title: Comparative effects of glibenclamide, tedisamil, dofetilide, E-4031, and BRL-32872 on protein kinase A-activated chloride current in guinea pig ventricular myocytes.
abstract: 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 microM isoproterenol and was inhibited by 1 microM propranolol, 10 microM 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 microM (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 microM). 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.
authors.affiliation: SmithKline Beecham Laboratories Pharmaceutiques, Saint-Grégoire, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Faivre
authors.forename: S
authors.initials: S
authors.lastname: Rouanet
authors.forename: A
authors.initials: A
authors.lastname: Bril
mesh_terms: D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002316:Cardiotonic Agents; D002712:Chlorides; D003521:Cyclopropanes; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C094198:BRL 32872; C063968:E 4031; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D011433:Propranolol; C059921:tedisamil; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D000109:Acetylcholine; C063533:dofetilide; D005905:Glyburide