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Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide
G J Grover1, A J D'Alonzo, S Dzwonczyk
1Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
The American Journal of Physiology
|September 1, 1996
Summary
Dofetilide, an antiarrhythmic drug, does not block the protective effects of preconditioning. Cardioprotection from preconditioning is independent of action potential duration shortening during ischemia.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cardiac Electrophysiology
Background:
- ATP-sensitive potassium channels are implicated in preconditioning, potentially via action potential duration (APD) shortening.
- The role of APD shortening in preconditioning's protective mechanisms requires further investigation.
Purpose of the Study:
- To investigate the effect of dofetilide, a class III antiarrhythmic agent, on preconditioning.
- To determine if dofetilide, at a dose that abolishes ischemia-induced APD shortening, alters the cardioprotective effects of preconditioning.
Main Methods:
- A pilot study identified a dofetilide dose (1 mg/kg + 0.01 mg/kg/h IV) that abolished ischemia-induced APD shortening in anesthetized dogs.
- Dogs underwent 5-min coronary occlusion/10-min reperfusion (preconditioning) followed by 60-min occlusion, with monophasic action potentials recorded.
- Infarct size and collateral blood flow were assessed in preconditioned and non-preconditioned groups, with and without dofetilide administration.
Main Results:
- Dofetilide abolished the significant APD shortening observed during both 5- and 60-min ischemic periods.
- Preconditioning significantly reduced infarct size compared to controls.
- Dofetilide did not affect infarct size in non-preconditioned hearts and did not alter the protective benefits of preconditioning.
- No differences in collateral blood flow were noted across groups.
Conclusions:
- The class III antiarrhythmic agent dofetilide does not abolish the cardioprotective effects of preconditioning.
- The cardioprotective mechanism of preconditioning is independent of APD shortening below baseline values during ischemia.