Enhanced basal late sodium current appears to underlie the age-related prolongation of action potential duration in guinea pig ventricular myocytes

Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses tha 1 ) the APD of ventricular myocytes increases with age; 2 ) the age-related prolongation of APD is due to an enhancement of basal late Na + current ( I NaL ); and 3 ) inhibition of I NaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H 2 O 2 ). Experiments were performed on ventricular myocytes isolated from (young) 1-mo- and (old) 1-yr-old guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the I NaL inhibitors GS967 and tetrodotoxin. The magnitude of I NaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the Na V 1.5-channel blocker methanethiosulfonate ethylammonium blocked the I NaL . There were no significant differences between myocytes from young and old GPs in L-type Ca 2+ current and the rapidly and slowly activating delayed rectifier K + currents, although the inward rectifier K + current was slightly decreased in myocytes from old GPs. H 2 O 2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H 2 O 2 was attenuated by GS967. The results suggest tha 1 ) the APD of myocytes from old GPs is prolonged, 2 ) a CaMKII-mediated increase in Na V 1.5-channel I NaL is responsible for the prolongation of APD, and 3 ) inhibition of I NaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs. NEW & NOTEWORTHY The action potential duration is significantly longer in ventricular myocytes from old than from young guinea pigs, which may explain, at the cellular level, the increase in QT interval with age. A CaMKII-mediated enhancement of Na V 1.5-channel late current is responsible for the age-related prolongation of action potential duration. The enhanced basal late sodium current may predispose cardiac myocytes of old animals to oxidative stress and arrhythmogenesis.