title: Effects of recombinant human erythropoietin on resistance artery endothelial function in stage 4 chronic kidney disease.
abstract: BACKGROUND
  Recent studies have raised concern about the safety of erythropoiesis-stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m(2)) aged 63±13 years.
  
  
  RESULTS
  Arteries were mounted on a pressurized myograph. EPO impaired endothelium-dependent relaxation in a concentration-dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO-induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine-induced vasoconstriction or sodium nitroprusside-induced relaxation. ABT-627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin-1 was found in the vessel wall after incubation with EPO.
  
  
  CONCLUSIONS
  EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO-induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Briet
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Muhammad Oneeb Rehman
authors.initials: MO
authors.lastname: Mian
authors.forename: Cristina
authors.initials: C
authors.lastname: Sierra
authors.forename: Pierre
authors.initials: P
authors.lastname: Boutouyrie
authors.forename: Michael
authors.initials: M
authors.lastname: Davidman
authors.forename: David
authors.initials: D
authors.lastname: Bercovitch
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Nessim
authors.forename: Gershon
authors.initials: G
authors.lastname: Frisch
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Mark L
authors.initials: ML
authors.lastname: Lipman
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism; D002081:Buttocks / Q000098:blood supply; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D059168:Carotid Intima-Media Thickness; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006397:Hematinics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D063177:Pulse Wave Analysis; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D006397:Hematinics; D011994:Recombinant Proteins; D014665:Vasodilator Agents; D004921:Erythropoietin; D000109:Acetylcholine