Central nicotinic acetylcholine receptor involved in Ca2+-calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects
Central nicotinic acetylcholine receptor involved in Ca2+-calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects
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DOI：
10.1111/j.1476-5381.2010.01124.x
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发表时间：
2011-07-01
影响因子：
7.3
通讯作者：
Tseng, Ching-Jiunn
中科院分区：
文献类型：
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作者：
Cheng, Pei-Wen;Lu, Pei-Jung;Tseng, Ching-Jiunn
背景和目的最近的证据表明，尼古丁可降低孤束核（NTS）的血压（BP）和心率（HR），表明烟碱乙酰胆碱受体（nAChR）在NTS的血压控制中发挥重要作用。然而，NTS 中 nAChR 介导的抑制作用所涉及的信号传导机制尚不清楚。因此，本研究的目的是研究这些信号传导机制。 实验方法在 α7 nAChR 拮抗剂、钙螯合剂乙二醇四乙酸、钙调蛋白特异性抑制剂、一氧化氮 (NO) 合酶存在和不存在的情况下，会引发对 Wistar-Kyoto 大鼠 NTS 中微量尼古丁注射的抑制反应。 (NOS) 抑制剂、内皮型一氧化氮合酶 (eNOS) 选择性抑制剂或神经元型一氧化氮合酶 (nNOS) 特异性抑制剂。 关键结果 将尼古丁微量注射到 NTS 中，可使血压和心率出现剂量依赖性下降，并增加硝酸盐水平。在用 nAChR 拮抗剂或钙调蛋白-eNOS 途径阻断剂预处理后，尼古丁的这种抑制作用减弱。相比之下，nNOS 特异性抑制剂 N5-(1-亚氨基-3-丁烯基)-L-鸟氨酸 (乙烯基-L-NIO) 并没有减弱这些尼古丁介导的作用。将尼古丁注射到 NTS 后，发现钙调蛋白与 eNOS 结合。然而，尼古丁并不影响 eNOS 磷酸化水平或 eNOS 上游细胞外信号调节激酶 (ERK) 1/2 和 Akt 磷酸化水平。此外，使用 ERK1/2 或 Akt 抑制剂进行预处理并不会减弱 NTS 中尼古丁诱导的降压作用。结论和意义这些结果表明，nAChR-Ca2+-钙调蛋白-eNOS-NO 信号通路（而非 nNOS）在中枢血压调节中发挥重要作用，并且 ERK1/2 和 Akt 信号通路均未显着参与 NTS 中的 nAChR 激活 eNOS。
BACKGROUND AND PURPOSERecent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms.EXPERIMENTAL APPROACHDepressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of an antagonist of alpha 7 nAChR, the calcium chelator ethylene glycol tetraacetic acid, a calmodulin-specific inhibitor, nitric oxide (NO) synthase (NOS) inhibitor, endothelial NOS (eNOS)-selective inhibitor or neuronal NOS (nNOS)-specific inhibitor.KEY RESULTSMicroinjection of nicotine into the NTS produced a dose-dependent decrease in BP and HR, and increased nitrate levels. This depressor effect of nicotine was attenuated after pretreatment with a nAChR antagonist or blockers of the calmodulin-eNOS pathway. In contrast, N5-(1-Imino-3-butenyl)-L-ornithine (vinyl-L-NIO), nNOS-specific inhibitor, did not diminish these nicotine-mediated effects. Calmodulin was found to bind eNOS after nicotine injection into NTS. However, nicotine did not affect the eNOS phosphorylation level or eNOS upstream extracellular signal-regulated kinases (ERK) 1/2 and Akt phosphorylation levels. Furthermore, pretreatment with an ERK1/2 or Akt inhibitor did not attenuate nicotine-induced depressor effects in the NTS.CONCLUSIONS AND IMPLICATIONSThese results suggest that the nAChR-Ca2+-calmodulin-eNOS-NO signalling pathway, but not nNOS, plays a significant role in central BP regulation, and neither the ERK1/2 nor Akt signalling pathway are significantly involved in the activation of eNOS by nAChRs in the NTS.