Abstract
The alteration of resting tension (RT) from 0.5 g to 2.5 g increased significantly airway smooth muscle contractions induced by acetylcholine (ACh) in rabbit trachea. The decrease in extracellular calcium concentration [Ca2+]o from 2 mM to 0.2 mM reduced ACh-induced contractions only at 2.5 g RT with no effect at 0.5 g RT. The nonselective inhibitor of nitric oxide synthase (NOS), NG-nitro-L-arginine methyl ester (L-NAME) increased ACh-induced contractions at 2.5 g RT. The inhibitor of inducible NOS, S-methylsothiourea or neuronal NOS, 7-nitroindazole had no effect. At 2.5 g RT, the reduction of [Ca2+]o from 2 mM to 0.2 mM abolished the effect of L-NAME on ACh-induced contractions. The NO precursor L-arginine or the tyrosine kinase inhibitors erbstatin A and genistein had no effect on ACh-induced contractions obtained at 2.5 g RT. Our results suggest that in airways, RT affects ACh-induced contractions by modulating the activity of epithelial NOS in a calcium-dependent, tyrosine-phosphorylation-independent way.
Highlights
Nitric oxide (NO) is released by a wide variety of cell types including epithelial cells, nerve, and inflammatory cells in airways [1]
At 2.5 g resting tension (RT), the decrease in extracellular calcium concentration reduced contractions induced by 10−6, 10−4, and 10−3 M ACh (P < .05), (Figure 1) with no effect on ACh-induced contractions obtained at 0.5 g RT
Our study was not extended to the underlying mechanism(s) for the RT effect on airway smooth muscle (ASM) responsiveness, our results provide evidence for the effect of RT on calcium influx
Summary
Nitric oxide (NO) is released by a wide variety of cell types including epithelial cells, nerve, and inflammatory cells in airways [1]. The constitutive isoforms of NOS, neuronal (nNOS), and endothelial (eNOS) seem to protect airways from excessive bronchoconstriction, while iNOS has a modulatory role in inflammatory disorders of the airways such as asthma [3]. Constitutive NOS is activated by an increase in intracellular calcium concentration that in turn promotes calmodulin binding to NOS and releases low amounts of NO for short periods in response to receptor and physical stimulation [4]. The activation of eNOS by receptor-dependent agonists like acetylcholine, histamine or bradykinin is mediated by an increase in intracellular calcium [4], while its activation by mechanical stimuli like shear stress is induced by its phosphorylation [5,6,7]
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