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Modulation of the Ca²⁺ sensitivity of airway smooth muscle cells in murine lung slices

Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 21 November 2005 ; accepted in final form 30 January 2006

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 µM), 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.

laser scanning microscopy; pulmonary blood vessels; Rho kinase; protein kinase C; adenosine 3',5'-cyclic monophosphate

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