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.
Yang
T
T
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Snyders
D J
DJ
Roden
D M
DM
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D007739:L Cells; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D011802:Quinidine / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015363:Quinolones; D011994:Recombinant Proteins; D013449:Sulfonamides; C077543:toborinone; D011802:Quinidine; C063533:dofetilide