Pharmacological Preconditioning by Adenosine A2a Receptor Stimulation: Features of the Protected Liver Cell Phenotype

Figure 1

Molecular mechanisms involved in hypoxic injury of primary rat hepatocytes and in their protection upon A2aR stimulation. Hypoxic damage: ATP depletion causes intracellular acidosis, inhibition of the Na⁺/K⁺ ATPase, and activation of the Na⁺/H⁺ exchanger with an increase in intracellular Na⁺ content and activation of the K⁺ channel. A2aR protection: A2aR stimulation induces the sequential activation of PKA, Gs and Gi protein, Src, PI3K, PLC, PKC δ, and ε and p38 MAPK. A2aR also inhibits the negative regulators of PKC and PI3K, DGK, and PTEN. PI3K activates V-ATPase that maintains intracellular pH avoiding the activation of the Na⁺/H⁺ exchanger and Na⁺ overload. PI3K and PKC δ and ε activate HIF with production of CAIX. CAIX converts CO₂ into bicarbonate that enters into hepatocyte through the exchanger. This neutralizes intracellular pH without activation of the Na⁺/H⁺ exchanger and the consequent Na⁺ increase. (See also text and [19, 20, 27, 28, 36, 37, 40].)