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.