Prolonged Action Potential and After depolarizations Are Not due to Changes in Potassium Currents in NOS3 Knockout Ventricular Myocytes

Ventricular myocytes deficient in endothelial nitric oxide synthase (NOS3(−/−)) exhibit prolonged action potential (AP) duration and enhanced spontaneous activity (early and delayed afterdepolarizations) during β-adrenergic (β-AR) stimulation. Studies have shown that nitric oxide is able to regulate various K(+) channels. Our objective was to examine if NOS3(−/−) myocytes had altered K(+) currents. APs, transient outward (I (to)), sustained (I (Ksus)), and inward rectifier (I (K1)) K(+) currents were measured in NOS3(−/−) and wild-type (WT) myocytes. During β-AR stimulation, AP duration (measured as 90% repolarization-APD(90)) was prolonged in NOS3(−/−) compared to WT myocytes. Nevertheless, we did not observe differences in I (to), I (Ksus), or I (K1) between WT and NOS3(−/−) myocytes. Our previous work showed that NOS3(−/−) myocytes had a greater Ca(2+) influx via L-type Ca(2+) channels with β-AR stimulation. Thus, we measured β-AR-stimulated SR Ca(2+) load and found a greater increase in NOS3(−/−) versus WT myocytes. Hence, our data suggest that the prolonged AP in NOS3(−/−) myocytes is not due to changes in I (to), I (Ksus), or I (K1). Furthermore, the increase in spontaneous activity in NOS3(−/−) myocytes may be due to a greater increase in SR Ca(2+) load. This may have important implications for heart failure patients, where arrhythmias are increased and NOS3 expression is decreased.