Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Renal function parameters.

<p>Changes in Creatinine clearance (A), Fractional excretion of sodium (FENA) (B) and diuresis (C) in response to lipopolysaccharide infusion and treatment with either the selective ETA antagonist, TBC 3711 (2 mg·kg ⁻¹, n = 8) or control (n = 8) Data are expressed as mean ± SEM. <b>#</b> indicates a significant difference between TBC 3711 and control in response to lipopolysaccharide. (ANOVA repeated measures including 120, 180, 240 and 300). * indicates a significant change in effect over time (120–300).</p

Systemic and renal parameters.

<p>Data are for TBC 3711 (TBC, n = 8) and Control (n = 8) expressed as mean ± SEM. ANOVA repeated measures including 120, 180, 240 and 300 was performed. The p-value refers to the time-treatment interaction using these time-points. Differences were considered significant at <i>p</i>≤0.05. ET-1 = Endothelin-1, RVC = Renal vascular conductance,.</p

Renal hemodynamics.

<p>Changes in mean arterial blood pressure (MAP) (A), renal blood flow (RBF) (B), Laser Doppler flowmetry renal cortex (LD Cortex) (C) and Laser Doppler flowmetry renal medulla (LD Medulla) (D) in response to lipopolysaccharide infusion and treatment with either the selective ETA antagonist, TBC 3711 (2 mg·kg⁻¹, n = 8) or control (n = 8). Data are expressed as mean ± SEM. # indicates a significant difference between TBC 3711 and control in response to lipopolysaccharide. (ANOVA repeated measures including 120, 180, 240 and 300). * indicates a significant change in effect over time (120–300).</p