咪达唑仑对离体犬肠系膜静脉肾上腺素能功能的抑制作用。
Inhibition by midazolam of the adrenergic function in the isolated canine mesenteric vein.
作者信息
Kobayashi Y, Muldoon S M, Kiyose M, Hagiwara T, Kumasaka S, Okabe E
机构信息
Department of Pharmacology, Kanagawa Dental College, Yokosuka, Japan.
出版信息
Acta Anaesthesiol Scand. 1998 Nov;42(10):1157-63. doi: 10.1111/j.1399-6576.1998.tb05269.x.
BACKGROUND
Midazolam has been reported to cause hypotension or to depress sympathetic activity following intravenous injection. However, little information is available concerning the mechanism of these effects. The aim of the present study was to determine the effects of midazolam on release of noradrenaline (NA) at nerve terminals and on receptors in the venous smooth muscle.
METHODS
The effect of midazolam at nerve terminals was examined by measuring the amount of NA release from superfused canine mesenteric vein helical strips during electrical stimulation (ES; 5 Hz, 2 ms, 9 V). The NA was quantified by high-performance liquid chromatography with electrochemical detection; tension development evoked by ES was also recorded simultaneously. In a separate series of experiments, ring preparations from the isolated vein were mounted in Krebs-Ringer solution for isometric tension recording to assess the effect of midazolam on alpha-adrenoceptors.
RESULTS
Application of tetrodotoxin (10(-6) M) or replacement of superfusate with Ca(2+)-free solution decreased both the release of NA and the tension development evoked by ES. Yohimbine (5 x 10(-8) M) increased the ES-evoked release of NA, whereas it decreased tension development in the vein strips. Midazolam (10(-4) M) did not affect either the basal release of NA or the basal tension, but inhibited both the NA release (P < 0.01) and the tension development (P < 0.01) during ES; midazolam at 10(-5) M inhibited the tension development (P < 0.05) but had no effect on NA release. In the ring preparations, midazolam (10(-5) and 10(-4) M) attenuated responses to NA (a mixed alpha 1- and alpha 2-adrenoceptor agonist, 10(-8) to 10(-3) M), phenylephrine (the alpha 1-adrenoceptor agonist, 10(-8) to 10(-3) M) and 5-bromo-6-[2-imidazolin-2yl-amino]-quinoxaline (UK14304; the alpha 2-adrenoceptor agonist, 10(-7) to 10(-3) M) in a dose-dependent manner.
CONCLUSION
The data obtained in the present study suggest that midazolam at 10(-4) M may reduce venous tone by inhibiting the release of NA from sympathetic nerve endings and both alpha 1- and alpha 2-adrenoceptor mediated smooth muscle contractions. It is also postulated that a stage of the post-receptor transduction mechanism linked to the venous smooth muscle contraction may be more sensitive to midazolam than the NA release mechanism at nerve terminals since midazolam at the low concentration tested inhibited ES-evoked tension development with no effect on the release of NA.
背景
已有报道称咪达唑仑静脉注射后可导致低血压或抑制交感神经活动。然而，关于这些效应的机制，目前几乎没有相关信息。本研究的目的是确定咪达唑仑对神经末梢去甲肾上腺素（NA）释放及静脉平滑肌中受体的影响。
方法
通过测量电刺激（ES；5Hz，2ms，9V）期间灌注犬肠系膜静脉螺旋条释放的NA量，来检测咪达唑仑对神经末梢的影响。NA通过高效液相色谱-电化学检测进行定量；同时记录ES诱发的张力变化。在另一系列实验中，将分离静脉的环行标本置于Krebs-Ringer溶液中进行等长张力记录，以评估咪达唑仑对α-肾上腺素能受体的影响。
结果
应用河豚毒素（10⁻⁶M）或用无钙溶液替换灌注液，均可降低NA的释放及ES诱发的张力变化。育亨宾（5×10⁻⁸M）可增加ES诱发的NA释放，而降低静脉条中的张力变化。咪达唑仑（10⁻⁴M）既不影响NA的基础释放，也不影响基础张力，但可抑制ES期间的NA释放（P<0.01）及张力变化（P<0.01）；10⁻⁵M的咪达唑仑可抑制张力变化（P<0.05），但对NA释放无影响。在环行标本中，咪达唑仑（10⁻⁵和10⁻⁴M）以剂量依赖方式减弱对NA（一种α₁和α₂肾上腺素能受体混合激动剂，10⁻⁸至10⁻³M）、去氧肾上腺素（α₁肾上腺素能受体激动剂，10⁻⁸至10⁻³M）及5-溴-6-[2-咪唑啉-2-基氨基]-喹喔啉（UK14304；α₂肾上腺素能受体激动剂，10⁻⁷至10⁻³M）的反应。
结论
本研究获得的数据表明，10⁻⁴M的咪达唑仑可能通过抑制交感神经末梢释放NA以及α₁和α₂肾上腺素能受体介导的平滑肌收缩来降低静脉张力。还推测，与静脉平滑肌收缩相关的受体后转导机制的某个阶段可能比神经末梢的NA释放机制对咪达唑仑更敏感，因为在测试的低浓度下，咪达唑仑抑制了ES诱发的张力变化，而对NA释放无影响。
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