Eta Receptors Blockade, by Activating Etb Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention

Endothelin receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ET B receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ET A-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 ET A-selective antagonists, bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ET A-selective antagonism caused dose-dependent haematocrit/haemoglobin decrease that was prevented by ET B-selective receptor antagonism. ET A-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 ET A-selective antagonism increased vascular permeability via ET B receptor overstimulation. Acutely, ET A-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. Haematocrit/haemoglobin decrease induced by ET A-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 ET A-selective antagonists, by activating ET B 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.