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This study was performed to determine if direct arterial dilating actions of propofol contribute to the drug's hypotensive actions. The effects of propofol were compared with those of thiopental on isolated vascular ring preparations from rat thoracic aorta and pulmonary artery. Thoracic aortic ring responses were evaluated in the presence and absence of endothelium, indomethacin, and Nω-nitro-L-arginine methyl ester (LNAME; a specific inhibitor of endothelium-derived relaxing factor–nitric oxide [EDRF/NO] synthase). Pulmonary artery responses were investigated with intact endothelium. After the induction of active isometric force by a predetermined EC50 dose of phenylephrine for each ring, effects of propofol (30, 100, 300 µM) and thiopental (10, 30, 100 µM) were examined. Propofol caused significant vasodilation in endothelium-intact, endothelium-denuded, and LNAME-treated aortic rings. In the endothelium-intact aortic and pulmonary artery rings, the initial vasodilation due to 30 and 100 µM propofol showed gradual and partial recovery over 15 min; 300 µM propofol caused sustained vasodilation. Endothelium-denuded rings and LNAME-pretreated endothelium-intact rings showed constant and sustained vasodilation with all propofol concentrations. Propofol also caused marked vasodilation in pulmonary arteries. In contrast, thiopental had no vasodilating effect in aortic or pulmonary artery preparations. In control experiments, propofol vehicle (Intralipid®) also had no effect on vascular rings. Indomethacin pretreatment induced a dose-dependent vasoconstriction by thiopental in endothelium-intact rings and decreased the vasodilation due to propofol. These results suggest that propofol directly relaxes arterial smooth muscle, with subsequent progressive attenuation, possibly through the gradual inhibition of EDRF/NO production. Effects in the presence of indomethacin suggest that propofol and thiopental induce the release of vasodilating cyclooxygenase metabolites from vascular rings with intact endothelium.