Allal C, Lazartigues E, Tran M A, Brefel-Courbon C, Gharib C, Montastruc J L, Rascol O
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U455 et U317, Faculté de Médecine, Toulouse, France.
Eur J Pharmacol. 1998 May 8;348(2-3):191-8. doi: 10.1016/s0014-2999(98)00143-5.
Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.
目前有报道称，中枢作用的胆碱能药物通过刺激毒蕈碱型胆碱受体，可使多种动物的血压升高。此外，临床研究也报告了其一些心血管不良反应。本研究旨在探讨他克林（一种据报道对阿尔茨海默病具有治疗潜力的乙酰胆碱酯酶抑制剂）对比格犬血压及两种升压系统（交感神经系统和血管升压素能系统）的影响。静脉注射他克林（2mg/kg）可使清醒和麻醉犬的收缩压和舒张压升高，并伴有心动过缓。这种升高呈剂量依赖性，给药后1.5分钟达到峰值效应。他克林还可使去甲肾上腺素、肾上腺素和血管升压素的血浆水平升高。预先静脉注射毒蕈碱受体拮抗剂阿托品（2mg/kg）可消除静脉注射他克林引起的升压反应，而预先静脉注射外周毒蕈碱受体拮抗剂甲基东莨菪碱（0.2mg/kg）则不会改变血压升高的情况。同样，甲基东莨菪碱不会改变血浆中去甲肾上腺素和肾上腺素水平的变化，但阿托品预处理可消除这种变化。血管升压素的血浆水平也观察到类似趋势，尽管不显著。目前的结果表明，在犬中，静脉注射他克林（2mg/kg）可刺激中枢毒蕈碱型胆碱受体，通过激活交感神经系统的两个组成部分（即神经元-神经元去甲肾上腺素能和神经激素肾上腺素能途径）以及升高去甲肾上腺素、肾上腺素和血管升压素的血浆水平来升高血压。
