AMILORIDE-INDUCED CONTRACTION OF ISOLATED GUINEA-PIG, MOUSE, AND HUMAN FETAL AIRWAYS

Nebulized amiloride has been proposed as therapy in cystic fibrosis to block Na+ hyperabsorption in airway epithelium and prevent dehydratio n of secretions. Patients with cystic fibrosis often have reactive air ways. Bovine and canine trachea relax to amiloride in vitro, suggestin g another benefit as a bronchodilator, whereas guinea pig trachea, a u seful model of human airways, does not. We hypothesized that human air ways would respond like guinea pig airways. Airway ring segments from guinea pigs, mice, and human fetuses were constricted with the concent ration of acetylcholine producing 50-75% maximum contraction. Subseque nt 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 contrac ted 30 +/- 8%. Contraction to amiloride was mimicked by dimethylamilor ide, a more selective inhibitor of the Na+/H+ antiporter, and was atte nuated by protein kinase C (PKC) inhibition with GF109203X and stauros porine. The present study indicates that amiloride-induced airway cont raction in guinea pigs and mice closely parallels the response in isol ated human airways and that the mechanism may involve the Na+/H+ antip orter and PKC.