Mode of Inhibition of Transient Outward Current by 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline in Rat Ventricular Cells.
In this study, we examined the effects of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (S49) on a transient outward current (I(to)) in rat ventricular myocytes using the whole-cell patch-clamp technique. Depolarization of ventricular myocytes not only activated I(to), but sustained outward currents as well. S49 dose-dependently inhibited the amplitude or integral of I(to), with a 50% inhibitory concentration (IC(50)) of 4.3 and 2.7 &mgr;M, respectively. The inhibition of I(to) by S49 was associated with an acceleration of I(to) decay. However, S49 had no effect on half inactivation voltage (V(0.5)) and slope factor of the voltage-dependent steady-state inactivation curve of I(to). Time-course analysis revealed that S49 developed a block during the depolarizing voltage-clamp step in a monoexponential manner. The rate and magnitude of block were concentration dependent. The equilibrium dissociation constant (K(d)) used to inhibit I(to) induced by S49, as calculated from the time constant of developing block, was 3.4 &mgr;M. The time constant of recovery of I(to) from the inactivation state was prolonged by S49. Following treatment with quinidine, the process of I(to) recovery was divided into rapid and extremely slow recovery components. Also, the relief from quinidine- or S49-induced block was assessed by comparing the recovery processes of I(to) with or without drugs. That comparison revealed the relief from the block of I(to) channels by S49 to be more rapid. In summary, the inhibition of I(to) by S49 was dose dependent, time dependent but voltage independent. The mechanisms of action might be an open-state block. Copyright 1996 S. Karger AG, Basel
Chen
L.
L
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lee
C.-S.
CS
Su
M.-J.
MJ