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

Abstract

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. (HEPATOLOGY 1998;28:768-773.)In 1986, Murry et al. discovered that short periods of ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. 1 This phenomenon, called ischemic preconditioning, has been commonly studied in the heart, but few studies have been performed on intestine 2 or liver. 3 The mechanism underlying preconditioning remains unknown and is currently under intense investigation. It has been suggested that protection depends on the release of substances by the organ helping to protect it against injury. Along this line, potential mediators include nitric oxide (NO) 2,4 and adenosine. 5 Vegh et al. 6 reported that the protection conferred by preconditioning in dog heart in vivo disappeared after NO inhibition. Nevertheless, other authors 7 found that endogenous NO is not a mediator in the ischemic preconditioning in the isolated rat heart. 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. 10 Bot...

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

“…It has been similarly reported in the liver that ischemic or heat shock preconditioning exerts a protective effect on 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.…”

“…Peralta et al have recently reported that ischemic preconditioning in rat liver is defined by the balance between the tissue concentrations of adenosine and xanthine. 15 They have also suggested that nitric oxide may play the critical role in the ischemic preconditioning. 14,16 In addition, heat-shock protein HSP72 also seems to play an important role for the protection against ischemiareperfusion injury.…”

Ischemic preconditioning of the liver: A few perspectives from the bench to bedside translation

“…Preconditioning strategies effective in the laboratory include ischemic preconditioning (IPC), anesthetic preconditioning, hyperthermic or heat-shock preconditioning, and pharmacological preconditioning. [1][2][3][4][5][6][7] In the past decade, serious efforts have commenced to translate some of the robust benefits of preconditioning against ischemia reperfusion (RP) to the clinical arena. Although all of the preconditioning methods offer potential clinical benefits, much of the initial translational effort has focused on IPC, probably due to its extensive and consistently beneficial laboratory experience.…”

Preconditioning protects liver and lung damage in rat liver transplantation: Role of xanthine/xanthine oxidase

“…This phenomenon, initially studied in the heart by Murry et al in 1986, 13 has been recently described in the liver. 14 The studies on liver ischemic preconditioning, focused mainly on warm ischemia, [14][15][16][17][18][19] suggest that this endogenous mechanism is able to confer protection against liver and lung injuries following hepatic I/R. However, few studies concerning the effectiveness of preconditioning on the I/R injury associated with liver transplantation have been reported, [20][21][22] and these have been mainly centered on the effectiveness of preconditioning in liver grafts submitted for 16 hours or more of cold ischemia.…”