Effect of pressure overload on cardioprotection of mitochondrial KATP channels and GSK-3beta: interaction with the MPT pore.
BACKGROUND
The mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardioprotective mechanisms, namely the mitochondrial K(ATP) channels and glycogen synthase kinase-3beta (GSK-3beta). We recently showed that augmented MPT pore induction contributes to pressure overload-induced exacerbation of infarct size. This study tests the hypotheses that (i) elevation in perfusion pressure attenuates cardioprotection associated with activation of mitochondrial KATP channels or inhibition of GSK-3beta and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial KATP channels and/or GSK-3beta.


METHODS
Langendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H2O. The perfusion medium contained no drug, diazoxide (80 micromol/l; mitochondrial KATP channel opener), lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3beta), SB-216763 (3 micromol/l; selective inhibitor of GSK-3beta), cyclosporine A (0.2 micromol/l; inhibitor of MPT pore induction), glibenclamide (50 micromol/l; inhibitor of KATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl.


RESULTS
The increase in perfusion pressure in the absence of a drug caused larger infarcts, an effect associated with poorer recovery of function following ischemia reperfusion. Treatment with either diazoxide or cyclosporine A reduced infarct size at both perfusion pressures but in contrast to diazoxide, cyclosporine A was more protective at the higher pressure. On the other hand, LiCl and SB-216763 reduced infarct size at both pressures, with the effect more marked at the higher perfusion pressure. Glibenclamide did not affect infarct size but eliminated the cardioprotective effect of cyclosporine A while having no effect on LiCl-induced cardioprotection.


CONCLUSIONS
Perfusion pressure primarily affects GSK-3beta-mediated regulation of MPT pore formation in the ischemic reperfused heart.
Mozaffari
Mahmood S
MS
Department of Oral Biology, Medical College of Georgia School of Dentistry, Augusta, Georgia, USA. Mmozaffa@mail.mcg.edu
Schaffer
Stephen W
SW
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D005905:Glyburide / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D007211:Indoles; D008301:Maleimides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; C417521:SB 216763; C117780:mitochondrial K(ATP) channel; D016572:Cyclosporine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D003981:Diazoxide; D005905:Glyburide