Hepatic preconditioning in rats is defined by a balance of adenosine and xanthine

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.