Inhibitory effects of openers of large-conductance Ca2+-activated K+channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

Abstract

Airway smooth muscle expresses abundant BKCachannels, but their role in regulating contractions remains controversial. This study examines the effects of two potent BKCachannel openers on agonist-induced phasic contractions in rabbit and mouse bronchi. First, we demonstrated the ability of 10 μM GoSlo-SR5-130 to activate BKCachannels in inside-out patches from rabbit bronchial myocytes, where it shifted the activation V1/2by −88 ± 11 mV (100 nM Ca2+, n = 7). In mouse airway smooth muscle cells, GoSlo-SR5-130 dose dependently shifted V1/2by 12–83 mV over a concentration range of 1–30 μM. Compound X, a racemic mixture of two enantiomers, reported to be potent BKCachannel openers, shifted V1/2by 20–79 mV over a concentration range of 0.3–3 μM. In rabbit bronchial rings, exposure to histamine (1 μM) induced phasic contractions after a delay of ~35 min. These were abolished by GoSlo-SR5-130 (30 μM). Nifedipine (100 nM) and CaCCinhA01 (10 μM), a TMEM16A blocker, also abolished histamine-induced phasic contractions. In mouse bronchi, similar phasic contractions were evoked by exposure to U46619 (100 nM) and carbachol (100 nM). In each case, these were inhibited by concentrations of GoSlo-SR5-130 and compound X that shifted the activation V1/2of BKCachannels in the order of −80 mV. In conclusion, membrane potential-dependent regulation of L-type Ca2+channels appears to be important for histamine-, U46619-, and carbachol-induced phasic contractions in airway smooth muscle. Contractions can be abolished by BKCachannel openers, suggesting that these channels are potential targets for treating some causes of airway obstruction.