Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: Role of nitric oxide and adenosine

Abstract

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

“…Recent work by our group, using a model of hepatic preconditioning in rat, demonstrated that inhibition of NO abolishes the effect of preconditioning. 8 In the same study, we suggested that NO production was stimulated by endogenous adenosine. It is known that pretreatment with adenosine or selective adenosine A 1 receptor agonists mimics the effect of preconditioning in heart.…”

“…Reflow was initiated by removal of the clamp. 8 The studies performed were in compliance with the European Union regulations for animal experiments. …”

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].…”