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These data indicate that endothelin-1 release during ischaemia may be involved in the pathogenesis of myocardial ischaemia and infarction.

The direct myocardial protective effects of intracoronary infusions of cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 micrograms/kg/min) or pinacidil (0.09 micrograms/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25 +/- 5%) compared with vehicle controls (55 +/- 7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in cromakalim-treated animals, particularly in the subepicardial region. When the same dose of cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 microM cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.

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.

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