Preconditioning is not abolished by the delayed rectifier k+
blocker dofetilide.
Grover, Gary J., Albert J. D'alonzo, Steven Dzwonczyk, Charles S.
Parham, and Raymond B. Darbenzio.
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical
Research Institute, P.O Box 4000, Princeton, N.J. 08543-4000
APStracts 3:0096H, 1996.
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 which abolishes APD shortening during
ischemia. A pilot study was performed to find a dose of dofetilide
which 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/hr, i.v.) 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 percent of the area
at risk compared to non-preconditioned hearts. Dofetilide had no
effect on infarct size when given to non-preconditioned 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.
Received 30 November 1995; accepted in final form 26 February
1996.
APS Manuscript Number H1115-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 20 March 96