Langer S Z, Duval N, Massingham R
J Cardiovasc Pharmacol. 1985;7 Suppl 8:S1-8.
The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.
神经递质可通过突触前抑制性自身受体调节其自身释放这一概念已得到充分确立。参与调节去甲肾上腺素释放的负反馈机制的突触前抑制性自身受体属于α₂亚型。可乐定、胍法辛和胍那苄等药物刺激中枢α₂肾上腺素能受体会通过降低交感神经张力产生降压和心动过缓效应。在血管平滑肌中，α₁肾上腺素能受体亚型占主导并介导血管收缩，尽管介导血管收缩的α₂肾上腺素能受体在一些血管床中也存在。去氧肾上腺素优先刺激血管平滑肌中的α₁肾上腺素能受体，胍那苄优先刺激α₂肾上腺素能受体，而去甲肾上腺素是α₁和α₂两种亚型的激动剂。哌唑嗪可显著降低对去氧肾上腺素的升压反应。相比之下，对去甲肾上腺素的反应相对不易被阻断，而对胍那苄的反应则完全不受哌唑嗪的阻断。可卡因或地昔帕明抑制神经元摄取以及用6-羟基多巴胺对猫进行预处理可增强哌唑嗪阻断对去甲肾上腺素升压反应的效果，但对胍那苄或去氧肾上腺素则无此作用。这些结果支持了这样的观点，即突触后α₁肾上腺素能受体优先被支配（即在神经效应器连接内），而突触后α₂肾上腺素能受体位于突触外位置。将α肾上腺素能受体分为α₁和α₂亚型为设计对这些受体亚型起激动剂或拮抗剂作用的选择性药物开辟了可能性。这些化合物具有有用的治疗应用，并且就选择性α₂肾上腺素能受体拮抗剂而言，在中枢神经系统和外周水平可能存在新的潜在用途。
