Q000473:pathology; D004562:Electrocardiography; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008991:Monitoring, Physiologic; D009203:Myocardial Infarction / Q000150:complications* / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013686:Telemetry; D018487:Ventricular Dysfunction, Left / Q000209:etiology
chemical_list: D020746:Calcium Channels, L-Type; D013481:Superoxides; D052248:Nitric Oxide Synthase Type I; D002118:Calcium