title: Chronic erythropoietin treatment enhances endogenous nitric oxide production in rats.
abstract: 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 NG-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 pressor 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.
authors.affiliation: Department of Pediatrics, Fukui Medical School, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsukahara
authors.forename: M
authors.initials: M
authors.lastname: Hiraoka
authors.forename: C
authors.initials: C
authors.lastname: Hori
authors.forename: I
authors.initials: I
authors.lastname: Hata
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: F
authors.initials: F
authors.lastname: Gejyo
authors.forename: M
authors.initials: M
authors.lastname: Sudo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006400:Hematocrit; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D011994:Recombinant Proteins; D004921:Erythropoietin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester