MIXED BLOCKADE OF K+ AND NA+ CURRENTS IN RAT VENTRICULAR MYOCYTES BY THE TEDISAMIL ANALOG, KC8851

The whole-cell voltage clamp method has been used to study the actions of KC8851, a structural analogue of tedisamil (KC8857), on the transi ent outward K+ current (I-to) and the Na+ current (I-Na) in rat ventri cular myocytes. KC8851 diminished the inactivation time course of I-to with an EC50 value of 2.2 mu M. Kinetic analysis of the time-dependen t effects of KC8851 on the decay of I-to was consistent with open chan nel 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 p otent inhibitor of peak Na+ current with an EC50 value of 5.1 mu M. Th e inhibition of I-Na was primarily use-dependent with some contributio n from tonic block. The results show KC8851 exhibits potent and select ive mixed blockade of I-to and I-Na a result different from that previ ously documented for the analogue, tedisamil, which was found to be a potent blocker of I-to, but not I-Na, in rat ventricular cells. (C) 19 97 Elsevier Science B.V.