Role of soluble guanylate cyclase in dilator responses of the cerebral microcirculation
Role of soluble guanylate cyclase in dilator responses of the cerebral microcirculation
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DOI：
10.1016/s0006-8993(99)01110-5
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发表时间：
1999-03-13
期刊：
影响因子：
2.9
通讯作者：
Sobey, CG
中科院分区：
文献类型：
--
作者：
Faraci, FM;Sobey, CG
脑血管对一氧化氮（NO）的反应是由可溶性鸟苷酸环化酶（sGC）依赖性和潜在的sGC非依赖性机制介导的。一氧化氮可能产生血管舒张的一种不依赖于sgc的机制是抑制通过细胞色素P450途径产生的血管收缩代谢物的形成。在这些实验中，我们检验了大脑微血管对NO反应的扩张依赖于sGC激活的假设。采用封闭颅窗测量麻醉家兔脑小动脉直径（基线直径= 94 +/- 5 μ m，平均+/- S.E.）。在对照条件下，sGC不依赖no的活化剂YC-1[3-（5′-羟甲基-2′-呋喃基）-1-苄基茚唑]产生血管舒张，被sGC抑制剂ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one)（10 μ M）阻断。这些发现表明sGC在脑小动脉中具有重要的功能。此外，乙酰胆碱（通过内皮细胞刺激内源性NO生成）可引起脑小动脉扩张，而ODQ可抑制这种扩张。例如，在ODQ （10 μ M）不存在和存在的情况下，1 μ M乙酰胆碱分别使脑小动脉扩张34 +/- 7%和5 +/- 1%。硝普钠（1 μ M， NO供体）引起的动脉直径增加被ODQ抑制约80%，但细胞色素P450途径抑制剂17-ODYA （10 μ M）或氯曲霉唑（10 μ M）不受影响。因此，外源性一氧化氮和内源性一氧化氮引起的脑微循环扩张在很大程度上依赖于sGC的激活。(C) 1999 Elsevier Science B.V.版权所有
Responses of cerebral blood vessels to nitric oxide (NO) are mediated by soluble guanylate cyclase (sGC)-dependent and potentially by sGC-independent mechanisms. One sGC-independent mechanism by which NO may produce vasodilatation is inhibition of formation of a vasoconstrictor metabolite produced through the cytochrome P450 pathway. In these experiments, we examined the hypothesis that dilatation of cerebral microvessels in response to NO is dependent on activation of sGC. Diameters of cerebral arterioles (baseline diameter = 94 +/- 5 mu m, mean +/- S.E.) were measured using a closed cranial window in anesthetized rabbits. Under control conditions, YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an NO-independent activator of sGC, produced vasodilation that was blocked by ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one)(10 mu M), an inhibitor of sGC. These findings indicate that sGC is functionally important in cerebral arterioles. In addition, acetylcholine (which stimulates endogenous production of NO by endothelium) produced dilatation of cerebral arterioles that was inhibited by ODQ. For example, 1 mu M acetylcholine dilated cerebral arterioles by 34 +/- 7 and 5 +/- 1% in the absence and presence of ODQ (10 mu M), respectively. Increases in arteriolar diameter in response to sodium nitroprusside (1 mu M, an NO donor) were inhibited by approximately 80% by ODQ, but were not affected by 17-ODYA (10 mu M) or clotrimazole (10 mu M), inhibitors of the cytochrome P450 pathway. Thus, dilatation of the cerebral microcirculation in response to exogenously applied and endogenously produced NO is dependent, in large part, on activation of sGC. (C) 1999 Elsevier Science B.V. All rights reserved.