Both adenosine and NO are synthesized in vascular endoThe effects of ischemic preconditioning on rat liver thelium and are released into the surrounding vascular and integrity, as well as the implication of nitric oxide (NO) interstitial compartments during the ischemic and reperfuand adenosine in this process, has been evaluated. Presion periods. Experimental data suggest that NO is a major conditioning before ischemia-reperfusion prevented the mediator of adenosine-induced vasodilatation. 9 In addition, increases in alanine transaminase (ALT), aspartate recent evidence suggests that adenosine stimulates, by a retransaminase (AST), and lactate dehydrogenase (LDH) ceptor-mediated mechanism, the production of NO by endolevels, but did not modify blood flow. Adenosine or NO thelial cells. 10 On the other hand, it has also been reported administration previous to hepatic ischemia-reperfuthat NO could modulate the adenosine release.11 sion simulated the effect of preconditioning, whereas Ischemic preconditioning has been commonly studied in inhibition of adenosine or NO synthesis abolished the the heart, but few studies have been performed on liver preprotective effect of hepatic preconditioning. Nevertheconditioning. 12 In this study, the concerted roles of NO and less, inhibition of adenosine and simultaneous adminisadenosine in the protective effect of preconditioning against tration of NO in preconditioned animals offered similar hepatic ischemia-reperfusion-induced injury have been results to those found in the preconditioned group, indistudied. cating that, in the absence of adenosine, NO is able to maintain the preconditioning benefits. It is suggested MATERIALS AND METHODS that, in preconditioning, adenosine stimulates NO production to protect against the injury associated with Surgical Procedure. Male Wistar rats (8 in each group; 250-300 g body weight) were used. All animals (including controls) were anes- ischemia-reperfusion. (HEPATOLOGY 1997;25:934-937.)thetized with urethane (10 mg/kg intraperitoneally) and placed in a supine position on a heating pad for maintenance of body temperaIt has been reported that repetitive, short periods of is-ture between 36ЊC and 37ЊC. To induce hepatic ischemia, laparotomy chemia, separated by intermittent reperfusion, render the was performed, and the blood supply to the right lobe of the liver heart more tolerant to subsequent, longer ischemic episodes, was interrupted by placement of a bulldog clamp at the level of the hepatic artery and portal vein. Reflow was initiated by removal of and attenuate the injury observed after ischemia-reperfusion.

Hepatic steatosis is a major risk factor in ischemiareperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. The ischemia-reperfusion (I/R) injury is an important cause of liver damage occurring during surgical procedures that include hepatic resections and liver transplantation.

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This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A 1 and A 2 receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A 2 receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A 2 receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A 2 receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A 2 receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A 2 receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia-reperfusion. (HEPATOLOGY 1999;29: 126-132.)Ischemic preconditioning, first shown in the myocardium has become a phenomenon described in the intestine, 1 brain, 2 and liver. 3 We have previously shown that ischemic preconditioning, induced by brief ischemia and reperfusion periods, renders the liver more tolerant to subsequent sustained ischemia-reperfusion. 4 We have also shown that the administration of adenosine mimics the effect of preconditioning in ischemic livers, and that the metabolization of endogenous adenosine by adenosine deaminase abolished the protective effect of preconditioning. We have further shown the beneficial effect of adenosine in inducing NO synthesis in ischemic tissue, 4 although the exact mechanism by which adenosine offered protection was not determined in that study. Recent work in heart preconditioning has shown that preconditioning-induced protection may require the activation of adenosine receptors. Thus, an adenosine receptor agonist can simulate the preconditioning whereas an adenosine receptor antagonist blocks its beneficial effect. 5 Also, recent studies in cerebral ischemia, have obtained evidence that the response to adenosine persists or is enhanced by nucleoside transport inhibitors such as propentofylline. Inhibition of adenosine uptake would increase its concentration in the extracellular space and hence potentiate its effects, particularly if adenosine binds to a specific receptor site on the external surface of the membrane. 6 Adenosine receptors have been divided into three major subclasses: A 1 , A 2 , and A 3 , 5,7 ...