Second-generation sulfonylureas preserve inhibition of mitochondrial permeability transition by the mitochondrial K+(ATP) opener nicorandil in experimental myocardial infarction.
Openers of K+(ATP) channels protect the myocardium from I/R injury. Sulfonylureas are known as potent blockers of K(ATP) channels. We investigated whether 1) mitochondrial permeability transition pore may be involved in the protection afforded by the mitoK+(ATP) opener nicorandil and 2) whether sulfonylureas may prevent this beneficial effect. Anesthetized New Zealand White rabbits underwent 30 min of coronary artery occlusion, followed by 60 (isolated mitochondria) or 240 min (infarct size) of reperfusion. They received an administration of either saline (control) or nicorandil (0.5 mg kg(-1), i.v.) 15 min before ischemia. Each control and nicorandil group was divided in four subgroups pretreated by either saline, glibenclamide (Glib; 1 mg kg(-1)), gliclazide (Glic; 1 mg kg(-1)), or glimepiride (Glim; 5 microg kg(-1)) 10 min before this. Infarct size was assessed by triphenyltetrazolium chloride staining. Mitochondria were isolated from the area at risk for further assessment of the calcium retention capacity. Glibenclamide (35 +/- 8), but neither Glic (61 +/- 9) nor Glim (48 +/- 7), reversed the improvement in calcium retention capacity due to nicorandil (58 +/- 10 vs. 27 +/- 8 nmoles CaCl2 mg(-1) proteins in control). Infarct size reduction by nicorandil (32% +/- 6% vs. 65% +/- 6% of area at risk) was abolished by Glib (55 +/- 5) but not by Glic (37 +/- 3) or Glim (31 +/- 5). These data suggest that 1) the protective effect of nicorandil involves the inhibition of the mitochondrial permeability transition pore and 2) that unlike Glib, second-generation sulfonylureas preserve this cardioprotection.
Argaud
Laurent
L
Inserm, U886-Cardioprotection, Lyon, France. laurent.argaud@chu-lyon.fr
Garrier
Olivier
O
Loufouat
Joseph
J
Gomez
Ludovic
L
Couture-Lepetit
Elisabeth
E
Gateau-Roesch
Odile
O
Robert
Dominique
D
Ovize
Michel
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005907:Gliclazide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020108:Nicorandil / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; C057619:glimepiride; D005907:Gliclazide; D005905:Glyburide; D002118:Calcium