Ischaemic and pharmacological preconditionings protect liver via adenosine and redox status following hepatic ischaemia/reperfusion in rats

Although IPC (ischaemic preconditioning) is considered as a protective strategy in HI/R (hepatic ischaemia/reperfusion), the mechanisms for this effect have not been fully elucidated. In the present study we investigate whether PPC (pharmacological preconditioning) by transient activation of A₁R (adenosine A₁ receptor) protects against long-term HI/R and whether the protective effects of IPC depend on A₁R activation and whether both preconditionings affect remote organs. Wistar rats underwent IPC and long-term HI/R. Another set of animals were pharmacologically preconditioned with the A₁R-agonist CCPA [2-chloro-N⁶-cyclopentyladenosine; 0.1 mg/kg of body weight, i.p. (intraperitoneally)] 24 h before HI/R. In other groups, rats received an A₁R-antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; 0.1 mg/kg of body weight, i.p.) 24 h before HI/R. Hepatic damage was evaluated by transaminase [AST (aspartate transaminase), ALT (alanine transaminase)] release; inflammation was assessed by hepatic MPO (myeloperoxidase) and serum TNFα (tumour necrosis factor α) and NO; oxidative stress was estimated by MDA (malondialdehyde) and 4-HDA (4-hydroxyalkenals), SOD (superoxide dismutase) activity, GSH and ADA (adenosine deaminase) as adenosine metabolism. Both preconditionings protected liver and lung against HI/R as indicated by the reduction in transaminases, MPO, MDA+4-HDA, NO, TNFα and ADA activity as compared with HI/R (P<0.05). However, pre-treatment with DPCPX abolished the protective effects of IPC and PPC. Preconditionings induced a significant increase in hepatic MnSOD (manganese SOD) activity and NO generation compared with the sham group, and this activity was abolished by DPCPX pre-treatment. A₁R activation induced hepatic delayed preconditioning and blockade of A₁R abolished hepatic IPC. IPC, as well as PPC, were able to prevent lung damage. These protective effects are associated with a reduction in oxidative stress, inflammation and endogenous antioxidant preservation.