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.