McCallum J B, Boban N, Hogan Q, Schmeling W T, Kampine J P, Bosnjak Z J
Department of Anesthesiology, The Medical College of Wisconsin and the Zablocki Veterans Administration Medical Center, Milwaukee 53226, USA.
Anesth Analg. 1998 Sep;87(3):503-10. doi: 10.1097/00000539-199809000-00001.
Alpha2-adrenergic agonists produce analgesia and reduce hemodynamic stress through central and peripheral mechanisms, but the effect of adrenergic agonists on pre- and postganglionic sites has not yet been clarified. In this study, we examined the effects of dexmedetomidine (DMT), an alpha2-agonist, on neural conduction and neurotransmitter release in sympathetic ganglia. The stellate ganglia from 48 mongrel dogs were isolated, desheathed, and superfused with Krebs' solution. Compound action potentials were evoked, and chromatography was used to detect acetylcholine released by preganglionic stimulation in the presence or absence of DMT. To further elucidate the mechanism of alpha2 effects, DMT was applied in combination with the alpha2-antagonist atipamezole (AT) or the imidazoline antagonist idazoxan (ID). In other experiments, DMT was applied in the presence of exogenous nicotinic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide or muscarinic stimulation with (+)cis-dioxolane. DMT dose-dependently inhibited synaptic transmission with a 50% effective dose of 71.6 (26.0-174.3) microM. Neurotransmitter release was reduced 25% by 70 microM DMT during low-frequency (0.4 Hz) stimulation, but this effect was abolished at higher frequency (5 Hz) stimulation. AT but not ID blocked the inhibitory action of DMT. DMT inhibited the excitatory postsynaptic response to exogenous muscarinic stimulation but not nicotinic stimulation. These results indicate that alpha2-receptor activation depresses ganglionic transmission through postsynaptic inhibition of muscarinic stimulation, although reduction of neurotransmitter release through a presynaptic autofeedback mechanism is also involved.
This article provides novel insights into the mechanism of drug action of alpha2-receptor agonists in the sympathetic ganglia of dogs by directly measuring the relative contribution of pre- and postganglionic receptors. Our study indicates that the central sympatholytic effects of alpha2-adrenoceptor stimulation are augmented by peripheral inhibition of ganglionic transmission.
α2肾上腺素能激动剂通过中枢和外周机制产生镇痛作用并减轻血流动力学应激，但肾上腺素能激动剂对神经节前和节后部位的作用尚未阐明。在本研究中，我们研究了α2激动剂右美托咪定（DMT）对交感神经节神经传导和神经递质释放的影响。从48只杂种犬分离出星状神经节，剥除其被膜，并用Krebs溶液进行灌流。诱发复合动作电位，并使用色谱法检测在有或没有DMT的情况下神经节前刺激释放的乙酰胆碱。为了进一步阐明α2效应的机制，将DMT与α2拮抗剂阿替美唑（AT）或咪唑啉拮抗剂伊达唑胺（ID）联合应用。在其他实验中，在存在外源性烟碱刺激（用碘化1,1-二甲基-4-苯基哌嗪）或毒蕈碱刺激（用（+）顺式二氧戊环）的情况下应用DMT。DMT剂量依赖性地抑制突触传递，半数有效剂量为71.6（26.0-174.3）μM。在低频（0.4Hz）刺激期间，70μM DMT使神经递质释放减少25％，但在高频（5Hz）刺激时该效应消失。AT而非ID阻断了DMT的抑制作用。DMT抑制对外源性毒蕈碱刺激的兴奋性突触后反应，但不抑制烟碱刺激。这些结果表明，α2受体激活通过毒蕈碱刺激的突触后抑制来抑制神经节传递，尽管也涉及通过突触前自反馈机制减少神经递质释放。
本文通过直接测量神经节前和节后受体的相对作用，为α2受体激动剂在犬交感神经节中的药物作用机制提供了新的见解。我们的研究表明，α2肾上腺素能受体刺激的中枢性交感神经抑制作用通过神经节传递的外周抑制而增强。
