Peralta C, Closa D, Xaus C, Gelpí E, Roselló-Catafau J, Hotter G
Department of Medical Bioanalysis, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
Hepatology. 1998 Sep;28(3):768-73. doi: 10.1002/hep.510280325.
The present work investigates the relationship between adenosine, nitric oxide (NO), and free radicals during ischemic preconditioning in rat liver. For this purpose, we evaluated: 1) the efficacy of different periods of preconditioning; 2) the changes in the concentration of adenine nucleotides during preconditioning; 3) the importance of adenosine and xanthine concentrations in the induction of preconditioning; and 4) the possible effect of xanthine oxidase-derived superoxide anion on NO during preconditioning. Results show that just a 10- to 15-minute period of ischemia followed by 10-minute reperfusion prevents the ischemic damage that would be induced by a subsequent 90 minutes of ischemia followed by 90 minutes of reperfusion. Administration of xanthine or metabolization of endogenous adenosine abolishes the protective effect of preconditioning. When rats have been subjected to a period of preconditioning not within the effective time window (10-15 minutes), and thus offering no protection, the administration of a NO donor was found to restore the protection. The dose needed to restore protection appears to be proportional to the endogenous xanthine concentration. In addition, when xanthine oxidase was inhibited, preconditioning effectively offered protection in front of ischemia and reperfusion, independently of the xanthine concentration. Altogether, this indicates that the time window of ischemia capable to induce preconditioning in liver is defined by the relative tissue concentrations of adenosine and xanthine. The lower limit of this window (10 minutes) is defined by the amount of adenosine able to induce NO generation. Its upper limit (15 minutes) is defined by the concentration of xanthine able to remove the generated NO.
本研究探讨大鼠肝脏缺血预处理过程中腺苷、一氧化氮（NO）和自由基之间的关系。为此，我们评估了：1）不同预处理时间的效果；2）预处理过程中腺嘌呤核苷酸浓度的变化；3）腺苷和黄嘌呤浓度在诱导预处理中的重要性；4）预处理过程中黄嘌呤氧化酶衍生的超氧阴离子对NO的可能影响。结果表明，仅10至15分钟的缺血期后再灌注10分钟，就能预防随后90分钟缺血再灌注90分钟所诱导的缺血损伤。给予黄嘌呤或内源性腺苷代谢会消除预处理的保护作用。当大鼠接受的预处理时间不在有效时间窗（10至15分钟）内，因而无保护作用时，发现给予NO供体可恢复保护作用。恢复保护所需的剂量似乎与内源性黄嘌呤浓度成正比。此外，当黄嘌呤氧化酶被抑制时，预处理能有效对抗缺血再灌注损伤，且与黄嘌呤浓度无关。总之，这表明肝脏中能够诱导预处理的缺血时间窗由腺苷和黄嘌呤的相对组织浓度决定。该时间窗的下限（10分钟）由能够诱导NO生成的腺苷量决定。其上限（15分钟）由能够清除生成的NO的黄嘌呤浓度决定。
