Antidiuretic effects of the endothelin receptor antagonist avosentan

Abstract

Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ET(A) receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ET(B) receptors may occur. Incremental doses of the predominant ET(A) receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate, and blood pressure (BP) were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while BP was reduced by 10 mmHg only by the highest dose of SPP301. Administration of the ET(B) selective receptor antagonist BQ-788 (3 mg/kg) following SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. 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 predominant ET(A) receptor blockers.

Keywords: diuresis; endothelin receptor antagonist; fluid retention; renal.

Figure 1

Study design. Group A study design: i.v. administration of BQ-788 (3 mg/kg) to anesthetized male SD rats undergoing saline diuresis. Group B study design: i.v. administration of incremental doses of SPP301 (0.003; 0.03; 3 mg/kg) followed by BQ-788 (3 mg/kg) to anesthetized male SD rats undergoing saline diuresis.

Figure 2

Urine and sodium excretion measured by: (A) urine output (μL/min); (B) fractional excretion of water (%); (C) urine sodium output (μmol/min); and (D) fractional excretion of sodium (%); in male SD rats treated with incremental doses of SPP301 (0.003; 0.03; 3 mg/kg) followed by BQ-788 (3 mg/kg). Fractional excretion of water (percentage of water excreted by the kidney from the total amount filtered) = urine output/GFR. Fractional excretion of sodium (percentage of Na⁺ excreted by the kidney from the total amount filtered) = urine Na⁺ output/[Plasma (Na⁺) × GFR]. *p < 0.05 compared with control (vehicle).

Figure 3

Glomerular filtration rate (mL/min) in male SD rats treated with incremental doses of SPP301 (0.003; 0.03; 3 mg/kg) followed by BQ-788 (3 mg/kg).

Figure 4

Mean arterial pressure (mm Hg) in male SD rats treated with incremental doses of SPP301 (0.003; 0.03; 3 mg/kg) followed by BQ-788 (3 mg/kg). *p < 0.05 compared with control (vehicle).

Figure 5

Hematocrit (%) in male SD rats treated with incremental doses of SPP301 (0.003; 0.03; 3 mg/kg) followed by BQ-788 (3 mg/kg). *p < 0.05 compared with control (vehicle).