Vasopressin is involved in endothelin receptor antagonist-induced fluid retention in rat. Differential effect of selective ETA and dual ETA/ETB receptor antagonists

Endothelin receptor antagonists (ERAs) are associated with varying degrees of fluid retention. As endothelin B (ETB) receptors have been involved in natriuresis and diuresis, it was paradoxical to observe that ETA-selective ERAs cause a significant risk of fluid overload in patients. Aim of the present study was to understand the contribution of each ET receptor subtype in the mechanism of fluid retention in rats. Changes in fluid balance were assessed after administration of the prototypic ETA-selective sitaxentan and the dual ETA/ETB receptor antagonist bosentan, by measuring haematocrit (Hct), haemoglobin (Hb), plasma volume (PV), body fluid content and renal excretory function. Acutely, sitaxentan caused marked dose-dependent decreases in Hct and Hb, whereas bosentan had a lesser effect. Chronic studies confirmed this difference and showed that sitaxentan increased PV (+50%) and elevated total body fluid content (+15%) compared with vehicle, while bosentan had a small non-significant effect (+16% for PV and +8% for total body water content). In addition, sitaxentan, but not bosentan, reduced water excretion and increased plasma vasopressin (AVP) concentration (3-fold increase) compared with vehicle-treated rats. In Brattleboro rats lacking AVP and in Wistar rats treated with either the AVP V2 receptor antagonist tolvaptan, or the ETB-selective antagonist BQ-788, hemodilution induced by sitaxentan was markedly reduced. These results demonstrate that ERAs, particularly ETA-selective antagonists cause fluid retention by activating the AVP system via secondary stimulation by endothelin of the uninhibited ETB receptors.