Actions of the benzopyran compound terikalant on macroscopic currents in rat ventricular myocytes

The putative Class III antiarrhythmic benzopyran compound terikalant (RP62719) has been applied to isolated rat ventricular myocytes. The drug, at extracellular concentrations from 1 to 60 microM, reduced the inactivation time constant of transient outward potassium current (I(to)) with the time constant decreased to 50% of the control value with terikalant at 11 microM. The peak value of I(to) was also diminished with terikalant in excess of 2 microM and analysis of the integral of charge movement showed this quantity to be halved with a drug concentration near 5 microM. The voltage dependence for both activation and inactivation of I(to) were not changed by terikalant and the drug had no effect on the time course of recovery from inactivation. The inhibition of I(to) currents was increased with time during depolarizing pulses suggesting drug interactions with the open channel and analysis of the time dependence of drug block gave estimates of 3.7 x 10(6) M-1 s-1 and 64 s-1 for the respective blocking and unblocking rate constants. At concentrations greater than 5 microM, terikalant also altered the peak amplitudes of inward rectifier K+ currents (IK1) elicited with hyperpolarizing or depolarizing steps from holding potential and diminished IK1 resulting from voltage ramps. The results of this study represent the initial characterization of terikalant actions in a species possessing abundant I(to) in ventricular myocytes.