Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat

Hepatic ischemia-reperfusion WR) injury associated with liver transplantati on and hepatic resections are an unresolved problem in the clinical practic e. Preconditioning is known to preserve energy metabolism in liver during s ustained ischemia, but the molecular mechanisms underlying this effect are still unclear, Different metabolic signals, including adenosine monophospha te (AMP) and nitric oxide (NO), have been implicated in preconditioning. AM P-activated protein kinase (AMPK) protects cells by acting as a low-fuel wa rning system, becoming switched on by adenosine triphosphate (ATP) depletio n. NO synthesis is induced by AMPK in the heart during ischemia. The aim of this study was to investigate: 1) whether preconditioning induces AMPK act ivation; and 2) if AMPK activation leads to ATP preservation and reduced la ctate accumulation during prolonged ischemia and its relationship with NO. Preconditioning activated AMPK and concomitantly reduced ATP degradation, l actate accumulation, and hepatic injury. The administration of an AMPK acti vator, AICAR, before ischemia simulated the benefits of preconditioning on energy metabolism and hepatic injury. The inhibition of AMPK abolished the protective effects of preconditioning. The effect of AMPK on energy metabol ism was independent of NO because the inhibition of NO synthesis in the pre conditioned group and the administration of the NO donor before ischemia, o r to the preconditioned group with previous inhibition of AMPK, had no effe ct on energy metabolism. Both preconditioning and AICAR pretreatment, throu gh AMPK activation, may be useful surgical and pharmacologic strategies aim ed at reducing hepatic I/R injury.