Szabó Gábor, Stumpf Nicole, Radovits Tamás, Sonnenberg Karin, Gerö Domokos, Hagl Siegfried, Szabó Csaba, Bährle Susanne
Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
Eur J Cardiothorac Surg. 2006 Jul;30(1):96-102. doi: 10.1016/j.ejcts.2006.04.003. Epub 2006 May 26.
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.
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.
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.
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.
肌苷是腺苷的分解产物，最近已显示出具有正性肌力和抗炎特性。我们在大鼠心脏移植模型中研究了肌苷对缺血/再灌注损伤的影响。
在Lewis大鼠中进行腹腔异位移植。缺血保存1小时后，应用生理盐水（对照组，n = 12）或肌苷（100 mg/kg，n = 12）后开始再灌注。再灌注1小时和24小时后，测量冠状动脉血流量、左心室功能、对乙酰胆碱的内皮依赖性血管舒张和对硝普钠的非内皮依赖性血管舒张以及高能磷酸含量。此外，通过免疫组织学检测聚（ADP-核糖）聚合酶的激活情况。
1小时后，肌苷组的冠状动脉血流量（4.1±0.3 ml/（min·g）对2.9±0.3 ml/（min·g），p<0.05）、左心室收缩压（102±9 mmHg对83±4 mmHg，p<0.05）和dP/dt（2765±609 mmHg/s对1740±116 mmHg/s，p<0.05）明显高于对照组。两组对硝普钠的血管舒张反应相似。乙酰胆碱导致肌苷组冠状动脉血流量的增加明显更高（76±5%对48±9%，p<0.05）。肌苷组的能量电荷电位明显更高（1.69±0.10 μmol/g对0.74±0.27 μmol/g，p<0.05）。24小时后，两组在基础冠状动脉血流量、左心室收缩压、dP/dt以及对硝普钠的反应方面没有差异。然而，乙酰胆碱在肌苷组中仍导致明显更高的反应（112±13%对88±7%，p<0.05）。免疫组织学染色显示对照组动物中聚（ADP-核糖）聚合酶被激活，而肌苷可消除这种激活。
因此，肌苷可改善心脏移植后早期再灌注期间的心肌和内皮功能，并对再灌注诱导的移植冠状动脉内皮功能障碍具有持续的有益作用。肌苷的作用至少部分是通过调节过氧亚硝酸盐-聚（ADP-核糖）聚合酶途径介导的。
