Dual role of hypoxanthine in the reoxygenation of hypoxic isolated rat hearts.
In the reoxygenated hypoxic heart, hypoxanthine is either oxidized by xanthine oxidase with production of toxic oxygen species or salvaged for the ATP pool by hypoxanthine-guanine phosphoribosyl transferase. To characterize the repartition of hypoxanthine between the two pathways, we have subjected rat hearts to 20 min hypoxia and monitored the recovery (ventricular, end-diastolic and coronary pressures, and the contraction rate) during the reoxygenation (30 min) in the presence of either hypoxanthine or guanine alone, or both. The rate-pressure product recovered 78% of the pre-hypoxia values in hearts reoxygenated with 100 microM hypoxanthine and 80% in hearts reoxygenated with 100 microM guanine, in contrast to 49% in the presence of both hypoxanthine and guanine (100 microM each). Thus, it is likely that hypoxanthine is salvaged when present alone and is oxidized generating the reperfusion injury when the salvage is prevented by guanine that competes with hypoxanthine from the same site of hypoxanthine-guanine phosphoribosyl transferase. The functional impairment was slower when hypoxanthine was replaced by xanthine, and was eliminated by superoxide dismutase and catalase, indicating that the injury is caused by toxic oxygen species generated from hypoxanthine and xanthine oxidase. These data suggest that the salvage pathway may be critical in preventing the reperfusion injury in hypoxic hearts.
Tarantola
M
M
Istituto Scientifico San Raffaele, Milano, Italy.
Motterlini
R
R
Beretta
M
M
Samaja
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000494:pharmacology; D007042:Hypoxanthines / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014969:Xanthine Oxidase / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology
D007042:Hypoxanthines; D014970:Xanthines; D006147:Guanine; D014969:Xanthine Oxidase; D010100:Oxygen