In vivo electrophysiologic studies in endothelial nitric oxide synthase (eNOS)-deficient mice

Endothelial nitric oxide synthase (eNOS) mediates attenuation of the L-type calcium channel and modulates myocyte contractility. Arrhythmogenic afterdepolarizations are seen in vitro in ouabain-treated isolated myocytes from eNOS-deficient mice. The aim of these studies was to characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice and their potential susceptibility to cardiac conduction abnormalities and inducible arrhythmias.

Surface ECG and in vivo intracardiac EP studies were performed in 27 mice lacking the eNOS gene and 21 wild-type littermate control mice. Baseline studies were performed in 10 eNOS-deficient mice and 10 wild-type controls. Subsequently, 17 eNOS-deficient mice and 11 wild-type controls were pretreated with digoxin, and ECG and EP testing were repeated. Data analysis revealed no significant differences in ECG intervals or cardiac conduction parameters, except sinus cycle length was higher in eNOS-deficient mice than wild-type mice (P < 0.01). After digoxin pretreatment, 7 of 17 eNOS-deficient mice had inducible ventricular tachycardia and 2 others had frequent ventricular premature beats, compared with only 3 of 11 wild-type mice with inducible ventricular tachycardia. In addition, 2 digoxin-treated eNOS-deficient mice and 1 wild-type mouse had inducible nonsustained atrial fibrillation.

Mice with a homozygous targeted disruption of the eNOS gene have slower heart rates but no other distinguishable EP characteristics under basal sedated conditions. Partial inhibition of the Na+/K+ ATPase pump with digoxin administration increases ventricular ectopic activity in eNOS-/- mice, a phenotype analogous to afterdepolarizations seen in vitro in this eNOS-deficient mouse model.