Antidiuretic Effects of Endothelin A Receptor Antagonism

Abstract

Selective ET‐A receptor antagonism has diuretic and natriuretic effects which may be potentiated by the unopposed activation of ET‐B receptors by endogenous endothelin. A major side effect of selective ET‐A receptor antagonists is fluid retention and edema. We hypothesized that compounds with high selectivity against ET‐A receptors produce fluid retention at concentrations where non‐specific blockade of ET‐B receptors may occur. Incremental doses of the ET‐A receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg; lower dose to target ET‐A receptor, highest dose to target both ET‐A and ET‐B receptors based on a CHO cell assay) were administered i.v. to anesthetized rats (SD, n=6) undergoing saline diuresis (15 mL/kg/h, 1% BSA). Urine was collected from the bladder while blood pressure (BP) and glomerular filtration rate (GFR) were monitored. SPP301 decreased urine output (49; 46; 32 ul/min, p<0.05) and fractional excretion of water (6; 5; 4 %, p<0.05) in a concentration‐dependent manner. Sodium excretion was initially increased but returned to control values after the highest dose of SPP301. GFR was unchanged while BP was reduced by 10 mmHg only by the highest dose of SPP301. Administration of BQ‐788 (ET‐B receptor antagonist, 3mg/kg) after SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on GFR. The highest dose of SPP301 caused a decrease of both 24‐hour diuresis (18.3%) and natriuresis (17.6%) with a consequent hematocrit decrease (8.3%) in a hypertensive transgenic model expressing both human renin and angiotensinogen genes. These data indicate that increasing concentrations of SPP301 may also block ET‐B receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with selective ET‐A receptor blockers.