title: Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice.
abstract: The endothelium controls blood flow and pressure by releasing several vasoactive factors, among them the vasodilator nitric oxide (NO) and the potent vasoconstrictor endothelin-1 (ET-1). Although increased NO levels have been found in excessive erythrocytosis, little is known concerning ET-1 expression in this condition. Thus, we examined the endothelin system in transgenic mice that due to constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of approximately 80%. Surprisingly, despite generalized vasodilatation, polycythemic mice exhibited a two- to fivefold elevation in ET-1 mRNA levels in aorta, liver, heart, and kidney. In line with this, increased expression of ET-1 protein was detected in the pulmonary artery by immunohistochemical analysis. Compared with their wild-type littermates, aortic rings of Epo transgenic animals exhibited a marked reduction in vascular reactivity to ET-1 and big ET-1, but this effect was abrogated upon preincubation with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). Pretreatment of polycythemic mice with the ET(A) receptor antagonist darusentan for 3 wk significantly prolonged their survival upon acute exposure to L-NAME. Taken together, these results demonstrate for the first time that excessive erythrocytosis induces a marked activation of the tissue endothelin system that results in increased mortality upon blockade of NO-mediated vasodilatation. Because ETA antagonism prolonged survival after acute blockade of NO synthesis, endothelin may be regarded as a contributor to the adverse cardiovascular effects of erythrocytosis and may thus represent a new target in the treatment of cardiovascular disease associated with erythrocytosis.
authors.affiliation: Cardiology and Cardiovascular Research and Institute of Physiology, University of Zürich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quaschning
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: Thomas
authors.initials: T
authors.lastname: Stallmach
authors.forename: Sidney
authors.initials: S
authors.lastname: Shaw
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
authors.forename: Winfried
authors.initials: W
authors.lastname: Goettsch
authors.forename: Matthias
authors.initials: M
authors.lastname: Hermann
authors.forename: Torsten
authors.initials: T
authors.lastname: Slowinski
authors.forename: Franz
authors.initials: F
authors.lastname: Theuring
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010666:Phenylpropionates / Q000494:pharmacology; D011086:Polycythemia / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D011498:Protein Precursors; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D004921:Erythropoietin; C107831:darusentan; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester