Stimulation of p38 MAP kinase reduces acidosis and Na+ overload in preconditioned hepatocytes

Ischemic preconditioning has been shown to improve liver resistance to hypo xia/reperfusion damage,A signal pathway involving A(2A)-adenosine receptor, G(i)-proteins, protein kinase C and p38 MAP kinase is responsible for the development of hypoxic preconditioning in hepatocytes. However, the couplin g of this signal pathway with the mechanisms responsible for cytoprotection is still unknown, We have observed that stimulation of A(2A)-adenosine rec eptors or of p38 MAPK by CGS21680 or anisomycin, respectively, appreciably reduced intracellular acidosis and Na+ accumulation developing during hypox ia. These effects were reverted by p38 MAPK inhibitor SB203580 as well as b y blocking vacuolar proton ATPase with bafilomycin A(1), SB203580 and bafil omycin cin A(1) also abolished the cytoprotective action exerted by both CG S21680 and anisomycin. We propose that the stimulation of p38 MAPK by preco nditioning might increase hepatocyte resistance to hypoxia by activating pr oton extrusion through vacuolar proton ATPase, thus limiting Na+ overload p romoted by Na+-dependent acid buffering systems. (C) 2001 Federation of Eur opean Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.