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We tested the hypothesis that opening myocardial ATP-dependent K + (ATP-K) channels by administration of (-)-pinacidil or (-)-3-pyridyl pinacidil intracoronarily (i.e.) 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 circumflex coronary artery (LCX) occlusion followed by 5-h reperfusion. Drugs were administered by one of two protocols. In the postocclusion treatment protocol (protocol post), either vehicle or (-)-3-pyridyl pinacidil [0.25 μ.g/kg/min (low dose) or 1 μg/kg/ min (high dose)] was infused i.e. distal to the site of coronary artery occlusion, through LCX beginning 10 min after LCX occlusion and continuing until 10 min after the beginning of reperfusion. In the preocclusion treatment protocol (protocol pre), vehicle, low dose (-)-3-pyridyl pinacidil, or (-)-pinacidil (1 μ.g/kg/min) was infused i.e. distal to the site of coronary artery occlusion through the LCX beginning 10 min before occlusion and continuing until the end of the experiment. In both protocols, (-)-pinacidil and (-)-3-pyridyl pinacidil failed to demonstrate a decrease in infarct size from that of the vehicle-treated groups. In protocol post, the 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 low 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, measured by radioactive microspheres, was significantly different among groups in either protocol. In protocol post, however, the endocardial/epicardial blood flow ration in the nonischemic zone was decreased by (-)-3-pyridyl pinacidil. In addition, the ischemic zone (LCX)/nonischemic 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 from the ischemic zone in general and away from the endocardium in particular. In protocol pre, the LCX/ LAD ratio tended to decrease with both drugs, but the difference achieved statistical significance only with (–)-3-pyridyl pinacidil (low dose). Evaluation of the incidence of ventricular fibrillation (VF) and the number of dogs that failed to complete the protocol showed that in protocol post, (-)-3-pyridyl pinacidil (high dose) was associated with a greater proportion of dogs that developed fibrillation and thus did not complete the protocol but not a greater overall incidence of VF, whereas in protocol pre, (-)-3-pyridyl 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 furthermore suggest that these compounds may increase either the incidence or severity of ventricular arrhythmias in this model.