Yalcin Murat, Cavun Sinan, Yilmaz M Sertac, Savci Vahide
Department of Physiology, Uludag University Veterinary Faculty, 16059, Gorukle, Bursa, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Jul;372(1):31-40. doi: 10.1007/s00210-005-1087-x. Epub 2005 Aug 26.
The aim of this study was to determine the involvement of the central cholinergic system in the rise in blood pressure evoked by the thromboxane A2 (TxA2) analog, U-46619, given centrally. Intracerebroventricular (i.c.v.) injections of U-46619 (0.5, 1.0 and 2.0 microg) caused dose- and time-related increases in blood pressure and decreased heart rate in awake rats. U-46619 (1 microg; i.c.v.) also produced an approximately 65% increase in posterior hypothalamic extracellular acetylcholine and choline levels. Pretreatment with SQ-29548 (8 microg; i.c.v.), selective TxA2 receptor antagonist, completely inhibited both the cardiovascular responses and the increase in acetylcholine and choline levels to subsequent injection of U-46619 (1 microg; i.c.v.). Atropine (10 microg; i.c.v.), nonselective muscarinic receptor antagonist, pretreatment did not affect the cardiovascular responses observed after U-46619 (1 microg; i.c.v.). Pretreatment with the nonselective nicotinic receptor antagonist, mecamylamine (50 microg; i.c.v.) attenuated the pressor effect of U-46619 (1 microg; i.c.v.). Higher doses of mecamylamine (75 and 100 microg; i.c.v.) pretreatments did not change the magnitude of the blockade of pressor response to U-46619; however, they abolished the bradycardic effect of U-46619 dose-dependently. Interestingly, pretreatment of rats with methyllycaconitine (10 microg; i.c.v.) or alpha-bungarotoxin (10 microg; i.c.v.), selective antagonists of alpha7 subtype of nicotinic acetylcholine receptors (alpha7nAChRs), partially abolished the pressor response to i.c.v. injection of U-46619 (1 microg). Similar to the mecamylamine data, the use of higher doses of methyllycaconitine (25 and 50 microg; i.c.v.) produced the same magnitude of blockade that was observed after the 10 microg methyllycaconitine pretreatment, but it completely abolished the bradycardic effect of U-46619 (1 microg; i.c.v.) at the dose of 25 microg. The present results show that central administration of U-46619 produces pressor and bradycardic effect and increase in hypothalamic acetylcholine and choline levels by activating central TxA2 receptors. The activation of central nicotinic receptors, predominantly alpha7nAChRs, partially mediates the cardiovascular responses to i.c.v. injection of U-46619.
本研究的目的是确定中枢胆碱能系统在中枢给予血栓素A2（TxA2）类似物U - 46619所诱发的血压升高中的作用。向清醒大鼠脑室内（i.c.v.）注射U - 46619（0.5、1.0和2.0微克）可引起血压呈剂量和时间依赖性升高以及心率降低。U - 46619（1微克；i.c.v.）还使下丘脑后部细胞外乙酰胆碱和胆碱水平升高约65%。用选择性TxA2受体拮抗剂SQ - 29548（8微克；i.c.v.）预处理可完全抑制心血管反应以及随后注射U - 46619（1微克；i.c.v.）所引起的乙酰胆碱和胆碱水平升高。非选择性毒蕈碱受体拮抗剂阿托品（10微克；i.c.v.）预处理不影响U - 46619（1微克；i.c.v.）注射后观察到的心血管反应。用非选择性烟碱受体拮抗剂美加明（50微克；i.c.v.）预处理可减弱U - 46619（1微克；i.c.v.）的升压作用。更高剂量的美加明（75和100微克；i.c.v.）预处理并未改变对U - 46619升压反应的阻断程度；然而，它们剂量依赖性地消除了U - 46619的心动过缓效应。有趣的是，用烟碱型乙酰胆碱受体α7亚型（α7nAChRs）的选择性拮抗剂甲基lycaconitine（10微克；i.c.v.）或α - 银环蛇毒素（10微克；i.c.v.）预处理大鼠可部分消除对脑室内注射U - 46619（1微克）的升压反应。与美加明的数据相似，使用更高剂量的甲基lycaconitine（25和50微克；i.c.v.）产生的阻断程度与10微克甲基lycaconitine预处理后观察到的相同，但在25微克剂量时它完全消除了U - 46619（1微克；i.c.v.）的心动过缓效应。目前的结果表明，中枢给予U - 46619通过激活中枢TxA2受体产生升压和心动过缓效应以及下丘脑乙酰胆碱和胆碱水平升高。中枢烟碱受体的激活，主要是α7nAChRs，部分介导了对脑室内注射U - 46619的心血管反应。
