Endothelin ET_A Receptor Blockade, by Activating ET_B Receptors, 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, ET receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ET-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-selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ET-selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ET-selective receptor antagonism. ET-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 ET-selective antagonism increased vascular permeability via ET receptor overstimulation. Acutely, ET-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ET-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 ET receptors, endothelin receptor antagonists (particularly ET-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.

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

“…Recently, experiments in rats demonstrated that the mechanisms of edema formation during selective ET A blockade result from the activation of ET B receptors leading to an increase in vascular permeability and fluid retention (Vercauteren et al 2017). Whatever are the mechanisms responsible for the unwanted fluid retention, the use of diuretics to overcome this problem seems to be reasonable.…”

Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse

“…The selective ET A antagonist, ambrisentan, and the myelosuppressive agent, hydroxyurea, have both been demonstrated to improve renal function and attenuate renal injury in SCD . However, neither treatment alone provides complete restoration of the renal injury phenotype seen in SCN and furthermore, both treatments are sometimes accompanied by adverse side effects . Many patients, however, cannot tolerate therapeutic doses of hydroxyurea or do not respond to treatment at all, leaving them limited treatment options for disease management .…”

“…Furthermore, blocking ET A receptor activity long‐term protects against the development of ET‐1‐induced renal glomerular injury and reduces inflammation in SCN; however, all aspects of tubular injury are not restored . In addition, despite its efficacy in SCN, selective ET A receptor blockade has also been demonstrated to promote fluid retention and vascular permeability via enhanced ET B activation …”

Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension

“…Other safety issues, mostly observed with ET A -selective ERAs, may be alleviated with dual ERAs. Secondary effects of ET A -selective antagonists, such as aggravation of cell proliferation (Hocher et al, 2003) or exaggerated fluid retention (Vercauteren et al, 2017), may be due to chronic stimulation of unantagonized ET B receptors during ET A blockade. The absence of reflex tachycardia secondary to BP reduction following aprocitentan treatment confirms previous observations with other dual, but not ET A -selective, ERAs, suggesting a buffering of autonomic reflexes and absence of reactive Fig.…”