Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice.
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.
Quaschning
Thomas
T
Cardiology and Cardiovascular Research and Institute of Physiology, University of Zürich, Switzerland.
Ruschitzka
Frank
F
Stallmach
Thomas
T
Shaw
Sidney
S
Morawietz
Henning
H
Goettsch
Winfried
W
Hermann
Matthias
M
Slowinski
Torsten
T
Theuring
Franz
F
Hocher
Berthold
B
Lüscher
Thomas F
TF
Gassmann
Max
M
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
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