NA-H+ EXCHANGE INHIBITION AT REPERFUSION IS CARDIOPROTECTIVE DURING MYOCARDIAL ISCHEMIA-REPERFUSION - P-31 NMR-STUDIES()

To help resolve the controversy as to whether or not Na+-H+ exchange i s functioning during reperfusion of the ischemic myocardium we assesse d the effects of dimethylamiloride (DMA, an amiloride analogue possess ing selectivity for inhibition of the Na+-H+ exchanger) on cardiac fun ction and intracellular pH during ischemia-reperfusion. Studies were p erformed in the presence of bicarbonate (modified Krebs-Henseleit buff er) or in the nominal absence of bicarbonate (HEPES buffer) in order t o determine if similar cardioprotection and effects on intracellular p H were observed in the presence and absence of bicarbonate dependent t ransport processes, Isovolumic rat hearts were perfused in the Langend orff mode at a constant pressure of 80 mm Hg and subjected to 28 min t otal global ischemia at 37 degrees C, Intracellular pH was determined from the pH dependent shift of the inorganic phosphate peak in P-31 nu clear magnetic resonance spectra. DMA (20 mu M) was infused for either 2.5 min before ischemia, for the initial 5 min of reperfusion, or at both time intervals. DMA had no effect on the intracellular pH during ischemia. Intracellular pH returned to pre-ischemic levels within 2.5 min of reperfusion in bicarbonate buffer. This normalization of pH was slower in HEPES perfusate. In both bicarbonate and HEPES perfused hea rts all drug dosing regimens caused a significant increase in the reco very of mechanical function after reperfusion and slowed the recovery of intracellular pit during reperfusion. These results suggest that th e Na+-H+ exchanger is activated during reperfusion of the ischemic myo cardium, that this activation of the exchanger contributes to ischemia -reperfusion induced cardiac dysfunction and that administration of an inhibitor of Na+-H+ exchange at reperfusion significantly attenuates the deleterious effects of exchanger activation.