Christ M J, Iwamoto L M, de Silva A, Lavallee S L, Nakamura K T
Department of Clinical Investigation, Tripler Army Medical Center, Honolulu 96859, USA.
Am J Physiol. 1998 Jan;274(1):R209-13. doi: 10.1152/ajpregu.1998.274.1.R209.
Nebulized amiloride has been proposed as therapy in cystic fibrosis to block Na+ hyperabsorption in airway epithelium and prevent dehydration of secretions. Patients with cystic fibrosis often have reaction airways. Bovine and canine trachea relax to amiloride in vitro, suggesting another benefit as a bronchodilator, whereas guinea pig trachea, a useful model of human airways, does not. We hypothesized that human airways would respond like guinea pig airways. Airway ring segments from guinea pigs, mice, and human fetuses were constricted with the concentration of acetylcholine producing 50-75% maximum contraction. Subsequent changes in isometric tension to cumulative additions of amiloride (10(-8)-10(-4) M) were measured. Guinea pig airways contracted 29 +/- 5%, mouse airways contracted 23 +/- 6%, and human fetal airways contracted 30 +/- 8%. Contraction to amiloride was mimicked by dimethylamiloride, a more selective inhibitor of the Na+/H+ antiporter, and was attenuated by protein kinase C (PKC) inhibition with GF109203X and staurosporine. The present study indicates that amiloride-induced airway contraction in guinea pigs and mice closely parallels the response in isolated human airways and that the mechanism may involve the Na+/H+ antiporter and PKC.
雾化阿米洛利已被提议用于治疗囊性纤维化，以阻断气道上皮细胞中的钠（Na⁺）过度吸收并防止分泌物脱水。囊性纤维化患者常有反应性气道。牛和犬的气管在体外对阿米洛利有舒张反应，提示其可能还有作为支气管扩张剂的益处，而豚鼠气管（一种有用的人类气道模型）则不然。我们假设人类气道的反应会与豚鼠气道相似。用能产生50 - 75%最大收缩的乙酰胆碱浓度使豚鼠、小鼠和人类胎儿的气道环段收缩。随后测量对累积添加的阿米洛利（10⁻⁸ - 10⁻⁴ M）等长张力的变化。豚鼠气道收缩29±5%，小鼠气道收缩23±6%，人类胎儿气道收缩30±8%。钠/氢（Na⁺/H⁺）反向转运体更具选择性的抑制剂二甲基阿米洛利模拟了对阿米洛利的收缩反应，并且用GF109203X和星形孢菌素抑制蛋白激酶C（PKC）可减弱这种反应。本研究表明，阿米洛利诱导的豚鼠和小鼠气道收缩与分离的人类气道反应非常相似，其机制可能涉及Na⁺/H⁺反向转运体和PKC。
