Hirota K, Sato T, Hashimoto Y, Yoshioka H, Ohtomo N, Ishihara H, Matsuki A
Department of Anesthesiology, University of Hirosaki School of Medicine, Japan.
Crit Care Med. 1999 Jun;27(6):1159-63. doi: 10.1097/00003246-199906000-00042.
Magnesium sulfate (MgSO4) has been reported to produce bronchodilation in asthmatic patients. In vitro studies have suggested that divalent cations inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and smooth muscles. In this study, we evaluated the in vitro and in vivo effects of magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine.
A university research laboratory.
Tracheal smooth muscle from guinea pigs.
Mongrel dogs.
The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer. The specimen was contracted with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath.
The bronchial cross-sectional area of mongrel dogs was measured by a direct visualization method demonstrated previously. The dogs were randomly assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n = 7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500 microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0 (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na, respectively. The bronchial cross-sectional area was assessed before (basal) and 30 mins after the start of histamine infusion and 5 mins after each dose of ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry. All data are expressed as mean +/- SEM. The doses of the divalent cations that reversed histamine-induced contraction by 50% were calculated by GraphPad Prism. MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine-contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose-dependently increased except when 1000 micromol/kg MgSO4 was administered.
Because the divalent cations tested produced a spasmolytic effect on the contracted airway, infusion of divalent cations might be effective against asthmatic attack. However, high concentrations of these cations produce significant toxicity, so dosage will be an important concern in development of these agents.
据报道，硫酸镁（MgSO4）可使哮喘患者支气管扩张。体外研究表明，二价阳离子可抑制心肌和平滑肌中的L型电压敏感性钙离子（Ca2+）通道。在本研究中，我们评估了镁离子（Mg2+）和锌离子（Zn2+）对组胺所致气道收缩的体外和体内效应。
大学研究实验室。
豚鼠气管平滑肌。
杂种犬。
用测力位移换能器等长测量分离的豚鼠气管条的张力。标本用组胺（10μM）收缩。然后，将硫酸镁（n = 6）、硫酸锌（ZnSO4，n = 6）或硫酸钠（Na2SO4，n = 6）累积加入器官浴中。
通过先前证实的直接可视化方法测量杂种犬的支气管横截面积。将犬随机分为三组：镁组（n = 7）、锌组（n = 7）和钠组（n = 7）。用组胺（10μg/kg加500μg/kg/小时静脉注射）诱发支气管收缩。组胺输注开始30分钟后，锌组、镁组或钠组分别静脉注射0（生理盐水）、1、10和100μmol/kg ZnSO4或1、10、100和1000μmol/kg MgSO4或Na2SO4。在组胺输注开始前（基础值）、开始后30分钟以及每次注射ZnSO4、MgSO4或Na2SO4后5分钟评估支气管横截面积。还采集动脉血，通过气相色谱-质谱法测量血浆肾上腺素和去甲肾上腺素水平。所有数据均表示为平均值±标准误。通过GraphPad Prism计算使组胺诱导的收缩逆转50%的二价阳离子剂量。硫酸镁和硫酸锌（分别为9.38±0.28和1.84±0.30 mM）以浓度依赖性方式舒张组胺收缩的气管条，而硫酸钠则无此作用。同样，体内研究表明，硫酸镁和硫酸锌剂量依赖性地逆转组胺诱导的支气管收缩（效力，硫酸锌>硫酸镁），而硫酸钠则无此作用。在镁组和锌组中，除给予1000μmol/kg硫酸镁外，血浆儿茶酚胺水平也呈剂量依赖性升高。
由于所测试的二价阳离子对收缩的气道产生解痉作用，输注二价阳离子可能对哮喘发作有效。然而，这些阳离子的高浓度会产生显著毒性，因此在这些药物的研发中，剂量将是一个重要问题。
