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.
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Research Article|
December 07 2011
Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion
Lindsey Tilling;
Lindsey Tilling
*British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, King's College London, St Thomas' Hospital, London SE1 7EH, U.K.
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Joanne Hunt;
Joanne Hunt
*British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, King's College London, St Thomas' Hospital, London SE1 7EH, U.K.
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Ann Donald;
Ann Donald
*British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, King's College London, St Thomas' Hospital, London SE1 7EH, U.K.
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Brian Clapp;
Brian Clapp
†Department of Cardiology, St Thomas' Hospital, London SE1 7EH, U.K.
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Phil Chowienczyk
*British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, King's College London, St Thomas' Hospital, London SE1 7EH, U.K.
Correspondence: Professor Phil Chowienczyk (email phil.chowienczyk@kcl.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 20 2011
Revision Received:
September 12 2011
Accepted:
October 03 2011
Accepted Manuscript online:
October 03 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 122 (7): 329–336.
Article history
Received:
July 20 2011
Revision Received:
September 12 2011
Accepted:
October 03 2011
Accepted Manuscript online:
October 03 2011
Citation
Lindsey Tilling, Joanne Hunt, Ann Donald, Brian Clapp, Phil Chowienczyk; Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion. Clin Sci (Lond) 1 April 2012; 122 (7): 329–336. doi: https://doi.org/10.1042/CS20110369
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