Bimakalim, an ATP-sensitive potassium channel opener, mimics the effects of ischemic preconditioning to reduce infarct size, adenosine release, and neutrophil function in dogs.
BACKGROUND
The primary goal of the present study was to determine whether the infarct size-reducing effect of preconditioning is associated with an increase in adenosine release from the ischemic myocardium during a prolonged occlusion period or the subsequent reperfusion period and by a decrease in neutrophil infiltration. A second objective was to determine whether bimakalim, a KATP channel opener, mimics the effects of ischemic preconditioning.


RESULTS
Barbital-anesthetized open-chest dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion followed by 3 hours of reperfusion. In the preconditioning group, 5 minutes of LAD occlusion followed by 10 minutes of reperfusion was elicited before the 60-minute occlusion period. In two other groups, bimakalim 1 microgram/kg bolus followed by a 0.05 micrograms.kg-1.min-1 infusion or an equivalent volume of saline was administered intravenously 15 minutes before occlusion and continued until the time of reperfusion. In a final group, bimakalim was administered 10 minutes before reperfusion and continued until the end of the experiment. To measure the release of adenosine from the ischemic region, coronary venous blood samples were collected at various times during ischemia and after reperfusion, and the concentration of adenosine was measured. Myocardial infarct size was determined by triphenyl tetrazolium chloride; transmural myocardial blood flow, by radioactive microspheres. Transmural myeloperoxidase (MPO) activity, an index of neutrophil infiltration in the area at risk, was also measured. Preconditioning produced a marked reduction in infarct size (9.8 +/- 3.0% versus 28.6 +/- 5.2% in the control group, mean +/- SEM); adenosine release at 5, 10, 15, and 30 minutes of the 3-hour reperfusion period; and transmural MPO activity in the risk area. Similarly, pretreatment with bimakalim resulted in reductions in infarct size, adenosine release, and transmural MPO activity to an extent almost identical to that of preconditioning. When bimakalim was administered 10 minutes before reperfusion, the drug also produced a significant reduction in infarct size and transmural MPO activity; however, no significant reduction in coronary venous adenosine concentrations was observed. There were no significant differences in collateral blood flow between groups.


CONCLUSIONS
These results indicate that myocardial preconditioning in the canine heart produced by a short period of ischemia or a KATP channel opener is not mediated by an increase in adenosine release, as measured by coronary venous adenosine concentrations, during 60 minutes of occlusion or the initial 30 minutes of reperfusion. A significant reduction in transmural MPO activity in the ischemic area also appears to result from KATP channel activation and may play a role, at least in part, in the reduction in infarct size observed, particularly when a KATP channel opener is administered just before reperfusion.
Mizumura
T
T
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Nithipatikom
K
K
Gross
G J
GJ
D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003097:Collateral Circulation / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D004095:Dihydropyridines / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D013997:Time Factors; D014665:Vasodilator Agents / Q000627:therapeutic use*
D001578:Benzopyrans; D004095:Dihydropyridines; D015221:Potassium Channels; D014665:Vasodilator Agents; C061050:bimakalim; D000255:Adenosine Triphosphate; D009195:Peroxidase; D000241:Adenosine