Activation of cardiac KATP channels: an endogenous protective mechanism during repetitive ischemia.
The role of KATP channels in myocardial stunning produced by repetitive coronary occlusions was studied in barbital-anesthetized dogs. Regional percent segment function (%SS) was measured by sonomicrometry, and the monophasic action potential (MAP) in the ischemic region was measured by an epicardial probe. Under control conditions, six 5-min periods of coronary occlusion, interspersed with 10-min periods of reperfusion, and ultimately followed by 2 h of reperfusion produced regional segment dysfunction and a similar rate and amount of shortening of the MAP measured at 50% repolarization duration (MAPD50) during each successive ischemic period. Pretreatment with glibenclamide (0.3 mg/kg iv), a KATP channel antagonist, significantly prevented the reduction of MAPD50, particularly during the first occlusion period, and it worsened postischemic dysfunction. In contrast, pretreatment with aprikalim (10 micrograms/kg bolus +/- 0.1 microgram.kg-1.min-1 iv), a KATP channel opener, accelerated the rate and extent of shortening of MAPD50 during each occlusion and markedly improved %SS throughout reperfusion. Pretreatment with d-sotalol (2 mg/kg iv), an antagonist of voltage-dependent K+ channels, significantly prolonged MAPD50 of the ischemic region before coronary occlusion but did not alter the rate of shortening of MAPD50 during ischemia and did not affect the recovery of %SS. These results indicate that activation of KATP channels during ischemia with the resultant shortening of the MAPD50 is an endogenous adaptive mechanism that affords functional myocardial protection during repetitive, brief periods of coronary arterial occlusion.
Yao
Z
Z
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Cavero
I
I
Gross
G J
GJ
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010847:Picolines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology; D011930:Reaction Time; D013015:Sotalol / Q000494:pharmacology
D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; C061043:aprikalim; D000255:Adenosine Triphosphate; D013015:Sotalol; D005905:Glyburide