Chronic erythropoietin treatment enhances endogenous nitric oxide production in rats

To examine the effect of chronic administration of recombinant human erythropoietin (rHuEPO) on endogenous nitric oxide (NO) activity, we treated Sprague-Dawley rats with rHuEPO (100 IU kg^-1 or 300 IU kg^-1) or a corresponding vehicle for 2 weeks, administered subcutaneously on alternate days. Treatment elicited increases in haematocrit and systolic blood pressure in a dose-dependent fashion. Simultaneous administration of N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg dl^-1 of drinking water), but not aminoguanidine (400 mg dl^-1), induced a further significant rise in blood pressure. The effect of L-NAME was inhibited by a large dose of L-arginine (2.0 g dl^-1). Polycythaemia and hypertension induced by chronic rHuEPO therapy were associated with increased urinary NO₂^- and NO₃^- (NOx^-) excretion, while co-administration of L-NAME, but not aminoguanidine, reduced NOx^- excretion. Our results indicate that chronic rHuEPO treatment has a significant presser effect, but induces a compensatory increase in the steady-state release of NO by constitutive NO synthase in normal rats. Such enhanced NO synthesis may act as a protective mechanism against the hypertensive effect of rHuEPO.