Kume H, Takagi K
Second Department of Internal Medicine, School of Medicine, Nagoya University, Japan.
Nihon Kyobu Shikkan Gakkai Zasshi. 1995 Dec;33 Suppl:116-24.
The mechanical tone of the airways is regulated by the autonomic nervous system, partly via the activity of ion channels. Ca(2+)-activated K+ (KCa) channels are densely distributed on tracheal smooth muscle cells. We found that beta-adrenergic agonists can augment KCa channel activity via the alpha subunit of the stimulatory GTP-binding (G) protein of adenylyl cyclase, Gs, linked with beta-receptors, and that muscarinic agonists can suppress the activity of this channel via the inhibitory G protein of adenylyl cyclase (pertussis toxin-sensitive G protein), Gi, linked with muscarinic receptors. These results show that there is a dual regulation system of KCa channels, which involves stimulation of the two receptors. Records of isometric tension from guinea pig tracheas incubated with pertussis toxin and cholera toxin show that regulation of KCa channels mediated by Gi and Gs may be important in the mechanical antagonism by the two receptor agonists, and they show that G proteins coupling between receptors and KCa channels may be important in beta-adrenergic bronchodilation in the treatment of asthma. In a previous study in eight atopic asthmatic patients, pretreatment with a beta-agonist abolished allergen-induced bronchoconstriction with no increment in mean plasma histamine, results that are similar to those obtained with cromyolyn sodium, a membrane stabilizer. The membrane-delimited reaction may be a key process in the autonomic regulation of airway tone. In immediate asthmatic reactions (IAR), histamine release from mast cells, contraction of airway smooth muscle, and transmitter release from post-ganglionic neurons within parasympathetic ganglia are believed to be caused by membrane hypopolarization. Because activation of KCa channels leads to hyperpolarization, beta-agonists that cause membrane hyperpolarization (short acting beta-agonists) may antagonize IAR at the level of the cell membrane. In late asthmatic reactions (LAR), short-acting beta-agonists do not have marked effects. However, recent reports have indicated that long-acting beta-agonists that do not cause hyperpolarization can inhibit LAR. Cromakalim, an ATP-sensitive K+ channel activator, reduces the "morning dip" when it is given orally to patients with nocturnal asthma. These findings show that activation of K+ channels may be useful in therapy of bronchial asthma.
气道的机械张力由自主神经系统调节，部分是通过离子通道的活性来实现的。钙激活钾（KCa）通道密集分布于气管平滑肌细胞上。我们发现，β-肾上腺素能激动剂可通过与β受体相偶联的腺苷酸环化酶刺激性GTP结合（G）蛋白的α亚基Gs来增强KCa通道活性，而毒蕈碱激动剂可通过与毒蕈碱受体相偶联的腺苷酸环化酶抑制性G蛋白（百日咳毒素敏感G蛋白）Gi来抑制该通道的活性。这些结果表明存在KCa通道的双重调节系统，这涉及两种受体的刺激。对用百日咳毒素和霍乱毒素孵育的豚鼠气管进行等长张力记录显示，由Gi和Gs介导的KCa通道调节可能在两种受体激动剂的机械性拮抗作用中起重要作用，并且表明受体与KCa通道之间偶联的G蛋白可能在哮喘治疗中的β-肾上腺素能支气管扩张中起重要作用。在先前对8名特应性哮喘患者的研究中，用β-激动剂预处理可消除变应原诱导的支气管收缩，而平均血浆组胺无增加，这一结果与用膜稳定剂色甘酸钠所获得的结果相似。膜限定反应可能是气道张力自主调节中的关键过程。在速发型哮喘反应（IAR）中，肥大细胞释放组胺、气道平滑肌收缩以及副交感神经节内节后神经元释放递质被认为是由膜去极化不足引起的。由于KCa通道的激活会导致超极化，引起膜超极化的β-激动剂（短效β-激动剂）可能在细胞膜水平拮抗IAR。在迟发型哮喘反应（LAR）中，短效β-激动剂没有明显作用。然而，最近的报告表明，不引起超极化的长效β-激动剂可抑制LAR。克罗卡林，一种ATP敏感性钾通道激活剂，口服给予夜间哮喘患者时可减轻“清晨低谷”。这些发现表明钾通道的激活可能对支气管哮喘的治疗有用。
