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 (IC₅₀) of 4.3 and 2.7 µM, 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 µM. 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.