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 pinacidil intracoronarily (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 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 micrograms/kg/min (low dose) or 1 micrograms/kg/min (high dose)] was infused i.c. 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 micrograms/kg/min) was infused i.c. 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).(ABSTRACT TRUNCATED AT 400 WORDS)
Smallwood
J K
JK
Department of Cardiovascular Pharmacology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Schelm
J A
JA
Bemis
K G
KG
Simpson
P J
PJ
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009195:Peroxidase / Q000378:metabolism; D020110:Pinacidil / Q000031:analogs & derivatives; D015221:Potassium Channels / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; C085178:3-pyridyl pinacidil; D020110:Pinacidil; D009195:Peroxidase