Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion

Lindsey Tilling, Joanne Hunt, Ann Donald, Brian Clapp, Phil Chowienczyk*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    4 Citations (Scopus)


    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 mu g) 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 II 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 CD 133(+) /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.

    Original languageEnglish
    Pages (from-to)329-336
    Number of pages8
    JournalClinical Science
    Issue number7-8
    Publication statusPublished - Apr 2012


    • endothelial function
    • endothelial progenitor cell
    • erythropoietin
    • ischaemia/reperfusion
    • nitric oxide
    • IN-VIVO
    • ALPHA


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