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

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Electrophysiology

Background:

• Endothelial nitric oxide synthase (eNOS) regulates L-type calcium channels and myocyte contractility.
• eNOS-deficient mice exhibit arrhythmogenic afterdepolarizations in vitro.
• Understanding the electrophysiologic (EP) phenotype of eNOS-deficient mice is crucial for assessing arrhythmia risk.

Purpose of the Study:

• To characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice.
• To evaluate the susceptibility of eNOS-deficient mice to cardiac conduction abnormalities and inducible arrhythmias.
• To investigate the impact of digoxin on the cardiac EP of eNOS-deficient mice.

Main Methods:

• Performed surface ECG and in vivo intracardiac EP studies on 27 eNOS-deficient and 21 wild-type mice.
• Baseline EP studies were conducted in 10 eNOS-deficient and 10 wild-type controls.
• Digoxin pretreatment was administered to 17 eNOS-deficient and 11 wild-type mice before repeat ECG and EP testing.

Main Results:

• No significant differences in baseline ECG intervals or cardiac conduction were found, except for a higher sinus cycle length in eNOS-deficient mice.
• Following digoxin, 7/17 eNOS-deficient mice developed inducible ventricular tachycardia, compared to 3/11 wild-type mice.
• Two digoxin-treated eNOS-deficient mice and one wild-type mouse experienced inducible nonsustained atrial fibrillation.

Conclusions:

• Homozygous eNOS gene disruption results in slower heart rates but no other basal EP differences.
• Digoxin administration, partially inhibiting the Na+/K+ ATPase pump, increases ventricular ectopic activity in eNOS-deficient mice.
• This digoxin-induced phenotype in eNOS-deficient mice mimics in vitro observed afterdepolarizations.