title: Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide.
abstract: ATP-sensitive potassium channels are thought to play an important role in preconditioning. possibly due to shortening of the action potential duration (APD). The purpose of this study was to determine the effect of the class III antiarrhythmic agent dofetilide on preconditioning at a dose that abolishes APD shortening during ischemia A pilot study was performed to find a dose of dofetilide that would abolish the APD shortening effect of preconditioning Anesthetized dogs were subjected to 5-min coronary occlusion (or sham) and 10-min reperfusion followed by 60-min coronary occlusion. Monophasic action potentials were recorded periodically throughout the experiment. Significant APD shortening was observed during the 5- and 60-min ischemic periods, although preconditioning did not further enhance APD shortening during the prolonged ischemia. Dofetilide (1 mg/kg + 0.01 mg.kg-1.h-1 iv) abolished the APD shortening effect of ischemia. The effect of this dose of dofetilide on the protective action of preconditioning was then determined. Preconditioning significantly reduced infarct size expressed as a percentage of the area at risk compared with nonpreconditioned hearts. Dofetilide had no effect on infarct size when given to nonpreconditioned hearts. In addition, dofetilide did not alter the protective effect of preconditioning. No differences in collateral blood flow during ischemia were observed for any group. This study shows that the class III antiarrhythmic agent dofetilide does not abolish preconditioning and that the cardioprotective effect of preconditioning is independent of APD shortening below baseline values.
authors.affiliation: Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Grover
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Alonzo
authors.forename: S
authors.initials: S
authors.lastname: Dzwonczyk
authors.forename: C S
authors.initials: CS
authors.lastname: Parham
authors.forename: R B
authors.initials: RB
authors.lastname: Darbenzio
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010627:Phenethylamines / Q000494:pharmacology*; D010865:Pilot Projects; D011188:Potassium / Q000037:antagonists & inhibitors*; D011930:Reaction Time / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide; D011188:Potassium