Fabiani M E, Story D F
Department of Medical Laboratory Science, Faculty of Biomedical and Health Sciences, RMIT University, Melbourne, Australia.
Pharmacol Res. 1996 Mar;33(3):171-80. doi: 10.1006/phrs.1996.0024.
The present study investigated the effects of the alpha 2-adrenoceptor agonist guanabenz and the adrenergic neurone blocking drug guanethidine on the resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline. The efflux of radioactivity evoked by electrical field stimulation of periarterial sympathetic nerves (60 s trains of 1 ms pulses, 2 Hz, 12 V) was taken as an index of transmitter noradrenaline release. Guanabenz (0.1-10 microM) decreased, in a concentration-dependent manner, both the resting and S-I effluxes of radioactivity. Guanethidine (0.1 and 1 microM) also decreased S-I efflux but increased resting efflux, both effects being concentration dependent. The inhibitory effects of guanabenz on both resting and S-I effluxes were reduced by blockade of the neuronal amine carrier with desipramine (1 microM). The inhibitory effect of guanabenz on resting efflux was prevented by inhibition of monoamine oxidase with pargyline (100 microM). The inhibitory effect of guanabenz on S-I efflux was not due to activation of prejunctional alpha 2-adrenoceptors since the inhibition was not blocked by the selective alpha 2-adrenoceptor antagonist idazoxan (0.1 microM). However, the inhibitory effect of guanabenz and guanethidine on S-I efflux was reduced by the inhibitor of Ca(2+)-activated potassium channels apamin (0.1 microM). The findings suggest that guanabenz, like guanethidine, enters noradrenergic nerve terminals by the neuronal amine carrier. The inhibition of resting efflux produced by guanabenz may be due to inhibition of neuronal monoamine oxidase. The enhancement of resting efflux produced by guanethidine is attributable to its indirect sympathomimetic action. Finally, guanabenz and guanethidine may inhibit transmitter noradrenaline release by activating potassium channels on sympathetic noradrenergic nerve terminals. These findings may be relevant to the mechanism of adrenergic neurone blockade.
本研究调查了α2-肾上腺素能受体激动剂胍那苄和肾上腺素能神经元阻断药胍乙啶对大鼠离体肠系膜动脉制剂静息和刺激诱导（S-I）放射性流出的影响，在该制剂中去甲肾上腺素能递质储存已用[3H]-去甲肾上腺素进行放射性标记。通过电场刺激动脉周围交感神经（1毫秒脉冲的60秒串，2赫兹，12伏）诱发的放射性流出被用作递质去甲肾上腺素释放的指标。胍那苄（0.1 - 10微摩尔）以浓度依赖的方式降低了放射性的静息和S-I流出。胍乙啶（0.1和1微摩尔）也降低了S-I流出，但增加了静息流出，两种效应均呈浓度依赖性。用去甲丙咪嗪（1微摩尔）阻断神经元胺载体可降低胍那苄对静息和S-I流出的抑制作用。用帕吉林（100微摩尔）抑制单胺氧化酶可阻止胍那苄对静息流出的抑制作用。胍那苄对S-I流出的抑制作用并非由于突触前α2-肾上腺素能受体的激活，因为该抑制作用未被选择性α2-肾上腺素能拮抗剂咪唑克生（0.1微摩尔）阻断。然而，钙激活钾通道抑制剂蜂毒明肽（0.1微摩尔）可降低胍那苄和胍乙啶对S-I流出的抑制作用。这些发现表明，胍那苄与胍乙啶一样，通过神经元胺载体进入去甲肾上腺素能神经末梢。胍那苄对静息流出的抑制作用可能是由于对神经元单胺氧化酶的抑制。胍乙啶产生的静息流出增强归因于其间接拟交感神经作用。最后，胍那苄和胍乙啶可能通过激活交感去甲肾上腺素能神经末梢上的钾通道来抑制递质去甲肾上腺素的释放。这些发现可能与肾上腺素能神经元阻断的机制有关。
