Effects of inosine on reperfusion injury after heart transplantation

Objective: Inosine, a break-down product of adenosine, has been recently shown to exert inodilatory and anti-inflammatory properties. We investigated the effects of inosine on ischemia/reperfusion injury in a rat heart transplantation model. Methods: Intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n = 12) or inosine (100 mg/kg, n = 12). Coronary blood flow, left ventricular function, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside, and high energy phosphate content were measured after I and 24 h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology. Results: After 1 h, coronary blood flow (4.1 +/- 0.3 ml/(min g) vs 2.9 +/- 0.3 mL/(min g), p < 0.05), left ventricular systolic pressure (102 +/- 19 mmHg vs 83 +/- 4 mmHg, p < 0.05) and dP/dt (2765 +/- 609 mmHg/s vs 1740 +/- 116 mmHg/s, p < 0.05) were significantly higher in the inosine group in comparison to control. Vasodilatatory response to sodium nitroprusside was similar in both groups. Acetylcholine resulted in a significantly higher increase in coronary blood flow in the inosine group (76 +/- 5% vs 48 +/- 9%, p < 0.05). Energy charge potential was significantly higher in the inosine group (1.69 +/- 0.10 mu mol/g vs 0.74 +/- 0.27 mu mol/g, p < 0.05). After 24 h, there was no difference between the groups in basal coronary blood flow, left ventricular systolic pressure, dP/dt, and the response to sodium nitroprusside. However, acetylcholine led to a still significantly higher response in the inosine group (112 +/- 13% vs 88 7%, p < 0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine. Conclusions: Thus, inosine improves myocardial and endothetial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothetial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway. (c) 2006 Published by Elsevier B.V.