Inhibition of cardiac potassium currents by the vesnarinone analog OPC-18790: comparison with quinidine and dofetilide.
OPC-18790 is a vesnarinone analog currently in clinical trials for treatment of heart failure. In vitro studies have shown that, in addition to its positive inotropic actions, OPC-18790 prolongs cardiac action potentials. Therefore, in this study, the effects of OPC-18790 on cardiac potassium currents were compared with those we previously observed for the blockers quinidine and dofetilide in two test systems, i.e., L-cells stably transfected with mammalian cardiac potassium channel clones (Kv1.4, Kv1.5 and Kv2.1) and mouse AT-1 cells, in which the rapidly inactivating component of the cardiac delayed rectifier (I(Kr)) is the major repolarizing current. In L-cells, 10 to 100 microM OPC-18790 reduced Kv1.4, Kv1.5 and Kv2.1 currents by <30%, whereas quinidine was a more potent blocker (EC50 < 10 microM) and the I(Kr)-specific blocker dofetilide was without effect. In contrast, in AT-1 cells, OPC-18790 blocked I(Kr) with an EC50 (0.96 +/- 0.12 microM, n = 10) similar to that of quinidine (0.9 +/- 0.2 microM). For both drugs, block was voltage dependent, increasing at positive potentials. OPC-18790 and quinidine showed no frequency dependence, implying block of resting channels and/or very rapid block of open channels; this is in contrast to dofetilide, which displayed slow onset kinetics of block. Thus, we conclude that, 1) unlike quinidine, OPC-18790 does not significantly inhibit currents obtained by expression of the cardiac potassium channel clones Kv1.4, Kv1.5 and Kv2.1; 2) like quinidine and dofetilide, OPC-18790 blocks I(Kr) in AT-1 cells, but the kinetics of block onset more closely resemble those of quinidine than dofetilide; and 3) block of I(Kr) appears to be an important mechanism underlying the action potential-prolonging properties of OPC-18790.[1]References
- Inhibition of cardiac potassium currents by the vesnarinone analog OPC-18790: comparison with quinidine and dofetilide. Yang, T., Snyders, D.J., Roden, D.M. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
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