Pathologic role of endothelin-1 in septic shock.

To elucidate the pathologic role of endothelin-1 (ET-1) in septic shock, we measured plasma ET-1 concentrations after bacterial lipopolysaccharide (LPS) administration in dogs and determined systemic, pulmonary, and renal hemodynamics and blood gas parameters with or without the nonselective ET receptor antagonist TAK-044. Plasma ET-1 concentrations increased significantly after LPS administration, which correlated positively with mean arterial pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, and central venous pressure. LPS infusion induced hypotension, metabolic acidosis, hypoxemia, and renal dysfunction. TAK-044 prevented LPS-induced metabolic acidosis, hypoxemia, and renal dysfunction, but not hypotension. These findings suggest that increased circulating ET-1 plays a compensatory role in the reversal of systemic vasodilatation in septic shock, but exerts deleterious effects on renal and pulmonary circulation.