Y-26763 protects the canine heart from a stunning injury through opening of the KATP channels.
The present study describes the protective effects of the ATP-sensitive K+ (KATP) channel opener Y-26763 ((-)-(3S,4R-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl -2H-1-benzopyran-3-ol), on a model of reversible ischemia/reperfusion injury ('stunned' myocardium). Stunning was caused by 10-min occlusion of the left circumflex coronary artery followed by 3-h reperfusion in pentobarbital anesthetized beagle dogs. This procedure reduced by over 80% myocardial segment function measured by sonomicrometry in control preparations. Y-26763, administered 10 min before the left circumflex coronary artery occlusion, at a dose (3 micrograms/kg, i.v.) lacking significant systemic hemodynamic effects, produced a rapid and marked (80%) recovery of the shortening of the ischemic segment. By contrast, nifedipine (1 microgram/kg plus 0.2 microgram/kg per min, i.v.) did not ameliorate postischemic function. Glibenclamide, administered before Y-26763 at a dose (0.3 mg/kg, i.v.) that did not affect adversely hemodynamics and stunning injury negated the beneficial action of Y-26763. However, glibenclamide failed to do so when administered 2 min before starting reperfusion. The ischemia/reperfusion areas, which were measured by digital image analysis with NIH image software, were similar among experimental groups. Overall, these results indicate that Y-26763 protects the canine myocardium from reversible ischemia/reperfusion injury, probably through activation of myocardial KATP channels which appear to be involved in affording protection during the ischemic insult and not at the reperfusion.
Fukunari
A
A
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Miyai
H
H
Shinagawa
K
K
Kawahara
K
K
Nakajima
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017682:Myocardial Stunning / Q000503:physiopathology / Q000517:prevention & control*; D009543:Nifedipine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D002121:Calcium Channel Blockers; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D009543:Nifedipine; C074338:Y 26763; D005905:Glyburide