Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine

1 This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750  ml.
2 Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5  mg  kg⁻¹ over 20  min, followed by 0.5  mg  kg⁻¹ min⁻¹), dipyridamole (0.21  mg  kg⁻¹ h⁻¹) or placebo (0.9% NaCl) for 6  h following the phlebotomy. EPO concentrations were followed up to 72  h after phlebotomy.
3 Following blood loss EPO concentrations increased during all treatments. The AUC_EPO (0,72  h) were not statistically significantly different (theophylline: 398±30, dipyridamole: 301±15, placebo: 332±57 [mu  ml⁻¹ h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activitiy was significantly increased during theophylline infusion.
4 In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.