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.