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 that 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 (INaL ); 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2 O2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the INaL inhibitors GS967 and tetrodotoxin. The magnitude of INaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the NaV 1.5-channel blocker MTSEA blocked the INaL . There were no significant differences between myocytes from young and old GPs in L-type Ca2+ 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. H2 O2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H2 O2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in NaV 1.5-channel INaL is responsible for the prolongation of APD, and 3) Inhibition of INaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs.