Abstract
BackgroundEndothelin-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 FindingsA 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.ConclusionsThese 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.
Highlights
Sepsis is a common cause of acute kidney injury (AKI)
These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia
We have previously shown that treatment with tezosentan, a dual endothelin type A receptor (ETA)/endothelin type B receptor (ETB) antagonist, improves renal artery blood flow and renal cortical microcirculation in endotoxemia, but has no effect on urine production [16]
Summary
The pathophysiology of septic AKI remains elusive but renal impairment during sepsis has been postulated to be mediated by kidney hypoperfusion owing to excessive renal vasoconstriction [1]. In animal experiments of endotoxemia dual ETA/ ETB endothelin blockade has been described to improve cardiopulmonary function [4], reduce pulmonary hypertension [5] and lung injury [6], attenuate intestinal microcirculatory dysfunction [7], reduce intestinal acidosis [8,9] and improve renal function [10]. ET-1 has tubular effects favoring diuresis and natriuresis This may be mediated by a reduction of Na/K ATPase activity in the collecting ducts [12] and through an inhibitory effect on the opening of epithelial Na channels by ETB [13]. Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. We investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors
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