Salvinorin A produces cerebrovasodilation through activation of nitric oxide synthase, κ receptor, and adenosine triphosphate-sensitive potassium channel.
Salvinorin A produces cerebrovasodilation through activation of nitric oxide synthase, κ receptor, and adenosine triphosphate-sensitive potassium channel.
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DOI：
10.1097/aln.0b013e318204e029
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发表时间：
2011-02
期刊：
影响因子：
8.8
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Su D;Riley J;Kiessling WJ;Armstead WM;Liu R
丹参素A是一种非阿片类、选择性κ阿片受体激动剂。尽管它具有很高的临床应用潜力，但其药理作用尚不为人所知。在目前的研究中，我们假设丹参甲素通过激活一氧化氮合酶、三磷酸腺苷敏感钾通道和阿片受体来扩张软脑膜动脉。对闭合颅窗仔猪的大脑动脉内径和蛛网膜下腔皮质脑脊液中的环鸟苷进行了监测。在给药前后观察有无阿片受体拮抗剂(纳洛酮)、κ阿片受体选择性拮抗剂(去甲肾上腺素)、一氧化氮合酶抑制剂(N(G)-硝基-L-精氨酸和7-硝基吲唑)、多巴胺受体D2拮抗剂(舒必利)、三磷酸腺苷敏感性钾和钙激活钾通道拮抗剂(格列本脲和伊比利亚毒素)。观察丹参甲素对低碳酸血症和内皮素性脑动脉狭窄的影响。数据采用重复测量方差分析(n=5)，P值小于0.05，有统计学意义。丹参甲素可引起即刻但短暂的血管扩张，每隔2分钟持续给药30分钟。预先给予N(G)-硝基-L-精氨酸可消除脑脊液的血管扩张和相应的环化鸟苷升高，但不能消除7-硝基吲唑。尽管纳洛酮、去甲肾上腺素和格列本脲可阻断萨尔维甲素A所致的脑血管扩张，但伊比利亚毒素和舒必利不能改变这一反应。在静息状态下，低碳酸血症和内皮缩窄的软脑膜动脉对丹参素A的反应相似。丹参素A通过激活一氧化氮合酶、三磷酸腺苷敏感钾通道和κ阿片受体来扩张大脑动脉。
Salvinorin A is a nonopioid, selective κ opioid–receptor agonist. Despite its high potential for clinical application, its pharmacologic profile is not well known. In the current study, we hypothesized that salvinorin A dilates pial arteries via activation of nitric oxide synthase, adenosine triphosphate–sensitive potassium channels, and opioid receptors. Cerebral artery diameters and cyclic guanosine monophosphate in cortical periarachnoid cerebrospinal fluid were monitored in piglets equipped with closed cranial windows. Observation took place before and after salvinorin A administration in the presence or absence of an opioid antagonist (naloxone), a κ opioid receptor–selective antagonist (norbinaltorphimine), nitric oxide synthase inhibitors (N(G)-nitro-L-arginine and 7-nitroindazole), a dopamine receptor D2 antagonist (sulpiride), and adenosine triphosphate–sensitive potassium and Ca2+-activated K channel antagonists (glibenclamide and iberiotoxin). The effects of salvinorin A on the constricted cerebral artery induced by hypocarbia and endothelin were investigated. Data were analyzed by repeated measures ANOVA (n = 5) with statistical significance set at a P value of less than 0.05. Salvinorin A induced immediate but brief vasodilatation that was sustained for 30 min via continual administration every 2 min. Vasodilatation and the associated cyclic guanosine monophosphate elevation in cerebrospinal fluid were abolished by preadministration N(G)-nitro-L-arginine, but not 7-nitroindazole. Although naloxone, norbinaltorphimine, and glibenclamide abolished salvinorin A–induced cerebrovasodilation, this response was unchanged by iberiotoxin and sulpiride. Hypocarbia and endothelin-constricted pial arteries responded similarly to salvinorin A, to the extent observed under resting tone. Salvinorin A dilates cerebral arteries via activation of nitric oxide synthase, adenosine triphosphate–sensitive potassium channel, and the κ opioid receptor.