Vercauteren Magali, Trensz Frederic, Pasquali Anne, Cattaneo Christophe, Strasser Daniel S, Hess Patrick, Iglarz Marc, Clozel Martine
Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
J Pharmacol Exp Ther. 2017 May;361(2):322-333. doi: 10.1124/jpet.116.234930. Epub 2017 Feb 21.
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.
内皮素（ET）受体拮抗剂与液体潴留有关。有人提出，在内皮素受体的两种亚型中，ET受体不应被阻断，因为它们参与了利钠和利尿过程。令人惊讶的是，临床数据表明，ET选择性拮抗剂比双重拮抗剂带来更大的液体超负荷风险。本研究的目的是评估每种内皮素受体对大鼠液体潴留和血管通透性的影响。分别使用西他生坦和安立生坦作为ET选择性拮抗剂，波生坦和马昔腾坦作为双重拮抗剂来代表每一类。ET选择性拮抗作用导致血细胞比容/血红蛋白呈剂量依赖性下降，而ET选择性受体拮抗作用可预防这种下降。与双重拮抗作用相比，ET选择性拮抗作用导致显著的血压降低、血浆容量扩张以及血管通透性更大幅度的增加。离体血管实验表明，ET选择性拮抗作用通过ET受体过度刺激增加血管通透性。急性情况下，ET选择性而非双重拮抗作用激活交感神经活性，并增加血浆精氨酸加压素和醛固酮浓度。在布拉特洛维大鼠和用精氨酸加压素受体拮抗剂治疗的Wistar大鼠中，ET选择性拮抗作用诱导的血细胞比容/血红蛋白下降有所减少。最后，静脉侧血细胞比容/血红蛋白的下降幅度大于动脉侧，提示液体重新分布。总之，通过激活ET受体，内皮素受体拮抗剂（尤其是ET选择性拮抗剂）通过以下方式促进水肿形成：1）血管舒张继发精氨酸加压素和醛固酮激活导致的液体潴留，以及2）血管通透性增加。血浆容量重新分布可能解释了即使在没有液体潴留迹象的情况下血细胞比容/血红蛋白下降的临床观察结果。
