Hypoxia or
anemia is the fundamental stimulus for
erythropoietin (EPO) production. Recent in vitro studies suggest that EPO secretion in response to
hypoxia is regulated by
adenosine in the kidney. In order to examine the in vivo effect of
adenosine on EPO production, we determined the effects of
adenosine receptor agonists and antagonists on serum EPO concentration in normal and anemic rats. In normal rats,
intravenous injection of
adenosine agonists (
NECA, CHA and
CGS-21680) dose-dependently stimulated EPO production. Pretreatment with
KW-3902, an
adenosine A1 antagonist with modest A2b antagonistic action, or KF17837, an
adenosine A2a antagonist, inhibited the
NECA (0.1 mg/kg, i.v.)-stimulated EPO production. Anemic
hypoxia, induced by 2% (v/w
body weight) blood withdrawal, increased serum EPO concentration from 38 +/- 2 to 352 +/- 76 mU/ml, with the increased serum
adenosine concentration in the renal vein. KF17837 (0.1 mg/kg, i.v.), but not
KW-3902 (0.1 mg/kg, i.v.), inhibited the anemic
hypoxia-induced increase in EPO production. The present findings support the notion that
adenosine mediates the EPO production in response to
hypoxia in the kidney.