The ability toresynthesize ATP during recovery from ischemia is limited tothe size of endogenous pool of adenine nucleotides. CytosolicAMP-specific 5'-nucleotidase (5'-NT) plays a key role inATP degradation and hence the capacity for ATP resynthesis. We havesuggested (
J. Clin. Invest. 93:40-49, 1994) that intracellular acidosis [intracellular pH(pH
i)] is a potentinhibitor of 5'-NT under in vivo conditions. To test thishypothesis further, we used the hyperthyroid rat heart because we couldalter pH
i during ischemiaand determine the consequences of lowerpH
i on AMPaccumulation (by chemical assay) and ATP resynthesis (by
31P nuclear magnetic resonancespectroscopy) during reperfusion. Global no-flow ischemiacaused pH
i to decrease from 7.1 under well-oxygenated control perfusion to 6.7. We found thatdecreasing pH
i further from pH 6.7 to 6.4 leads to increased accumulation (30%) of AMP duringischemia and to a 2.5-fold increase in ATP resynthesis duringreperfusion. Analysis of all known substrates, products, activators,and inhibitors of the 5'-NT suggests that 5'-NT isactivated primarily by Mg
2+ andADP and is inhibited by H
+. Thusthese observations provide evidence for a salutary effect ofintracellular acidosis on preserving the AMP pool due to inhibition of5'-NT and suggest a novel role ofH
+ in protecting ischemic tissue.
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