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

Objectives: During endotoxemia, there is a marked and intractable decrease in systemic blood pressure, as well as profound vasoconstriction of the ren al artery, thereby leading to septic shock and acute renal failure. The pur pose of this study was to elucidate the effect of endothelin-1, a potent en dothelium derived vasoconstrictor peptide, on the hemodynamic and renal vas cular 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 pentobarbita l anesthesia. Interventions: Four groups of animals were studied: a) the lipopolysacchari de (LPS) group (n =10), which received LPS (250 ng/kg/min for 2 hrs); b) th e TAK-044 (a nonselective endothelin(A)/endothelin(B) 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 vehic le infusion; and d) the central 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 art erial pressure, arterial pH, PaO2, base excess, urine volume, renal blood f low, creatinine clearance, and urine osmolality. The administration of TAK 044 before LPS infusion did not affect the LPS-induced hypotension. In cont rast, 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 vehicl e administered alone resulted in no significant hemodynamic or blood gas ch anges. Plasma endothelin-1 concentrations significantly increased after LPS infusion, with or without TAK044. Conclusions: The present study suggests that endothelin-1 plays an importan t role in the impaired renal hemodynamics and renal function associated wit h endotoxemia, and that endothelin receptor antagonists may be useful as th erapeutic agents for acute renal failure during endotoxemia.