Adenosine A(2A) and A(2B) receptor activation of erythropoietin production

We have examined the effects of adenosine receptors and protein kinases A a nd C in the regulation of erythropoietin (Epo) production using hepatocellu lar carcinoma (Hep3B) cells in culture and in vivo in normal mice under nor moxic and hypoxic conditions. CGS-21680, a selective adenosine A(2A) agonis t, significantly increased levels of Epo in normoxic Hep3B cell cultures an d in serum of normal mice under both normoxic and hypoxic conditions. CGS-2 1680 also produced a significant increase in Epo mRNA levels in Hep3B cell cultures. SCH-58261, a selective adenosine A(2A) receptor antagonist, signi ficantly inhibited the increase in medium levels of Epo in Hep3B cell cultu res exposed to hypoxia (1% O-2). Enprofylline, a selective adenosine A(2B) receptor antagonist, significantly inhibited the increase in plasma levels of Epo in normal mice exposed to hypoxia. Chelerythrine chloride, an antago nist of protein kinase C activation, significantly inhibited hypoxia-induce d increases in serum levels of Epo in normal mice. A model is presented for adenosine in hypoxic regulation of Epo production that involves kinases A and C and phospholipase A(2) pathways.