Lazartigues E, Freslon J L, Tellioglu T, Brefel-Courbon C, Pelat M, Tran M A, Montastruc J L, Rascol O
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317 et U455, Faculté de Médecine, Toulouse, France.
Eur J Pharmacol. 1998 Nov 13;361(1):61-71. doi: 10.1016/s0014-2999(98)00717-1.
The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.
在自由活动的Wistar大鼠中，比较了通过静脉注射途径给予的三种不同乙酰胆碱酯酶抑制剂毒扁豆碱、他克林和卡巴拉汀对心血管系统的影响。这三种药物均显著升高收缩压和舒张压，并降低心率。与毒扁豆碱相比，他克林需要高20倍的剂量，卡巴拉汀需要高40倍的剂量才能产生相当的升压效果。选择他克林作为研究静脉注射胆碱酯酶抑制剂心血管作用机制的模型。阿托品可完全消除他克林的升压作用，而甲基阿托品对他克林的升压作用无影响。相反，两种药物均能消除他克林引起的心动过缓。α1肾上腺素能受体拮抗剂哌唑嗪或血管加压素V1受体拮抗剂[β-巯基-β,β-环戊亚甲基丙酰基1，O-甲基-Tyr2，Arg8]血管加压素可部分但显著降低他克林的升压作用，同时给药时大多可消除该作用。通过脑室内注射非选择性毒蕈碱受体拮抗剂阿托品（半数抑制剂量ID50 = 1.45微克）、毒蕈碱M1受体拮抗剂哌仑西平（ID50 = 4.33微克）、毒蕈碱M2受体拮抗剂甲溴东莨菪碱（ID50 = 1.39微克）和毒蕈碱M3受体拮抗剂对氟六氢硅二苯醇（ID50 = 31.19微克），他克林的升压反应呈剂量依赖性受到抑制。脑室内注射此类毒蕈碱受体拮抗剂不影响他克林引起的心动过缓。我们的结果表明，乙酰胆碱酯酶抑制剂可引起显著的心血管效应，其升压反应主要由中枢毒蕈碱M2受体的刺激介导，导致交感神经传出和血管加压素释放继发性增加。相反，乙酰胆碱酯酶抑制剂引起的心动过缓似乎由外周毒蕈碱机制介导。
