title: Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion.
abstract: Vasoprotective effects of erythropoietin in animal models are mediated by endothelium-derived NO and/or mobilization of EPCs (endothelial progenitor cells) and may be enhanced by ischaemia: whether they are present in humans is unknown. We examined whether the erythropoietin analogue darbepoetin improves FMD (flow-mediated dilatation), a measure of endothelium-derived NO, and whether this is influenced by preceding I/R (ischaemia/reperfusion). A total of 36 patients (50-75 years) with stable coronary artery disease were randomized to receive a single dose of darbepoetin (300 μg) or saline placebo. FMD was measured at the brachial artery using high-resolution ultrasound. CD133⁺/CD34⁺/VEGFR2⁺ (vascular endothelial growth factor receptor 2) circulating EPCs were enumerated by flow cytometry. Measurements were made immediately before darbepoetin/placebo and at 24 h, 72 h and 7 days. At 24 h, FMD was repeated after 20 min of I/R of the upper limb. A further group of 11 patients was studied according to the same protocol, all receiving darbepoetin, with omission of forearm I/R at 24 h. Immunoreactive erythropoietin peaked at 24 h and remained elevated at approximately 50-fold of baseline at 72 h. FMD did not differ significantly between groups at 24 h (before I/R). At 72 h (48 h after I/R), FMD was greater (by 2.3±0.5% in the darbepoetin compared with the placebo group, a 66% increase over baseline; P<0.001) and greater than FMD at the same time point without preceding I/R (P<0.01). Increases in CD133⁺/CD34⁺/VEGFR2⁺ cells after darbepoetin did not differ according to the presence or absence of preceding I/R. Preceding I/R is required for darbepoetin to enhance endothelial function, possibly by increasing expression of the erythropoietin receptor and by a mechanism likely to involve Akt/NO rather than circulating EPCs.
authors.affiliation: British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, King's College London, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Tilling
authors.forename: Joanne
authors.initials: J
authors.lastname: Hunt
authors.forename: Ann
authors.initials: A
authors.lastname: Donald
authors.forename: Brian
authors.initials: B
authors.lastname: Clapp
authors.forename: Phil
authors.initials: P
authors.lastname: Chowienczyk
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003324:Coronary Artery Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D000068256:Darbepoetin alfa; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004727:Endothelium / Q000187:drug effects* / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000188:drug therapy*; D015539:Platelet Activation / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D014666:Vasomotor System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004921:Erythropoietin; D000068256:Darbepoetin alfa