期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 291, 期 2, 页码 L208-L221出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00494.2005
关键词
laser scanning microscopy; pulmonary blood vessels; Rho kinase; protein kinase C; adenosine 3 ',5 ',-cyclic monophosphate
资金
- NHLBI NIH HHS [HL-71930] Funding Source: Medline
To investigate the phenomenon of Ca2+ sensitization, we developed a new intact airway and arteriole smooth muscle cell (SMC) model by treating murine lung slices with ryanodine-receptor antagonist, ryanodine (50 mu M), and caffeine (20 mM). A sustained elevation in intracellular Ca2+ concentration ([Ca2+](i)) was induced in both SMC types by the ryanodine-caffeine treatment due to the depletion of internal Ca2+ stores and the stimulation of a persistent influx of Ca2+. Arterioles responded to this sustained increase in [Ca2+](i) with a sustained contraction. By contrast, airways responded to sustained high [Ca2+](i) with a transient contraction followed by relaxation. Subsequent exposure to methacholine (MCh) induced a sustained concentration-dependent contraction of the airway without a change in the [Ca2+](i). During sustained MCh-induced contraction, Y-27632 (a Rho-kinase inhibitor) and GF-109203X (a protein kinase C inhibitor) induced a concentration-dependent relaxation without changing the [Ca2+](i). The cAMP-elevating agents, forskolin (an adenylyl cyclase activator), IBMX ( a phosphodiesterase inhibitor), and caffeine (also acting as a phosphodiesterase inhibitor), exerted similar relaxing effects. These results indicate that 1) ryanodine-caffeine treatment is a valuable tool for investigating the contractile mechanisms of SMCs while avoiding nonspecific effects due to cell permeabilization, 2) in the absence of agonist, sustained high [Ca2+](i) has a differential time-dependent effect on the Ca2+ sensitivity of airway and arteriole SMCs, 3) MCh facilitates the contraction of airway SMCs by inducing Ca2+ sensitization via the activation of Rho-kinase and protein kinase C, and 4) cAMP-elevating agents contribute to the relaxation of airway SMCs through Ca2+ desensitization.
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