Selective Inhibition of Cardiac Late Na⁺ Current Is Based on Fast Offset Kinetics of the Inhibitor

The present study was designed to test the hypothesis that the selectivity of blocking the late Na⁺ current (I_NaL) over the peak Na⁺ current (I_NaP) is related to the fast offset kinetics of the Na⁺ channel inhibitor. Therefore, the effects of 1 µM GS967 (I_NaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on I_NaL and I_NaP were compared in canine ventricular myocardium. I_NaP was estimated as the maximum velocity of action potential upstroke (V⁺_max). Equal amounts of I_NaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of I_NaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V⁺_max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of I_NaL over I_NaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of I_NaL over I_NaP is related to the fast offset kinetics of the Na⁺ channel inhibitor.