Increased Nav 1.5 channel late current underlies prolongation of action potential duration of ventricular myocytes from aged guinea pigs

Background The action potential duration (APD) of aged hearts is prolonged. Because the late Na + current (I NaL ) has been shown to play a significant role in modulating cardiac APD, we sought to determine whether the age-related prolongation of APD is due to an increase in endogenous I NaL . Methods Experiments were performed on ventricular myocytes isolated from the hearts of young (one-month old) or aged (one-year old) guinea pigs. The APD and the amplitude of I NaL were determined using the whole-cell patch-electrode technique at 36 o C. The APD was measured at 50% repolarization (APD 50 ). I NaL was activated by 250-ms voltage-clamp pulses from -90 to -30 mV under conditions wherein K + and Ca 2+ currents were inhibited. The amplitude of I NaL was calculated as the average current during the last 100-ms of the voltage clamp. Results The APD 50 of myocytes from aged hearts (323±9 ms, n=29) was significantly longer than those from young hearts (229±6 ms, n=43, p NaL inhibitor GS967 (0.01 - 1 µmol/L, n=7) and the Na + channel blocker tetrodotoxin (0.1 - 10 µmol/L, n=9) shortened the APD 50 of myocytes from aged hearts by 24±4 to 44±4% and by 32±4 to 45±4%, respectively (p NaL of aged myocytes (-0.51±0.05 pA/pF, n=17) was significantly greater than that of young myocytes (-0.22±0.02 pA/pF, n=27, p v 1.5 channel blocker, reduced the I NaL of young and aged myocytes by 94±3% (n = 10) and 96±1% (n = 8), respectively, suggesting that the Na v 1.5 channel is the major contributor to I NaL of both young and aged guinea pig ventricular myocytes. Conclusion The present results suggest that 1) an increase in endogenous I NaL is responsible for the prolongation of APD in aged guinea pig ventricular myocytes, and 2) Na v 1.5 channels are the major contributor to the increased I NaL .