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 1h 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 1 and 24h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology.


RESULTS
After 1h, coronary blood flow (4.1+/-0.3 ml/(ming) vs 2.9+/-0.3 ml/(ming), p<0.05), left ventricular systolic pressure (102+/-9 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 micromol/g vs 0.74+/-0.27 micromol/g, p<0.05). After 24h, 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 endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. dzsi@hotmail.com
Stumpf
Nicole
N
Radovits
Tamás
T
Sonnenberg
Karin
K
Gerö
Domokos
D
Hagl
Siegfried
S
Szabó
Csaba
C
Bährle
Susanne
S
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D016027:Heart Transplantation / Q000009:adverse effects*; D007288:Inosine / Q000627:therapeutic use*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D007288:Inosine; D011065:Poly(ADP-ribose) Polymerases