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Acetylcholine causes endothelium-dependent contraction of mouse arteries

Davis Heart and Lung Research Institute, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio

Submitted 8 March 2005 ; accepted in final form 4 May 2005

The goal of this study was to determine whether acetylcholine evokes endothelium-dependent contraction in mouse arteries and to define the mechanisms involved in regulating this response. Arterial rings isolated from wild-type (WT) and endothelial nitric oxide (NO) synthase knockout (eNOS^–/–) mice were suspended for isometric tension recording. In abdominal aorta from WT mice contracted with phenylephrine, acetylcholine caused a relaxation that reversed at the concentration of 0.3–3 µM. After inhibition of NO synthase [with N-nitro-L-arginine methyl ester (L-NAME), 1 mM], acetylcholine (0.1–10 µM) caused contraction under basal conditions or during constriction to phenylephrine, which was abolished by endothelial denudation. This contraction was inhibited by the cyclooxygenase inhibitor indomethacin (1 µM) or by a thromboxane A₂ (TxA₂) and/or prostaglandin H₂ receptor antagonist SQ-29548 (1 µM) and was associated with endothelium-dependent generation of the TxA₂ metabolite TxB_2. Also, SQ-29548 (1 µM) abolished the reversal in relaxation evoked by 0.3–3 µM acetylcholine and subsequently enhanced the relaxation to the agonist. The magnitude of the endothelium-dependent contraction to acetylcholine (0.1–10 µM) was similar in aortas from WT mice treated in vitro with L-NAME and from eNOS^–/– mice. In addition, we found that acetylcholine (10 µM) also caused endothelium-dependent contraction in carotid and femoral arteries of eNOS^–/– mice. These results suggest that acetylcholine initiates two competing responses in mouse arteries: endothelium-dependent relaxation mediated predominantly by NO and endothelium-dependent contraction mediated most likely by TxA₂.

endothelial nitric oxide synthase; gene knockout; cyclooxygenase; endothelium-derived contracting factor

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