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.