Erythropoietin enhances oxygenation in critically perfused tissue through modulation of nitric oxide synthase.
The aim of this study was to investigate the effect of human recombinant erythropoietin (EPO) on the microcirculation and oxygenation of critically ischemic tissue and to elucidate the role of endothelial NO synthase in EPO-mediated tissue protection. Island flaps were dissected from the back skin of anesthetized male Syrian golden hamsters including a critically ischemic, hypoxic area that was perfused via a collateralized vasculature. Before ischemia, animals received an injection of epoetin beta at a dose of 5,000 U/kg body weight with (n = 7) or without (n = 7) blocking NO synthase by 30 mg/kg body weight L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride). Saline-treated animals served as control (n = 7). Ischemic tissue damage was characterized by severe hypoperfusion and inflammation, hypoxia, and accumulation of apoptotic cell nuclei after 5 h of collateralization. Erythropoietin pretreatment increased arteriolar and venular blood flow by 33% and 37%, respectively (P < 0.05), and attenuated leukocytic inflammation by approximately 75% (P < 0.05). Furthermore, partial tissue oxygen tension in the ischemic tissue increased from 8.2 to 15.8 mmHg (P < 0.05), which was paralleled by a 21% increased density of patent capillaries (P < 0.05) and a 50% reduced apoptotic cell count (P < 0.05). The improved microcirculation and oxygenation were associated with a 2.2-fold (P < 0.05) increase of endothelial NO synthase protein expression. Of interest, L-NAME completely abolished all the beneficial effects of EPO pretreatment. Our study demonstrates that, in critically ischemic and hypoxic collateralized tissue, EPO pretreatment improves tissue perfusion and oxygenation in vivo. This effect may be attributed to NO-dependent vasodilative effects and anti-inflammatory actions on the altered vascular endothelium.
Division of Plastic and Reconstructive Surgery, University Hospital, Zurich, Switzerland. claudio.contaldo@usz.ch
Claudio
C
Contaldo
Ahmed
A
Elsherbiny
Nicole
N
Lindenblatt
Jan A
JA
Plock
Otmar
O
Trentz
Pietro
P
Giovanoli
Michael D
MD
Menger
Guido A
GA
Wanner
D000818:Animals; D006224:Cricetinae; D016638:Critical Illness; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011994:Recombinant Proteins; D012039:Regional Blood Flow / Q000187:drug effects; D013524:Surgical Flaps / Q000098:blood supply
D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin; D019001:Nitric Oxide Synthase; D010100:Oxygen