Abstract
The direct actions of OPC-8490 on mammalian myocardium were examined by determination of the drug's effects on the action potentials of isolated guinea-pig single ventricular cells and on the underlying ionic currents. OPC-8490 (10(-6) to 10(-4) M) did not alter the resting membrane potential, but rather produced a dose-dependent prolongation of the duration of the action potential. The amplitude of the action-potential plateau was also increased by OPC-8490. Whole-cell voltage clamp experiments revealed that OPC-8490 blocks myocardial delayed outward K+ current (IK), which regulates repolarization of the action potentials. However Ik1, which regulates the resting membrane potential, was not changed by OPC-8490. Ca current (ICa) was increased by OPC-8490 in a dose-dependent and reversible manner. These results suggest that OPC-8490 augments the plateau amplitude and increases the duration of the action potentials by not only increasing ICa, but also by decreasing delayed outward K+ currents. Moreover, OPC-8490 did not affect the intracellular concentration of cyclic AMP in single cells. The OPC-8490 increase in ICa was thus unlikely to be mediated by a process involving cyclic AMP.
Published Version
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