Contraction to endothelin-1 in pulmonary arteries from endotoxin-treated rats is modulated by endothelium.

Sepsis is characterized by hyporesponsiveness of vascular smooth muscle to pressor agents. Levels of the potent vasoconstrictor, endothelin-1 (ET-1), are elevated in animal models of sepsis and in patients. This study assesses the contractile response of pulmonary artery from endotoxin-pretreated rats to ET-1 to determine whether this contraction is modified by the endothelium. Both intact and denuded rings from endotoxin-pretreated rats exhibited hyporesponsiveness to ET-1, but the endothelium was found to be essential for maximal ET-1-induced contraction. Upon pretreatment of vessels with the cyclooxygenase inhibitor, indomethacin (10(-5) M), the novel ETB-receptor antagonist, BQ-788 (10(-8) and 10(-6) M), and the thromboxane A2-receptor antagonist, ICI-192605 (10(-5) M), each of these agents caused a reduction in the ET-1-induced contraction of endotoxin-pretreated rat pulmonary artery only in the presence of the endothelium but had no effect in endothelium-denuded vessels or in sham-treated groups. These findings demonstrate that ET-1-induced contraction in pulmonary arteries from septic rats is partially dependent upon an endothelially derived cyclooxygenase product, the release of which appears to involve ETB-receptor stimulation.