EFFECTS OF CROMAKALIM AND GLIBENCLAMIDE ON MYOCARDIAL HIGH-ENERGY PHOSPHATES AND INTRACELLULAR PH DURING ISCHEMIA-REPERFUSION - P-31 NMR-STUDIES

ATP sensitive potassium channel (K-ATP) openers (e.g. cromakalim) are thought to be cardioprotective during ischemia-reperfusion, while K-AT P blockers (e.g. glibenclamide) may potentiate ischemia-reperfusion da mage. We studied cardiac energetics and intracellular pH, by P-31 magn etic resonance spectroscopy, during ischemia-reperfusion of buffer per fused, isolated rat hearts in the presence of cromakalim (10 mu M) or glibenclamide (1, 10 and 50 mu M). Hearts were subjected to 25 min tot al global ischemia at 36.5 degrees C and reperfused for 45 min. Pre-tr eatment 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 imp roved recovery of function at 45 min reperfusion (84 +/- 11% pre-ische mic 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 contra cture; 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 mu M 1 glibenclamide respec tively. 50 mu M glibenclamide significantly improved functional recove ry at 45 min reperfusion but 1 and 10 mu M 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 mu M glibenclamide. During ischemia, intracellul ar ATP was depleted more rapidly in the presence of 50 mu M glibenclam ide and intracellular acidosis was significantly attenuated (final pH 6.3 v 5.8 for control). 50 mu M glibenclamide also decreased tissue la ctate content at the end of ischemia (75 +/- 3 mu mol/g dry weight v 1 25 +/- 18 for control, P<0.05) and this attenuation of lactate accumul ation and consequent decreased intracellular acidosis may be responsib le for the cardioprotection observed under these conditions. These lat ter effects are unlikely to be related to glibenclamide's K-ATP blocki ng activity. This study demonstrates that blocking of myocardial K-ATP does not potentiate ischemia-reperfusion injury and, in addition, ill ustrates the important role played by intracellular acidosis in myocar dial ischemia-reperfusion injury. (C) 1997 Academic Press Limited.