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.