The whole-cell voltage clamp method has been used to study the actions of KC8851, a structural analogue of tedisamil (KC8857), on the transient outward K+ current (Ito) and the Na+ current (INa) in rat ventricular myocytes. KC8851 diminished the inactivation time course of Ito with an EC50 value of 2.2 microM. Kinetic analysis of the time-dependent effects of KC8851 on the decay of Ito was consistent with open channel blockade with respective blocking and unblocking rate constants of 9.3 X 10(6) M(-1) s(-1) and 19.3 s(-1). KC8851 was also found to be a potent inhibitor of peak Na+ current with an EC50 value of 5.1 microM. The inhibition of INa was primarily use-dependent with some contribution from tonic block. The results show KC8851 exhibits potent and selective mixed blockade of Ito and INa a result different from that previously documented for the analogue, tedisamil, which was found to be a potent blocker of Ito, but not INa, in rat ventricular cells.