Prevention of free radical-induced myocardial injury by allopurinol: Experimental study in cardiac preservation and transplantation

Abstract

To determine the role of free radical-induced injury during heart preservation and transplantation, we harvested hearts from 28 mongrel dogs (12.5 to 16.5 kg), divided them into four groups, and orthotopically transplanted them. A group of seven hearts were orthotopically transplanted immediately after excision (group A). A second group of seven animals received allopurinol pretreatment (50 mg/kg/day) for 72 hours, and the hearts were orthotopically transplanted immediately after excision (group B). A third group of seven hearts were transplanted after continuous perfusion with oxygenated modified Collins solutions at 4 degrees C, pH 7.4, and a pressure of 20 mm Hg for 18 hours (group C). A fourth group of seven animals received allopurinol pretreatment (50 mg/kg/day) for 72 hours, and the hearts were orthotopically transplanted after perfusion with modified Collins solutions in the same manner as group C hearts (group D). The generation of free radicals, estimated by measurement of thiobarbituric acid reactive substances (malondialdehyde) in the coronary effluent, stayed at low levels during perfusion in groups C and D and also remained at low levels during operational ischemia in group A and B. During reperfusion, their levels abruptly and significantly increased and were associated with a corresponding increase in creatinine kinase MB isoenzyme (malondialdehyde levels at 30 minutes' reperfusion: A, 2.25 +/- 0.43; B, 1.55 +/- 0.25 nmol/ml/100 gm wet weight [p less than 0.05 versus group A]; C, 2.67 +/- 0.28; D, 1.77 +/- 0.27 nmol/ml/100 gm wet weight [p less than 0.05 versus group C]). In the allopurinol pretreatment groups, allopurinol significantly slowed the appearance of malondialdehyde and the release of creatinine kinase MB isoenzyme during reperfusion. Furthermore, cardiac functions during reperfusion, expressed as percent of control (mean +/- standard deviation), were significantly better in the allopurinol pretreatment groups than in the untreated groups: maximum first derivative of left ventricular pressure: A, 76.4 +/- 9.5; B, 99.7 +/- 14.3 [p less than 0.05 versus group A]; C, 25.2 +/- 2.6; D, 42.7 +/- 7.9 [p less than 0.05 versus group C]). These results indicate that (1) the generation of oxygen free radical is not significant during perfusion with modified Collins solutions nor during operational ischemia, but only during reperfusion, and (2) allopurinol reduces free radical-induced injury during reperfusion. Allopurinol has potential application in the prevention of reperfusion injury during heart transplantation.