title: Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio.
abstract: Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.
authors.affiliation: EA4278, Laboratoire de pharm-écologie cardiovasculaire, Pôle sportif et de recherche universitaire, Université d'Avignon et des Pays de Vaucluse, 15 Boulevard Limbert, 84000 Avignon, France.
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jallat
authors.forename: Alain
authors.initials: A
authors.lastname: Berthelot
authors.forename: Pascal
authors.initials: P
authors.lastname: Laurant
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D002460:Cell Line; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004921:Erythropoietin / Q000494:pharmacology*; D006397:Hematinics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006397:Hematinics; D011994:Recombinant Proteins; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C103998:epoetin beta; D004921:Erythropoietin; D009569:Nitric Oxide; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester