Endogenous A1 adenosine receptors protect against hepatic ischemia reperfusion injury in mice

Hepatic ischemia reperfusion (IR) injury is a major clinical problem during the perioperative period and occurs frequently after major hepatic resection or liver transplantation. Exogenous and endogenous A(1) adenosine receptor (A(1)AR) activation protects against renal IR injury. In this study, we questioned whether exogenous and endogenous A(1)AR activation protects against hepatic IR injury in vivo. A(1)AR wild-type (WT) or knockout mice were subjected to 60 minutes of partial hepatic IR. Some animals were treated with a selective A(1)AR agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.1 mg/kg), or a selective A(1)AR antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.4 mg/kg), 15 minutes before hepatic ischemia. Twenty-four hours after hepatic IR, the A(1) knockout mice and DPCPX-treated A(1) wild-type (A(1)WT) mice developed significantly worse liver injury (alanine aminotransferase, liver necrosis, neutrophil infiltration, and apoptosis) compared to A(1)AR WT mice. However, the selective A(1)AR agonist CCPA failed to protect against hepatic IR injury in A(1)WT mice. Our results show that the endogenous A(1)ARs protect against hepatic IR injury in vivo by primarily reducing apoptosis and necrosis with subsequent reductions in proinflammatory neutrophil infiltration. However, in contrast to the kidneys, in which exogenous A(1)AR activation protected against IR injury, exogenous A(1)AR activation failed to protect against liver injury after IR. We conclude that endogenous A(1)AR activation prevents worsened murine liver IR injury primarily by reducing necrotic and apoptotic cell death. Harnessing the mechanisms of cytoprotection with endogenous A(1)AR activation may lead to new therapies for perioperative hepatic IR injury.