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Effects of intracoronary cromakalim on postischaemic contractile function and action potential duration
A J D'Alonzo1, R B Darbenzio, C S Parham
1Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, NJ 08543-4000.
Objective:
The effects of intracoronary cromakalim (1 microgram.kg-1 x min-1) on postischaemic contractile function and monophasic action potential duration at the 95% repolarisation level (APD95) were assessed in a canine model of stunned myocardium.
Methods:
Animals (n = 24) were anaesthetised, subjected to a left thoracotomy, and the left anterior descending coronary artery was isolated. Measurements of segmental shortening and monophasic action potential were taken before drug, after drug, during a 15 min occlusion, and at times following reperfusion.
Results:
Cromakalim significantly improved reperfusion recovery of function. Both preischaemic and postischaemic myocardial blood flows were increased with cromakalim, although there was no significant change in collateral blood flow during ischaemia relative to vehicle. In the absence of ischaemia, cromakalim reduced APD95 by 8%. There was no change in APD95 with vehicle alone. During coronary occlusion, cromakalim significantly reduced APD95 by 27% as compared with 8% in the vehicle group. APD95 values returned to preocclusion levels within minutes of reperfusion and remained there throughout reperfusion (30 min). Glyburide (3.0 mg.kg-1 intravenously), a blocker of ATP sensitive potassium channels, abolished the APD95 effects of cromakalim. One out of six animals given glyburide survived through reperfusion. In contrast, four out of five of the glyburide+cromakalim treated animals survived through reperfusion.
Conclusions:
Cardioprotection with cromakalim is likely to be mediated through activation of ATP sensitive potassium channels, measured as a decrease in action potential duration. Shortening of action potential duration with cromakalim was shown to be augmented in the presence of ischaemia. It is suggested that a possible interrelationship between cardioprotection and action potential duration shortening may exist such that the cardioprotective effects of cromakalim may be selective for ischaemic conditions.