Hepatic
ischemia-reperfusion (I/R) injury associated with
liver transplantation and hepatic resections are an unresolved problem in the clinical practice. Preconditioning is known to preserve energy metabolism in liver during sustained
ischemia, but the molecular mechanisms underlying this effect are still unclear. Different metabolic signals, including
adenosine monophosphate (
AMP) and
nitric oxide (NO), have been implicated in preconditioning.
AMP-activated protein kinase (AMPK) protects cells by acting as a low-fuel warning system, becoming switched on by
adenosine triphosphate (
ATP) depletion. NO synthesis is induced by AMPK in the heart during
ischemia. The aim of this study was to investigate: 1) whether preconditioning induces AMPK activation; and 2) if AMPK activation leads to
ATP preservation and reduced
lactate accumulation during prolonged
ischemia and its relationship with NO. Preconditioning activated AMPK and concomitantly reduced
ATP degradation,
lactate accumulation, and hepatic injury. The administration of an AMPK activator,
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 metabolism was independent of NO because the inhibition of NO synthesis in the preconditioned group and the administration of the NO donor before
ischemia, or to the preconditioned group with previous inhibition of AMPK, had no effect on energy metabolism. Both preconditioning and
AICAR pretreatment, through AMPK activation, may be useful surgical and pharmacologic strategies aimed at reducing hepatic I/R injury.