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.
Curzen
N P
NP
Unit of Critical Care, National Heart and Lung Institute, London, United Kingdom.
Griffiths
M J
MJ
Evans
T W
TW
D000818:Animals; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology* / Q000503:physiopathology; D004731:Endotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D015999:Multivariate Analysis; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012477:Salmonella enteritidis
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004731:Endotoxins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010880:Piperidines; C057498:ICI 192605; C086539:BQ 788; D007213:Indomethacin