Pelat M, Lazartigues E, Tran M A, Gharib C, Montastruc J L, Montastruc P, Rascol O
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317 et U455, Faculté de Médecine, Toulouse, France.
Eur J Pharmacol. 1999 Aug 27;379(2-3):117-24. doi: 10.1016/s0014-2999(99)00508-7.
Previous reports have shown that an intracisternal (i.c.) injection of acetylcholine in the dog increases both arterial blood pressure and plasma levels of noradrenaline and vasopressin via central muscarinic receptors. The aim of the present study was to characterize the central muscarinic cholinoceptor subtypes involved in such central cholinergic responses in anesthetized male Beagle-Harrier dogs (n = 12). For this purpose, we studied the relative potency of various muscarinic receptor antagonists to block the acetylcholine-induced pressor responses (30 microg kg(-1) i.c.). The acetylcholine-induced pressor response was inhibited in a dose-dependent manner by the i.c. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 0.5 microg kg(-1)), the muscarinic M receptor antagonist pirenzepine (ID50 = 0.45 microg kg(-1)), the muscarinic M2 receptor antagonist methoctramine (ID50 = 8.5 microg kg(-1)) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50) = 43.7 microg kg(-1)). The order of potency of these four muscarinic receptor antagonists was: atropine = pirenzepine > methoctramine >> para-fluoro-hexahydro-sila-difenidol. In order to confirm the selectivity for muscarinic M1 receptors of this dose of pirenzepine, we checked that 40- to 50-fold higher concentrations were necessary to block a typical muscarinic M2 receptor response (bradycardia) and a typical muscarinic M3 receptor response (endothelial vasodilation) compared with methoctramine and para-fluoro-hexahydro-sila-difenidol, respectively. These results suggest that the pressor response elicited by intracisternal injection of acetylcholine in anesthetized Beagle-Harrier dogs is mediated through the activation of the muscarinic M1 cholinoceptor subtype.
先前的报道表明，向犬脑池内注射乙酰胆碱可通过中枢毒蕈碱受体使动脉血压以及去甲肾上腺素和血管加压素的血浆水平升高。本研究的目的是明确参与麻醉的雄性比格-哈利犬（n = 12）此类中枢胆碱能反应的中枢毒蕈碱胆碱能受体亚型。为此，我们研究了各种毒蕈碱受体拮抗剂阻断乙酰胆碱诱导的升压反应（30 μg·kg⁻¹ 脑池内注射）的相对效能。脑池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] = 0.5 μg·kg⁻¹）、毒蕈碱M受体拮抗剂哌仑西平（ID50 = 0.45 μg·kg⁻¹）、毒蕈碱M2受体拮抗剂甲溴东莨菪碱（ID50 = 8.5 μg·kg⁻¹）和毒蕈碱M3受体拮抗剂对氟六氢硅二苯醚（ID50 = 43.7 μg·kg⁻¹），乙酰胆碱诱导的升压反应呈剂量依赖性受到抑制。这四种毒蕈碱受体拮抗剂的效能顺序为：阿托品 = 哌仑西平 > 甲溴东莨菪碱 >> 对氟六氢硅二苯醚。为了证实该剂量的哌仑西平对毒蕈碱M1受体的选择性，我们检查发现，与甲溴东莨菪碱和对氟六氢硅二苯醚相比，分别需要高40至50倍的浓度才能阻断典型的毒蕈碱M2受体反应（心动过缓）和典型的毒蕈碱M3受体反应（内皮血管舒张）。这些结果表明，在麻醉的比格-哈利犬中，脑池内注射乙酰胆碱引发的升压反应是通过毒蕈碱M1胆碱能受体亚型的激活介导的。
