Effect of nucleoside transport inhibition on adenosine and hypoxanthine accumulation in the ischemic human myocardium.

The effect of nucleoside transport inhibition on the adenylate catabolism was studied in the human myocardium under normothermic ischemic conditions. Ten hearts from cardiac transplant recipients and two hearts from cardiac homograft donors were used in this study. The hearts were excised under hypothermic conditions (25 degrees C body temperature), the coronary arteries flushed with 500 ml ice-cold Ringer solution (n = 6; group I) or with ice-cold Ringer solution containing 1 mg/l of the nucleoside transport inhibitor R75231 (n = 6; group II). After transportation at 0 degree C from the operation room, the hearts were quickly rewarmed to 37 degrees C. Serial transmural biopsy specimens were taken during normothermic ischemia for determination of purine catabolites. The level of ATP before normothermic ischemia was 17.5 +/- 1.0 mumol/g dry weight in the control group (group I) and 19.3 +/- 0.4 mumol/g dry weight in the drug group. ATP, expressed as percentage of total purine content, was similar in both groups before rewarming (79.5 +/- 4.3% in group I and 79.5 +/- 2.9% in group II). There was no significant difference in the rate of ATP breakdown in both groups throughout the experiment (ATP was 3.0 +/- 1.4% of total purines in group I and 1.4 +/- 0.2% in group II at 120 min of normothermic ischemia). Adenine nucleotide content changed also similarly in both groups. Adenosine accumulation was, however, significantly higher in group II than in group I (peak values: 4.6 +/- 1.0% of total purines in group I vs 14.0 +/- 1.7% in group II; p < 0.01). The ratio between adenosine and inosine was significantly higher in group II throughout normothermic ischemia (p < 0.01). In spite of a larger accumulation of adenosine in group II, the increase in inosine was similar in both groups. We conclude that nucleoside transport inhibition significantly delays the breakdown of adenosine and the formation of hypoxanthine in the ischemic human myocardium.