title: Effects of cromakalim and glibenclamide on myocardial high energy phosphates and intracellular pH during ischemia-reperfusion: 31P NMR studies.
abstract: ATP sensitive potassium channel (KATP) openers (e.g. cromakalim) are thought to be cardioprotective during ischemia-reperfusion, while KATP blockers (e.g. glibenclamide) may potentiate ischemia-reperfusion damage. We studied cardiac energetics and intracellular pH, by 31P magnetic resonance spectroscopy, during ischemia-reperfusion of buffer perfused, isolated rat hearts in the presence of cromakalim (10 microM) or glibenclamide (1, 10 and 50 microM). Hearts were subjected to 25 min total global ischemia at 36.5 degrees C and reperfused for 45 min. Pre-treatment with cromakalim delayed the time to ischemic contracture (19.3 +/- 1.5 min v 15.3 +/- 0.6 for control, P < 0.05) and significantly improved recovery of function at 45 min reperfusion (84 +/- 11% pre-ischemic rate pressure product (RPP) v 38 +/- 5 for control, P < 0.05). This was accompanied by an attenuation in the loss of ATP during ischemia. Pre-treatment with glibenclamide decreased the time to ischemic contracture: 16.1 +/- 0.8 min. 15.1 +/- 0.7, 12.0 +/- 1.2 (P < 0.01) and 9.5 +/- 0.9 (P < 0.001) for control, 1, 10 and 50 microM glibenclamide respectively. 50 microM glibenclamide significantly improved functional recovery at 45 min reperfusion but 1 and 10 microM were without effect; 24 +/- 6, 22 +/- 4, 29 +/- 4 and 58 +/- 7% (P < 0.05) of pre-ischemic RPP for control, 1, 10 and 50 microM glibenclamide. During ischemia, intracellular ATP was depleted more rapidly in the presence of 50 microM glibenclamide and intracellular acidosis was significantly attenuated (final pH 6.3 v 5.8 for control). 50 microM glibenclamide also decreased tissue lactate content at the end of ischemia (75 +/- 3 mumol/g dry weight v 125 +/- 18 for control, P < 0.05) and this attenuation of lactate accumulation and consequent decreased intracellular acidosis may be responsible for the cardioprotection observed under these conditions. These latter effects are unlikely to be related to glibenclamide's KATP blocking activity. This study demonstrates that blocking of myocardial KATP does not potentiate ischemia-reperfusion injury and, in addition, illustrates the important role played by intracellular acidosis in myocardial ischemia-reperfusion injury.
authors.affiliation: Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Manitoba, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Docherty
authors.forename: H E
authors.initials: HE
authors.lastname: Gunter
authors.forename: B
authors.initials: B
authors.lastname: Kuzio
authors.forename: L
authors.initials: L
authors.lastname: Shoemaker
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Deslauriers
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006880:Hydroxy Acids / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D010759:Phosphorus Isotopes; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007004:Hypoglycemic Agents; D007773:Lactates; D010759:Phosphorus Isotopes; D011758:Pyrroles; D019806:Cromakalim; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D005905:Glyburide