Protection from reperfusion injury after cardiac transplantation by inhibition of adenosine metabolism and nucleotide precursor supply

Background-Adenosine (Ado) triggers numerous protective mechanisms in the h eart that may attenuate ischemia-reperfusion injury in cardiac grafts. We a imed to establish whether sustained increase in endogenous Ado production b y the combined application of Ado metabolism inhibitors and nucleotide prec ursors attenuates reperfusion injury in transplanted hearts. Methods and Results-Rat hearts were collected after the infusion of St Thom as' Hospital cardioplegic solution, stored at 4 degreesC for 4 hours, and h eterotopically transplanted into the abdomen of recipient rats. A solution containing Ado deaminase inhibitor erythro-9(2-hydroxy-3-nonyl)adenine, Ado kinase inhibitor 5 ' -aminoadenosine. and nucleotide precursors adenine an d ribose was administered at the time of reperfusion in the treated group, whereas saline was administered to control animals, After 1 or 24 hours, me chanical function of the transplanted hearts was evaluated in an ex vivo pe rfusion system followed by the determination of myocardial ATP with related metabolites and measurement of the activity of neutrophil-specific enzyme myeloperoxidase in cardiac homogenates. After 24 hours of reperfusion, maxi mum left ventricular developed pressure increased from 87.0 +/-6.8 mm Hg (m ean +/- SEM) in controls to 118.1 +/-8.2 mm Hg in the treated group (P <0.0 5), ATP increased from 11.0 +/-0.8 mu mol/g dry wt in controls to 15.1 +/-1 .2 mu mol/g dry wt in the treated group (P <0.01), and myeloperoxidase acti vity decreased from 2.23 +/-0.60 U/g wet wt in controls to 0.58 +/-0.12 U/g wet wt in the treated group (P <0.001). No differences in cardiac function , ATP, or myeloperoxidase activity were observed between the treated group and controls after I hour of reperfusion. Conclusions-The administration of Ado metabolism inhibitors with nucleotide precursors causes a sustained increase in endogenous Ado production and ex erts a potent protective effect against reperfusion injury in transplanted hearts. Improved cardiac function and elevated ATP concentration were accom panied by complete amelioration of neutrophil infiltration in treated heart s. suggesting that reduction in postischemic inflammation could be an impor tant mechanism of this protective effect.