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1 Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: zweier-1{at}medctr.osu.edu.
The goal of this study was to determine whether acetylcholine evokes endothelium-dependent contraction in mouse arteries and define the mechanisms in regulating this response. Arterial rings isolated from wildtype (WT) and endothelial nitric oxide synthase knockout (eNOS-/-) mice were suspended for isometric tension recording. In abdominal aorta from WT mouse contracted with phenylephrine, acetylcholine caused a relaxation that reversed at the concentration of 0.3 to 3 µM. After inhibition of nitric oxide synthase [with N
-nitro-L-arginine methyl ester (L-NAME); 1 mM], acetylcholine (0.1 to 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/prostaglandin H2 (TXA2/PGH2) receptor antagonist, SQ29548 (1 µM) and was associated with endothelium-dependent generation of the TXA2 metabolite, thromboxane B2. Also, SQ29548 (1 µM) abolished the reversal in relaxation evoked by 0.3 to 3 µM acetylcholine, and subsequently enhanced the relaxation to the agonist. The magnitude of the endothelium-dependent contraction to acetylcholine (0.1 to 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.
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