The protective role of adenosine in inducing nitric oxide synthesis in rat liver ischemia preconditioning is mediated by activation of adenosine A₂receptors

Abstract

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 ...

Doxorubicin preconditioning: A protection against rat hepatic ischemia-reperfusion injury

“…[10][11][12][13][14][15][16][17][18]24 Although little is known about the molecular basis of the preconditioning, oxidative stress seems to be one of the causes. Peralta et al 15,25 and Yin et al 26 have reported the role of nitric oxide and free radicals during ischemic preconditioning in the liver. In addition, HSPs induced by the stresses may also play a critical role for the subsequent hepatic injury.…”

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

“…Experiments, mainly performed in the heart, suggest a number of substances as potential ligands, including adenosine, bradykinin, catecholamines, reactive oxygen species, opiods, angiotensin II, and NO [68]. With regard to the liver, adenosine has thus far been considered the major player in triggering preconditioning [62,63,65,69,70]. Adenosine is a breakdown product of ATP that is released in large quantities into the extracellular space within seconds of the onset of ischemia.…”

“…A 1 and A 2 receptors have been chiefly implicated in the ischemic preconditioning of the myocardium and liver, respectively [62,63,65,69,71].…”

“…Recent studies have demonstrated that ischemic preconditioning induces activation of adenosine A 2 receptors, which in turn, by induction of NO synthesis, confer cytoprotection against postischemic damage [63,65]. Along these lines, it has been shown that inhibition of NO synthesis with N-nitro-L-arginine methylester, an L-arginine analogue that competitively blocks NO synthase, abolished the protective effect of preconditioning, whereas administration of a NO donor or L-arginine to ischemic and reperfused livers simulated the protective effect of preconditioning against hepatic injury [63,65].…”

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes

“…The work by Peralta and colleagues has shown that adenosine is implicated in liver preconditioning by stimulating NO generation. 4,11,12 In isolated hepatocytes we have observed that the treatment with 4-phorbol-12-myristate-13-acetate (PMA) or with 1,2 dioctanoyl-glycerol mimics the effects of preconditioning. 8 Conversely, the PKC inhibitor chelerythrine abolishes the citoprotection, 8 suggesting that PKC activation might play a role in liver preconditioning.…”