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Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655

Address correspondence to Michael J. Sanderson, Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Fax: (508) 856-5997; E-mail: michael.sanderson{at}umassmed.edu

The Ca²⁺ signaling and contractility of airway smooth muscle cells (SMCs) were investigated with confocal microscopy in murine lung slices (75-µm thick) that maintained the in situ organization of the airways and the contractility of the SMCs for at least 5 d. 10–500 nM acetylcholine (ACH) induced a contraction of the airway lumen and a transient increase in [Ca²⁺]_i in individual SMCs that subsequently declined to initiate multiple intracellular Ca²⁺ oscillations. These Ca²⁺ oscillations spread as Ca²⁺ waves through the SMCs at 48 µm/s. The magnitude of the airway contraction, the initial Ca²⁺ transient, and the frequency of the subsequent Ca²⁺ oscillations were all concentration-dependent. In a Ca²⁺-free solution, ACH induced a similar Ca²⁺ response, except that the Ca²⁺ oscillations ceased after 1–1.5 min. Incubation with thapsigargin, xestospongin, or ryanodine inhibited the ACH-induced Ca²⁺ signaling. A comparison of airway contraction with the ACH-induced Ca²⁺ response of the SMCs revealed that the onset of airway contraction correlated with the initial Ca²⁺ transient, and that sustained airway contraction correlated with the occurrence of the Ca²⁺ oscillations. Buffering intracellular Ca²⁺ with BAPTA prohibited Ca²⁺ signaling and airway contraction, indicating a Ca²⁺-dependent pathway. Cessation of the Ca²⁺ oscillations, induced by ACH-esterase, halothane, or the absence of extracellular Ca²⁺ resulted in a relaxation of the airway. The concentration dependence of the airway contraction matched the concentration dependence of the increased frequency of the Ca²⁺ oscillations. These results indicate that Ca²⁺ oscillations, induced by ACH in murine bronchial SMCs, are generated by Ca²⁺ release from the SR involving IP₃- and ryanodine receptors, and are required to maintain airway contraction.

Key Words: asthma • hyper-reactivity • confocal microscopy • Ca²⁺ oscillations • frequency modulation

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