Effects of Cromakalim and Glibenclamide on Myocardial High Energy Phosphates and Intracellular pH During Ischemia-reperfusion:31P NMR Studies

ATP sensitive potassium channel (KATP) openers (e.g. cromakalim) are thought to be cardioprotective during ischemia-reperfusion, while KATPblockers (e.g. glibenclamide) may potentiate ischemia-reperfusion damage. We studied cardiac energetics and intracellular pH, by31P magnetic resonance spectroscopy, during ischemia-reperfusion of buffer perfused, isolated rat hearts in the presence of cromakalim (10μ ) or glibenclamide (1, 10 and 50μ ). Hearts were subjected to 25 min total global ischemia at 36.5°C and reperfused for 45 min. Pre-treatment with cromakalim delayed the time to ischemic contracture (19.3±1.5 minv15.3±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)v38±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 50μ glibenclamide respectively. 50μ glibenclamide significantly improved functional recovery at 45 min reperfusion but 1 and 10μ were without effect; 24±6, 22±4, 29±4 and 58±7% (P<0.05) of pre-ischemic RPP for control, 1, 10 and 50μ glibenclamide. During ischemia, intracellular ATP was depleted more rapidly in the presence of 50μ glibenclamide and intracellular acidosis was significantly attenuated (final pH 6.3v5.8 for control). 50μ glibenclamide also decreased tissue lactate content at the end of ischemia (75±3μmol/g dry weightv125±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 glibenclamideʹs KATPblocking activity. This study demonstrates that blocking of myocardial KATPdoes not potentiate ischemia-reperfusion injury and, in addition, illustrates the important role played by intracellular acidosis in myocardial ischemia-reperfusion injury.