Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice
Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice
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DOI：
10.1016/j.ejphar.2004.04.012
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发表时间：
2004-06-16
影响因子：
5
通讯作者：
Kennedy, RH
中科院分区：
文献类型：
--
作者：
Khurana, S;Chacon, I;Kennedy, RH
乙酰胆碱与血管内皮细胞的M受体相互作用，促进一氧化氮(NO)的释放，从而引起血管扩张。本研究旨在确定乙酰胆碱的这种作用是否由M-3受体介导。从野生型(WT)和M-3受体敲除(M3R-/-)雄性小鼠分离胸主动脉，内皮完整(1)和去内皮(D)的主动脉环浸泡在生理缓冲液中。分别加入苯肾上腺素(1×10(-8)~3×10(-4)M)、乙酰胆碱(10(-8)~10(-4)M)、卡巴胆碱(10(-9)~10(-4)M)、三磷酸腺苷(3×10(-5)M)和一氧化氮供体SIN-1(10(-4)M)。在WT小鼠分离的主动脉中，乙酰胆碱和卡巴胆碱的内皮依赖性血管扩张作用明显(在苯肾上腺素诱导的收缩中分别减少56.3+/-9.8%和49.1+/-4.1%；p<；0.05)，而在内皮完整的M3R-/-制剂中观察到的乙酰胆碱和卡巴胆碱相关的舒缩作用(分别减少17.9+/-2.6%和13.5+/-4.2%)与时间控制值没有显著差异。在M3R-/-和WT小鼠的制剂中，ATP诱导的内皮依赖性血管扩张相似，SIN-1在完整和剥离的WT和M3R-/-节段中产生类似的扩张效应。去除内皮后，两组苯肾上腺素浓度-反应曲线左移(EC50值：WT-I/D-25.59+/-6.86/3.13+/-1.01×10(-7)M；M3R-/-I/D-13.92+/-4.21/1.52+/-0.46×10(-7)M；P<；0.05)，但WT组和M3R-/-组之间苯肾上腺素反应无显著差异。这些结果表明，乙酰胆碱对M3R-/-小鼠血管内皮完整的扩张作用是由于缺乏M-3受体所致，提示M-3受体在血管内皮依赖性的乙酰胆碱诱导的血管扩张中起主要作用。(C)2004爱思唯尔B.V.保留所有权利。
Acetylcholine interacts with endothelial muscarinic receptors to enhance nitric oxide (NO) release and thereby cause vasodilation. The present study was designed to determine if this effect of acetylcholine is mediated by muscarinic M-3 receptors. Thoracic aortae were isolated from wild-type (WT) and M-3 receptor knock out (M3R-/-) male mice, and endothelium-intact (1) and -denuded (D) aortic rings were bathed in physiological buffer. Preparations were utilized to examine the contractile response to phenylephrine (1 x 10(-8) -3 x 10(-4) M added cumulatively) and the vasodilatory actions of acetylcholine (10(-8) - 10(-4) M), carbachol (10(-9)- 10(-4) M), ATP (3 x 10(-5) M) and the NO donor SIN-1 (10(-4) M), each added in the presence of phenylephrine. Endothelium-dependent vasodilatory effects of acetylcholine and carbachol were obvious in aortae isolated from WT mice (56.3 +/- 9.8% and 49.1 +/- 4.1% reductions, respectively, in phenylephrine-induced contraction; p < 0.05), while acetylcholine and carbachol-associated relaxations observed in endothelium-intact M3R-/- preparations (17.9 +/- 2.6% and 13.5 +/- 4.2% reductions, respectively) did not differ significantly from time-control values. ATP-induced, endothelium-dependent vasodilation was similar in preparations from M3R-/- and WT mice, and SIN-1 elicited similar dilatory effects in intact and denuded WT and M3R-/- segments. Phenylephrine concentration-response curves were shifted leftwards by removal of the endothelium in both groups (EC50 values: WT-I/D-25.59 +/- 6.86/3.13 +/- 1.01 x 10(-7) M; M3R-/-I/D-13.92 +/- 4.21/1.52 +/- 0.46 x 10(-7) M; both p < 0.05); however, the phenylephrine response did not differ significantly when compared between the WT and M3R-/- groups. These results indicate that the attenuated vasodilatory effect of acetylcholine in endothelium-intact aortae from M3R-/- mice is due to the absence of muscarinic M-3 receptors, and thus suggest that in mouse aorta, muscarinic M-3 receptors play a major role in the endothelium-dependent acetylcholine-induced vasodilation. (C) 2004 Elsevier B.V. All rights reserved.