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1 Department of Medicine, McMaster University, Hamilton, ON, Canada
2 Toronto Lung Transplant Program, Division of Thoracic Surgery, University of Toronto, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: janssenl{at}mcmaster.ca.
Airway smooth muscle (ASM) cells express voltage-dependent Ca2+ channels, primarily of the L-subtype. These may play a role in excitation-contraction coupling of ASM, although other signaling pathways may also contribute: one of these includes Rho and its down-stream effector molecule Rho-kinase (ROCK). While voltage-dependent Ca2+ influx and Rho/ROCK signaling have traditionally been viewed as entirely separate pathways, recent evidence in vascular smooth muscle suggest differently. In this study, we monitored contractile activity (muscle baths) in bronchial and/or tracheal preparations from the pig, cow and human, and further examined Rho and ROCK activities (Western blots and kinase assays) and cytosolic levels of Ca2+ (fluo4-based fluorimetry) in porcine tracheal myoctyes. KCl (0-60 mM) evoked substantial contractions which were suppressed in the tracheal preparations by removal of external Ca2+ or using the selective L-type Ca2+ channel blocker nifedipine (1 µM); porcine bronchial preparations were much less sensitive, and bovine bronchi were essentially unaffected by 1 µM nifedipine. Surprisingly, KCl-evoked contractions were also highly sensitive to two structurally different ROCK inhibitors: Y27632 (10 µM) and HA1077 (10 and 30 µM). Furthermore, the inhibitory effects of nifedipine and of the ROCK inhibitors were not additive. KCl also caused marked stimulation of Rho and ROCK activities, and both these changes were suppressed by nifedipine or by removal of external Ca2+. KCl-induced elevation of [Ca2+]i was not affected by Y27632 (10 µM), but was reversed by NiCl2 (1 mM) or by BAPTA-AM (0.1 mM for 20 minutes). We conclude that KCl acts in part through stimulation of Rho and Rho-kinase, possible secondary to voltage-dependent Ca2+-influx.
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