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-ICl) 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-ICl. Experiments were conducted by using the patch-clamp technique in guinea pig ventricular myocytes. PKA-ICl was activated by application of 1 μM isoproterenol and was inhibited by 1 μM propranolol, 10 μM acetylcholine, or 1 mM 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid (SITS). The sulfonylurea receptor inhibitor, glibenclamide, inhibited PKA-ICl at micromolar concentration. Among class III anti-arrhythmic agents, tedisamil induced a dose-dependent inhibition of PKA-ICl with a half effective concentration (EC50) of 7.15 μM (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 (IKr), dofetilide, and E-4031, as well as BRL-32872, that blocks IKr and the L-type calcium current, did not significantly affect the amplitude of PKA-ICl, even at high concentrations (10-30 μM). 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-ICl. Furthermore it appears that blockade of PKA-ICl is not a common feature for all class III antiarrhythmic agents.