Adenosine A2 receptor stimulation protects the predamaged liver from cold preservation through activation of cyclic adenosine monophosphate-protein kinase a pathway

Abstract

The shortage of organ donors has led to reconsideration for the use of non-heart-beating donors (NHBDs). However, graft injury caused by warm ischemia in livers from NHBDs strongly affects posttransplantation outcome. The aim of the present study is to investigate the role of adenosine A2 receptor with regard to hepatic viability after cold preservation of NHBD livers. Cardiac arrest was induced in Wistar rats by phrenotomy of the anesthetized nonheparinized animal. After 60 minutes, the livers were excised and flushed with 60 mL of histidine-tryptophan-ketoglutarate (HTK) and stored submerged in HTK at 4ЊC for 24 hours. Reperfusion was performed in vitro after all livers were incubated at 22ЊC in saline solution to account for the period of slow rewarming during surgical implantation in vivo. Addition of the selective A2-receptor agonist (CGS 21680; 30g/ 100 mL) to the preservation solution resulted in a significant reduction to one quarter of the parenchymal enzyme release of alanine aminotransferase or lactate dehydrogenase on reperfusion and promoted a 2-fold increase in hepatic bile production. This salutory effect was accompanied by a significant increase (40%) in the activity ratio of protein kinase A (PKA) in the liver tissue and could be abrogated in large part by the PKA inhibitor, Rp-cAMPs. Stimulation of the adenosine A2 receptor during harvest and storage of the graft improves maintenance of tissue integrity in liver grafts. A major part of this effect, which may represent a promising approach for the use of NHBD grafts, seems to be mediated through activation of PKA.

Fructose Protects Murine Hepatocytes from Tumor Necrosis Factor-induced Apoptosis by Modulating JNK Signaling

“…3, C and D). It was shown that adenosine has the potential to protect the liver during ischemia/reperfusion injury adenosine receptor 2-mediated activation of adenylate cyclase resulting in the formation of cAMP (26). In agreement with these observations we demonstrated that fructose, as well as adenosine, lead to increased levels of intracellular cAMP in primary murine hepatocytes (Fig.…”

The Effect of Normothermic Recirculation is Mediated by Ischemic Preconditioning in NHBD Liver Transplantation

“…Moreover, it has been recently shown that cyclic AMP (cAMP) may also play a role in liver IP (32,33). The stimulation of A2-type receptors may in fact stimulate this cyclic AMP production, while A1 stimulation decreases cyclic AMP producing a deleterious effect (34).…”

“…This unexpected beneficial effect could be very well explained if we understand that by the use of DPCPX we block all A1 receptors in such a way that the activated adenosine produced by NR may significantly affect A2 receptors (the predominant type). Moreover, it has been recently shown that cyclic AMP (cAMP) may also play a role in liver IP (32,33). The stimulation of A2-type receptors may in fact stimulate this cyclic AMP production, while A1 stimulation decreases cyclic AMP producing a deleterious effect (34).…”

Protective Effects of Adenosine Receptor Agonist in a Cirrhotic Liver Resection Model

“…Further analysis of the slides also revealed infiltration of inflammatory cells in certain areas, along with necrotic/apoptotic cells. Minor et al showed that stimulation of A2ARs better protected pre-damaged cold-stored liver grafts, and there was much less IRI-related damage ( 35 ). In another similar study, Ben-Ari et al showed that rats treated with CGS21680 showed significantly lower levels of apoptotic cells; they also showed that the histological sections revealed a high level of acidophilic bodies ( 25 ).…”