Mj. Christ et al., AMILORIDE-INDUCED CONTRACTION OF ISOLATED GUINEA-PIG, MOUSE, AND HUMAN FETAL AIRWAYS, American journal of physiology. Regulatory, integrative and comparative physiology, 43(1), 1998, pp. 209-213
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.