부산대학교 도서관

The present study was designed to test the hypothesis that the selectivity of blocking the late Na[sup.+] current (I[sub.NaL]) over the peak Na[sup.+] current (I[sub.NaP]) is related to the fast offset kinetics of the Na[sup.+] channel inhibitor. Therefore, the effects of 1 µM GS967 (I[sub.NaL] inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on I[sub.NaL] and I[sub.NaP] were compared in canine ventricular myocardium. I[sub.NaP] was estimated as the maximum velocity of action potential upstroke (V[sup.+] [sub.max]). Equal amounts of I[sub.NaL] were dissected by the applied drug concentrations under APVC conditions. The inhibition of I[sub.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[sup.+] [sub.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[sub.NaL] over I[sub.NaP] inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of I[sub.NaL] over I[sub.NaP] is related to the fast offset kinetics of the Na[sup.+] channel inhibitor.
Author(s): Muhammad Naveed [1,†]; Aiman Saleh A. Mohammed [1,†]; Leila Topal [1]; Zsigmond Máté Kovács [2]; Csaba Dienes [2]; József Ovári [2]; Norbert Szentandrássy [2,3]; János Magyar [2,4]; Tamás Bányász [...]