Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes.

The mechanism of drug-induced inhibition of the transient outward current, Ito, has been investigated in rat ventricular myocytes using the whole cell patch clamp technique. Ito was activated by 300 ms depolarizing voltage clamp steps in 10 mV increments from -50 mV up to +40 mV. At +40 mV, Ito peaked after about 3 ms, and the time course of inactivation was appropriately described by two time constants, tau fast = 17 ms and tau slow = 203 ms. Verapamil, quinidine sulfate and nifedipine preferentially depressed Ito at the end of the 300 ms depolarizing voltage clamp step; the inactivation of Ito was accelerated by all drugs, whereas peak Ito was less affected. The time course of drug action at +40 mV was calculated by the fractional changes of Ito. Verapamil, quinidine sulfate and nifedipine exerted a block of Ito increasing during the depolarizing voltage clamp step. The onset of block in response to verapamil, quinidine sulfate and nifedipine (30 mumol/each) was appropriately described by monoexponential functions with time constants tau on = 9.3, 1.7 and 1.1 ms, respectively. Relief from block by verapamil, quinidine sulfate and nifedipine at -50 mV was assessed by comparison of the recovery process of peak Ito from inactivation with or without drugs. tau off amounted to 695 ms in the case of quinidine sulfate; verapamil and nifedipine did not significantly affect the recovery process so that the determination of the time course of relief from block was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)