The role of Ca^<2+>-activated K^+ channels of tracheal smooth musde on anti-asthmatic agents

为阐明Ca~(2+)激活的K~(++)通道在平喘药中的作用，观察了新型水溶性Forsklin衍生物(NKH477)、β-激动剂、心房利钠肽(ANP)和尿鸟苷对豚鼠和人的气管平滑肌的作用。我们已经证明，NKH477的松弛作用可能至少部分是通过激活钙激活的K^+通道来实现的，这可能导致平滑肌细胞膜和β-激动剂的超极化。此外，我们还发现，持续和重复的接触。β-激动剂导致β-肾上腺素能脱敏，Gs激活的钾通道可阻止豚鼠和人气管的这种脱敏。静脉注射尿鸟苷可明显抑制卵蛋白引起的小鼠支气管收缩和微血管渗漏，且呈剂量依赖关系。这些发现首次表明尿鸟苷具有强大的支气管扩张作用。我们进一步证明，钙激活的K~+通道活性增强在cGMP引起的人气道平滑肌松弛中起重要作用，ANP可能具有适度的支气管扩张剂的作用。我们的结果提示，通过Ca~(2+)和Gt~(2+)激活的K~(++)通道的药物有可能用于哮喘患者的治疗。

In order to clarify the role of Ca^<2+>-activated K^+ channels in anti-asthmatic agents, effects of a new water-soluble forskolin derivative (NKH477), beta-agonists, atrial natriuuretic peptide (ANP) and uroguanylin on tracheal smooth muscle isolated from guinea-pigs or humans were investigated. We have demonstrated that the bronchorelaxant action of NKH477 may result, at least in part, from activation of Ca^<2+>-activated K^+ channels, which may cause a hyperpolarization of smooth muscle cell membranes as well as beta-agonists. In addition, we showed that continuous and repeated exposure to. beta-agonists leads to beta-adrenergic desensitization, and that activation of Oa^<2+>-activated K^+ channels by Gs prevents this ddesensitization in guinea-pigs and human trachealis. On the other hand, intravenous pretreatment of uroguanylin significantly inhibited ovalbumin-induced bronchoconstriction and microvascular leakage in a dose-dependent manner. These findings are the first to show that uroguanylin has potent bronchodilatory effect. We further demonstrated that augmentation of the activity of Ca^<2+>-activated K^+ channels plays a functionally important role in the cGMP-induced relaxation in human airway smooth muscle, and that ANP may have modest potency as a bronchodilator. Our results suggest the possibility that agents via Ca^<2+>-activated K^+ channels are useful for the treatment of asthmatic patients.