Regulation of cardiac AMP-specific 5'-nucleotidase during ischemia mediates ATP resynthesis on reflow.
The ability to resynthesize ATP during recovery from ischemia is limited to the size of endogenous pool of adenine nucleotides. Cytosolic AMP-specific 5'-nucleotidase (5'-NT) plays a key role in ATP degradation and hence the capacity for ATP resynthesis. We have suggested (J. Clin. Invest. 93: 40-49, 1994) that intracellular acidosis [intracellular pH (pHi)] is a potent inhibitor of 5'-NT under in vivo conditions. To test this hypothesis further, we used the hyperthyroid rat heart because we could alter pHi during ischemia and determine the consequences of lower pHi on AMP accumulation (by chemical assay) and ATP resynthesis (by 31P nuclear magnetic resonance spectroscopy) during reperfusion. Global no-flow ischemia caused pHi to decrease from 7.1 under well-oxygenated control perfusion to 6.7. We found that decreasing pHi further from pH 6.7 to 6.4 leads to increased accumulation (30%) of AMP during ischemia and to a 2.5-fold increase in ATP resynthesis during reperfusion. Analysis of all known substrates, products, activators, and inhibitors of the 5'-NT suggests that 5'-NT is activated primarily by Mg2+ and ADP and is inhibited by H+. Thus these observations provide evidence for a salutary effect of intracellular acidosis on preserving the AMP pool due to inhibition of 5'-NT and suggest a novel role of H+ in protecting ischemic tissue.
Bak
M I
MI
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ingwall
J S
JS
D015720:5'-Nucleotidase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D006859:Hydrogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007477:Ions; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology*; D011687:Purines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014284:Triiodothyronine / Q000494:pharmacology
D007477:Ions; D011687:Purines; D014284:Triiodothyronine; D006859:Hydrogen; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase