title: Endothelin ETAReceptor Blockade, by Activating ETBReceptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention.
abstract: Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ETBreceptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ETA-selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ETA-selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ETA-selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ETB-selective receptor antagonism. ETA-selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ETA-selective antagonism increased vascular permeability via ETBreceptor overstimulation. Acutely, ETA-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ETA-selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ETBreceptors, endothelin receptor antagonists (particularly ETA-selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Trensz
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Pasquali
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cattaneo
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland martine.clozel@actelion.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000378:metabolism; D000077300:Bosentan; D002199:Capillary Permeability / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006400:Hematocrit / Q000379:methods; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011910:Rats, Brattleboro; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D006454:Hemoglobins; D010666:Phenylpropionates; D011724:Pyridazines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017483:Receptors, Vasopressin; D013449:Sulfonamides; D001127:Arginine Vasopressin; D000450:Aldosterone; C467894:ambrisentan; D000077300:Bosentan; C533860:macitentan