Abstract
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 (IKr) is the major repolarizing current. In L-cells, 10 to 100 μM OPC-18790 reduced Kv1.4, Kv1.5 and Kv2.1 currents by <30%, whereas quinidine was a more potent blocker (EC50 < 10 μM) and the IKr-specific blocker dofetilide was without effect. In contrast, in AT-1 cells, OPC-18790 blocked IKr with an EC50 (0.96 ± 0.12 μM, n = 10) similar to that of quinidine (0.9 ± 0.2 μM). 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 IKr in AT-1 cells, but the kinetics of block onset more closely resemble those of quinidine than dofetilide; and 3) block of IKr appears to be an important mechanism underlying the action potential-prolonging properties of OPC-18790.
Footnotes
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Send reprint requests to: Dan M. Roden, M.D., Division of Clinical Pharmacology, 532 Medical Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
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↵1 This work was supported in part by grants from the United States Public Health Service (HL49989, HL46681 and HL47599) and Otsuka America Pharmaceutical, Inc. D.M.R. is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corporation.
- Abbreviations:
- IKr
- rapidly activating component of cardiac delayed rectifier
- PBS
- phosphate-buffered saline
- Received August 12, 1996.
- Accepted November 27, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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