The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

Peralta, Carmen; Hotter, Georgina; Closa, Daniel; Prats, Neus; Xaus, Carme; Gelpí, E.; Roselló‐Catafau, Joan

doi:10.1002/hep.510290104

Cited by 197 publications

(192 citation statements)

References 24 publications

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“…[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.…”

Section: Discussionmentioning

confidence: 99%

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

Itō

Ozasa²,

Sanada

et al. 2000

Hepatology

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Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO-1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zincprotoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO-1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods. (HEPATOLOGY 2000;31:416-419.)

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Section: Discussionmentioning

confidence: 99%

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

Itō

Ozasa²,

Sanada

et al. 2000

Hepatology

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“…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.…”

Section: Protective Mechanisms Of Early Ischemic Preconditioningmentioning

confidence: 99%

“…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].…”

Section: Protective Mechanisms Of Early Ischemic Preconditioningmentioning

confidence: 99%

“…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].…”

Section: Protective Mechanisms Of Delayed Ischemic Preconditioningmentioning

confidence: 99%

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

Cutrn

Perrelli

Cavalieri

et al. 2002

Free Radical Biology and Medicine

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150

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Abstract-Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-␣, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.

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“…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.…”

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confidence: 99%

Signal Pathway Involved in the Development of Hypoxic Preconditioning in Rat Hepatocytes

Carini¹,

Cesaris²,

Splendore³

et al. 2001

Hepatology

102

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Ischemic preconditioning improves liver resistance to hypoxia and reduces reperfusion injury following transplantation. However, the intracellular signals that mediate the development of liver hypoxic preconditioning are largely unknown. We have investigated the signal pathway leading to preconditioning in freshly isolated rat hepatocytes. Hepatocytes were preconditioned by 10-minute incubation under hypoxic conditions followed by 10 minutes of reoxygenation and subsequently exposed to 90 minutes of hypoxia. Preconditioning reduced hepatocyte killing by hypoxia by about 35%. A similar protection was also obtained by preincubation with chloro-adenosine or with A 2A -adenosine receptor agonist CGS21680, whereas A 1 -adenosine receptor agonist N-phenyl-isopropyladenosine (R-PIA) was inactive. Conversely, the development of preconditioning was blocked by A 2 -receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), but not by A 1 -receptor antagonist 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX). In either preconditioned or CGS21680-treated hepatocytes a selective activation of ␦ and protein kinase C (PKC) isoforms was also evident. Inhibition of heterotrimeric G i protein or of phospholypase C by, respectively, pertussis toxin or U73122, prevented PKC activation as well as the development of preconditioning. MEK inhibitor PD98509 did not interfere with preconditioning that was instead blocked by p38 MAP kinase inhibitor SB203580. The direct activation of p38 MAPK by anisomycin A mimicked the protection against hypoxic injury given by preconditioning. Consistently, an increased phosphorylation of p38 MAPK was observed in preconditioned or CGS21680-treated hepatocytes, and this effect was abolished by PKC-blocker, chelerythrine. We propose that a signal pathway involving A 2A -adenosine receptors, G i -proteins, phospholypase C, ␦-and -PKCs, and p38 MAPK, is responsible for the deve- The term ischemic preconditioning refers to the resistance to ischemic injury acquired by tissue following one or more brief periods of ischemia followed by reperfusion. 1,2 Ischemic preconditioning was first described in the myocardium, 1 but has been shown in several other organs, including the brain, the skeletal muscles, and the small intestine. 3 In the heart, ischemic preconditioning occurs in 2 phases: an early phase (early preconditioning) that immediately follows the transient hypoxia and lasts 2 to 3 hours and a late phase (late preconditioning), which begins 12 to 24 hours from the transient ischemia and lasts for about 3 to 4 days. 3 Recent studies have shown that the same phenomenon could also be observed in the liver. [4][5][6][7][8][9][10] In particular, 10-minute interruption of liver blood supply in anesthetized rats followed by 10 minutes of reperfusion reduces transaminases released during a subsequent 90-minute period of ischemia and 90-minute reoxygenation. 5 A similar effect has also been observed in steatosic livers following heat shock preconditioning. 7 Furthermore, ischemic preconditioning before cold preserva...

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The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

Cited by 197 publications

References 24 publications

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

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

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

Signal Pathway Involved in the Development of Hypoxic Preconditioning in Rat Hepatocytes

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