Improvement of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist

Abstract

Objectives: During endotoxemia, there is a marked and intractable decrease in systemic blood pressure, as well as profound vasoconstriction of the renal artery, thereby leading to septic shock and acute renal failure. The purpose of this study was to elucidate the effect of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, on the hemodynamic and renal vascular changes seen in endotoxemia.

Design: Prospective, comparative, experimental study.

Setting: Laboratory at a university hospital.

Subjects: Thirty-two male mongrel dogs (12.1+/-0.4 kg) under pentobarbital anesthesia.

Interventions: Four groups of animals were studied: a) the lipopolysaccharide (LPS) group (n = 10), which received LPS (250 ng/kg/min for 2 hrs); b) the TAK-044 (a nonselective endothelinA/ endothelinB receptor antagonist) plus LPS group (n = 12), which received a bolus of TAK-044 (5 mg/kg) 0.5 hr before the start of LPS infusion; c) the TAK-044 plus vehicle group (n = 5), which received the same dose of TAK-044 0.5 hr before the start of vehicle infusion; and d) the control group (n = 5), which received only vehicle infusion.

Measurements and main results: Changes in systemic and renal hemodynamics, blood gas, and renal function were measured at baseline, and at 0.5, 1, 2, 3, and 4 hrs. Infusion of LPS resulted in significant decreases in mean arterial pressure, arterial pH, Pao2, base excess, urine volume, renal blood flow, creatinine clearance, and urine osmolality. The administration of TAK-044 before LPS infusion did not affect the LPS-induced hypotension. In contrast, the receptor antagonist prevented LPS-induced metabolic acidosis and hypoxemia, and improved LPS-induced decreases in urine volume, renal blood flow, creatinine clearance, and urine osmolality, whereas TAK-044 or vehicle administered alone resulted in no significant hemodynamic or blood gas changes. Plasma endothelin-1 concentrations significantly increased after LPS infusion, with or without TAK-044.

Conclusions: The present study suggests that endothelin-1 plays an important role in the impaired renal hemodynamics and renal function associated with endotoxemia, and that endothelin receptor antagonists may be useful as therapeutic agents for acute renal failure during endotoxemia.