Enhanced postischemic ATP repletion by pharmacological inhibition of nucleoside washout and catabolism.
We tested the hypothesis that inhibition of adenosine transport by dipyridamole and inhibition of adenosine deamination by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) prevents nucleoside loss and stimulates postischemic ATP-repletion. In an open chest canine model, dipyridamole (0.5 mg/kg/h) and EHNA (5 mg/kg/h) were infused intra-atrially during a coronary occlusion period of 45 min and a reperfusion period of 180 min. Transmural needle biopsies, obtained during the ischemic period and within the reperfusion period, were analyzed using high performance liquid chromatography for adenine nucleotides and adenosine, inosine, xanthine, and hypoxanthine as well as creatine phosphate. During ischemia and under the influence of dipyridamole plus EHNA, 56% of the catabolized adenine nucleotides were recovered stoichiometrically as adenosine, whereas in the untreated group less than 10% of the nucleotides were recovered as adenosine because of rapid deamination to inosine. In the control group, ATP levels decreased during ischemia from control values of 5.25 +/- 0.28 microns/g to 2.01 +/- 0.18 microns/g. In the group treated with dipyridamole and EHNA, ATP levels fell to 2.2 +/- 0.22 microns/g but rose to 3.22 +/- 0.29 microns/g within 180 min of reperfusion, whereas in the untreated control group tissue levels of ATP did not increase. However, a significant proportion of the adenosine accumulated during ischemia under the influence of dipyridamole plus EHNA was not used for the restoration of the ATP level during reperfusion. A significant amount of adenosine was probably trapped in the interstitial space and could not be transported back into the myocytes in the presence of dipyridamole during reperfusion. In both groups, creatine phosphate levels were restored to normal levels during reperfusion.
Henrichs
K J
KJ
Max-Planck-Institute, Bad Nauheim, Federal Republic of Germany.
Matsuoka
H
H
Schaper
W
W
D000227:Adenine Nucleotides / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003327:Coronary Disease / Q000378:metabolism* / Q000503:physiopathology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism
D000227:Adenine Nucleotides; D009705:Nucleosides; D010725:Phosphocreatine; D000255:Adenosine Triphosphate