RT Journal Article
SR Electronic
T1 ETA RECEPTORS BLOCKADE, BY ACTIVATING ETB RECEPTORS, INCREASES VASCULAR PERMEABILITY AND INDUCES EXAGGERATED FLUID RETENTION.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.116.234930
DO 10.1124/jpet.116.234930
A1 Magali Vercauteren
A1 Frederic Trensz
A1 Anne Pasquali
A1 Christophe Cattaneo
A1 Daniel S Strasser
A1 Patrick Hess
A1 Marc Iglarz
A1 Martine Clozel
YR 2017
UL http://jpet.aspetjournals.org/content/early/2017/02/21/jpet.116.234930.abstract
AB Endothelin receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ETB receptors 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, bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ETA-selective antagonism caused dose-dependent haematocrit/haemoglobin decrease that was prevented by ETB-selective receptor antagonism. ETA-selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and more vascular permeability increase than dual antagonism. Isolated vessels experiments showed that ETA-selective antagonism increased vascular permeability via ETB receptor overstimulation. Acutely, ETA-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. Haematocrit/haemoglobin decrease induced by ETA-selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally haematocrit/haemoglobin decrease was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, endothelin receptor antagonists, and particularly ETA-selective antagonists, by activating ETB receptors, favour edema formation by causing 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, 2) vascular permeability increase. Plasma volume redistribution may explain the clinical observation of haematocrit/haemoglobin decrease even in the absence of signs of fluid retention.