Effects of adenosine antagonists on hexose uptake and preconditioning in perfused rat heart.
Preconditioning with brief intermittent periods of ischemia has been shown to lessen the detrimental effects of a subsequent sustained (30-60 min) period of ischemia. Because adenosine has been suggested to be the mediator of preconditioning, we were interested in investigating whether adenosine antagonists would block the effect of preconditioning on ionic changes during ischemia. We found that 10 microM of the adenosine antagonist BW-A1433U did not reverse the effect of preconditioning on intracellular pH (pHi). Hearts preconditioned with BW-A1433U had virtually no decrease in pHi during the 30-min sustained period of ischemia; after 30 min of ischemia, the pH in untreated hearts was 5.97 +/- 0.16 compared with 6.52 +/- 0.10 in preconditioned hearts and 6.90 +/- 0.08 in hearts preconditioned plus BW-A1433U. Because anaerobic glycolysis is largely responsible for the fall in pHi during ischemia, we examined the effect of BW-A1433U [and other adenosine antagonists, such as PD-115,199 and 8-cyclopentyl-1,3-dipropylxanthine (CPDPX)] on glucose uptake and phosphorylation during aerobic perfusion using 31P-nuclear magnetic resonance to monitor uptake and phosphorylation of 2-deoxyglucose (2-DG) to 2-deoxyglucose 6-phosphate (2-DG-6-P) when one-half of the glucose in the perfusate was replaced with 2-DG. Uptake of 2-DG-6-P after 15 min was reduced by 66% in the presence of BW-A1433U and 82% in the presence of PD-115,199 as compared with untreated hearts, but was not reduced in the presence of CPDPX. Thus CPDPX was the only adenosine antagonist tested that did not block accumulation of 2-DG-6-P. We also found that CPDPX did not block the beneficial effect of preconditioning on ionic alterations during a sustained 30-min period of ischemia or the improved recovery of function on reflow.
Murphy
E
E
Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park 27709.
Fralix
T A
TA
London
R E
RE
Steenbergen
C
C
D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D003847:Deoxyglucose / Q000493:pharmacokinetics; D006601:Hexoses / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D017682:Myocardial Stunning; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000241:Adenosine; D003847:Deoxyglucose; D006601:Hexoses; D011687:Purines; D013449:Sulfonamides; D014970:Xanthines; C052023:N-(2-(dimethylamino)ethyl)-N-methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C053414:BW A1433U; C051360:1,3-dipropyl-8-cyclopentylxanthine