Comparative effects of glibenclamide, tedisamil, dofetilide, E-4031, and BRL-32872 on protein kinase A-activated chloride current in guinea pig ventricular myocytes

The modulation of the protein kinase A-activated chloride current (PKA-I-Cl) may lead to modification of the cardiac action potential shape. The purpose of this study was to evaluate the effects of glibenclamide, tedisamil, dofetilide, E-4031, and BRL-32872 on the PKA-I-Cl. Experiments were conducted by using the patch-clamp technique in guinea pig ventricular myocytes. PKA-I-Cl was activated by application of 1 mu M isoproterenol and was inhibited by 1 mu M propranolol, 10 mu M acetylcholine, or 1 mM 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS). The sulfonylurea receptor inhibitor, glibenclamide, inhibited PKA-I-Cl at micromolar concentration. Among class III antiarrhythmic agents, tedisamil induced a dose-dependent inhibition of PKA-I-Cl with a half effective concentration (EC50) of 7.15 mu M (Hill coefficient, 0.54). This effect may contribute to action potential widening induced by tedisamil. In contrast, the selective inhibitors of the rapid component of the delayed rectifier K current (I-Kr), dofetilide, and E-4031, as well as BRL-32872, that blocks I-Kr and the L-type calcium current, did not significantly affect the amplitude of PKA-I-Cl, even at high concentrations (10-30 mu M). These results demonstrate that compounds such as glibenclamide and tedisamil that are known to block the adenosine triphosphate (ATP)-sensitive K current also affect PKA-I-Cl. Furthermore it appears that blockade of PKA-I-Cl is not a common feature for all class III antiarrhythmic agents.