Infarct size-reducing effect of nicorandil is mediated by the KATP channel but not by its nitrate-like properties in dogs.
OBJECTIVE
We wished to determine whether the cardioprotective effect of nicorandil to reduce infarct size is blocked by glibenclamide, a selective KATP channel antagonist, or methylene blue, a nitric oxide (NO)/guanylate cyclase inhibitor, in dogs. The second aim was to determine if glyceryl trinitrate produces a cardioprotective effect in the same model and to test if this effect is blocked by methylene blue and not by glibenclamide. We also determined whether adenosine release from the ischemic-reperfused area is an accurate index of ischemic severity in the presence of these drugs.


METHODS
Barbiturate-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. In the first three groups, either nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), glyceryl trinitrate (10 micrograms/kg bolus + 1 microgram/kg/min) or an equivalent volume of saline was given intravenously 15 min before LAD occlusion and continued to the time of reperfusion. In the next three groups, glibenclamide (0.3 mg/kg) was administered 15 min before drug infusion. In the final three groups, methylene blue (80 microM) was given intracoronarily 5 min before nicorandil or glyceryl trinitrate and continued until 15 min following reperfusion. Coronary venous blood samples were collected at various times during ischemia and following reperfusion and the concentration of adenosine measured.


RESULTS
Nicorandil produced a marked reduction in infarct size expressed as a percent of the area at risk (NC group, 12.2 +/- 3.2% vs. Control group, 25.7 +/- 4.1%, P < 0.05) and this effect was completely abolished by pretreatment with glibenclamide. However, intracoronary administration of methylene blue did not block the cardioprotective effect of nicorandil. On the other hand, glyceryl trinitrate also produced a significant reduction in infarct size (GTN group, 13.0 +/- 3.1%) and this effect was reversed by methylene blue but not by glibenclamide. Adenosine concentrations in coronary venous blood were significantly reduced after reperfusion in the groups with small infarctions as compared with the Control group.


CONCLUSIONS
These results suggest that at equieffective cardioprotective doses the infarct size-reducing effect of nicorandil in dogs is mediated via opening of myocardial KATP channels and that the cardioprotective effect of glyceryl trinitrate is most likely to be mediated via activation of guanylate cyclase at a site yet to be determined.
Mizumura
T
T
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 63226, USA.
Nithipatikom
K
K
Gross
G J
GJ
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D015640:Ion Channel Gating; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D009569:Nitric Oxide; D005996:Nitroglycerin; D000241:Adenosine; D005905:Glyburide; D008751:Methylene Blue