EFFECT OF ACTIVATION OF ATP-DEPENDENT POTASSIUM CHANNELS WITH (-)-PINACIDIL AND (-)-3-PYRIDYL PINACIDIL ON INFARCT SIZE IN A CANINE MODEL OF ISCHEMIA-REPERFUSION INJURY

We tested the hypothesis that opening myocardial ATP-dependent K+ (ATP -K) channels by administration of (-)-pinacidil or (-)-3-pyridyl pinac idil intra-coronarily (i.c.) either during ischemia or as pretreatment could decrease infarct size in a canine model of ischemia-reperfusion injury in anesthetized male hounds subjected to 90-min left circumfle x coronary artery (LCX) occlusion followed by 5-h reperfusion. Drugs w ere administered by one of two protocols. In the postocclusion treatme nt protocol (protocol post), either vehicle or (-)-3-pyridyl pinacidil [0.25 mug/kg/min (low dose) or 1 mug/kg/min (high dose)] was infused i.c. distal to the site of coronary artery occlusion, through LCX begi nning 10 min after LCX occlusion and continuing until 10 min after the beginning of reperfusion. In the preocclusion treatment protocol (pro tocol pre), vehicle, low dose (-)-3-pyridyl pinacidil, or (-)-pinacidi l (1 mug/kg/min) was infused i.c. distal to the site of coronary arter y occlusion through the LCX beginning 10 min before occlusion and cont inuing until the end of the experiment. In both protocols, (-)-pinacid il and (-)-3-pyridyl pinacidil failed to demonstrate a decrease in inf arct size from that of the vehicle-treated groups. In protocol post, t he mean sizes of the infarcts in the vehicle, low-dose, and high-dose (-)-3-pyridyl pinacidil-treated groups were 26.4 +/- 5.0, 35.6 +/- 6.6 , and 28.9 +/- 6.1% of the area at risk, respectively. In protocol pre , the mean sizes of the infarcts in the vehicle, (-)-pinacidil, and lo w dose (-)-3-pyridyl pinacidil-treated groups were 29.4 +/- 1.7, 27.0 +/- 3.9, and 35.6 +/- 4.1% of the area at risk, respectively. Neither subepicardial nor subendocardial blood flow in the ischemic zone, meas ured by radioactive microspheres, was significantly different among gr oups in either protocol. In protocol post, however, the endocardial/ep icardial blood flow ration in the nonischemic zone was decreased by (- )-3-pyridyl pinacidil. In addition, the ischemic zone (LCX)/nonischemi c left anterior descending coronary artery (LAD) zone blood flow ratio in the subepicardial region were decreased by (-)-3-pyridyl pinacidil . These observations suggest that the drug may shift blood flow away f rom the ischemic zone in general and away from the endocardium in part icular. In protocol pre, the LCX/LAD ratio tended to decrease with bot h drugs, but the difference achieved statistical significance only wit h (-)-3-pyridyl pinacidil (low dose). Evaluation of the incidence of v entricular fibrillation (VF) and the number of dogs that failed to com plete the protocol showed that in protocol post, (-)-3-pyridyl pinacid il (high dose) was associated with a greater proportion of dogs that d eveloped fibrillation and thus did not complete the protocol but not a greater overall incidence of VF, whereas in protocol pre, (-)-3-pyrid yl pinacidil (low dose) was associated with a higher incidence of VF. These results do not support the hypothesis that ATP-K channel openers protect the ischemic myocardium from infarction, possibly because of disadvantageous effect on coronary blood flow distribution, and furthe rmore suggest that these compounds may increase either the incidence o r severity of ventricular arrhythmias in this model.