Allopurinol-enhanced myocardial protection does not involve xanthine oxidase inhibition or purine salvage.
Isolated working rat hearts were subjected to aerobic perfusion (25 min), cardioplegic infusion (3 min), global ischemia (30 min at 37 degrees C) and reperfusion (35 min). Measurements of myocardial xanthine oxidase and dehydrogenase activity, together with various adenine nucleotides and metabolites, were made at defined stages of the protocol (n = 6/group). Allopurinol pretreatment (20 mg/kg body wt/day for 3 days) improved the postischemic recovery of cardiac function; thus, aortic flow (a representative index) recovered to 68.8 +/- 4.2% compared with 53.2 +/- 2.3% in untreated controls (p less than 0.05). In fresh tissue, allopurinol pretreatment inhibited xanthine dehydrogenase activity by 73.1% (from 11.9 +/- 0.5 to 3.2 +/- 0.8 mIU/g wet wt: p less than 0.05) and xanthine oxidase activity by 95.2% (from 8.3 +/- 1.2 to 0.4 +/- 0.2 mIU/g wet wt: p less than 0.05); however, this inhibition was not maintained during perfusion. During reperfusion, myocardial xanthine dehydrogenase and oxidase activity was reduced by 40-60% (p less than 0.05) in both allopurinol pretreated and control hearts. Tissue content of creatine phosphate, adenosine triphosphate and catabolites, NAD and inorganic phosphate were not different in allopurinol pretreated or control hearts during either ischemia or reperfusion. This study does not support the concept that allopurinol protects the rat heart during ischemia and reperfusion by inhibition of xanthine oxidase activity or by conservation of purines. It appears that allopurinol achieves its protective effects by some, as yet undefined, mechanism.
Chambers
D J
DJ
Cardiovascular Research, Rayne Institute, St. Thomas' Hospital, London.
Takahashi
A
A
Humphrey
S M
SM
Harvey
D M
DM
Hearse
D J
DJ
D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D003327:Coronary Disease / Q000188:drug therapy; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000493:Allopurinol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase