Pharmacological postconditioning protects against hepatic ischemia/reperfusion injury

Abstract

Postconditioning is a procedure based on the induction of intracellular protective reactions immediately after the onset of reperfusion. Because of the growing need to prevent ischemia/reperfusion (I/R) injury during liver surgery and transplantation, we investigated the possibility of pharmacologically inducing hepatic postconditioning. The effects of the adenosine A2A receptor agonist 2p-(2-carboxyethyl)-phenyl-amino-5 0 -N-ethylcarboxyamido-adenosine (CGS21680; 5 lmol/L) and the phosphatase and tensin homologue deleted from chromosome 10 (PTEN) inhibitor dipotassium bisperoxo-(5-hydroxypyridine-2-carboxyl)-oxovanadate [bpV(HOpic); 250 nmol/L] were investigated in primary rat hepatocytes during reoxygenation after 24 hours of cold storage and in an in vivo model of rat liver warm I/R. The addition of CGS21680 at reoxygenation significantly reduced hepatocyte death through the activation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/ Akt signal pathway and through the reduction of the intracellular level of PTEN. PTEN lowering was associated with the increased generation of reactive oxygen species after A2A receptor-mediated stimulation of b-nicotinamide adenine dinucleotide phosphate oxidase (NOX). The inhibition of PI3K or NOX with wortmannin or diphenyleneiodonium chloride, respectively, and the addition of the antioxidant N,N 0 -diphenyl-p-phenylenediamine reversed the effects of CGS21680. The PTEN inhibitor bpV(HOpic) mimicked the protection provided by CGS21680 against reoxygenation damage. An in vivo rat treatment with CGS21680 or bpV(HOpic) during reperfusion after 1 hour of partial hepatic ischemia also promoted PKB/Akt activation and ameliorated alanine aminotransferase release and histological lesions induced by 2 hours of reperfusion. We conclude that adenosine A2A receptor agonists and PTEN inhibitors are possibly useful agents for the pharmacological induction of postconditioning in the liver.

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide

“…Dal Ponte et al [8] also reported that pretreatment with a PI3K inhibitor prevented A2A receptor agonist-induced PostC of the liver. Previous studies showed that milrinone administration stimulated immediate accumulation of cAMP and elevation of PKA in the liver tissue, and pretreatment with a PKA inhibitor prevented milrinone-induced PreC [14,15].…”

“…Ischemia-and A2A receptor agonist-or ginsenoside Rb1-induced PostC markedly enhanced Akt phosphorylation of the liver tissues at reperfusion, and attenuated hepatic warm IR injury [6,8,22].…”

“…Although the mechanisms responsible for ischemic PostC of the liver are not fully understood, some studies have shown that the two processes have many similarities [6][7][8]. Recent studies have demonstrated that some agents, such as adenosine A2A receptor agonist [8], rhEPO [9], and sevoflurane [10], can be used as pharmacological inducers of PostC as well as PreC. Milrinone has been shown to have PreC properties using an orthotopic liver transplantation model and warm IR injury model in rats [14,15].…”

“…Although the mechanisms responsible for ischemic PostC of the liver are not as well characterized as those responsible for PreC, recent studies have shown that the two processes have many similarities, including adenosine- [8], phosphoinositide 3-kinase (PI3K)/Akt- [6], and endothelial and inducible nitric oxide synthase (eNOS and iNOS)-mediated NO production [5], as well as inhibition of the opening of the mitochondrial permeability transition pore (mPTP) [7].…”

“…Similarly, studies have demonstrated that some agents, such as adenosine A2A receptor agonist [8], recombinant erythropoietin (rhEPO) [9], and the volatile anesthetic sevoflurane [10], can be used as pharmacological inducers of PostC as well as PreC.…”