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Acetylcholine-Induced Asynchronous Calcium Waves in Intact Human Bronchial Muscle Bundle

The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Cornelis van Breemen, D.V.M., Ph.D., The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: breemen{at}interchange.ubc.ca

Calcium (Ca²⁺) is an important activator of the contractile machinery in airway smooth muscle (ASM). While agonist-induced Ca²⁺ signals are well characterized in animal ASM, little is known about what occurs in adult human ASM. In this study, we examined the Ca²⁺ signal elicited by acetylcholine (ACh) in smooth muscle cells of the intact human bronchial muscle strips obtained from fresh surgical specimens in relation to muscle contraction. We found that ACh induces repetitive Ca²⁺ waves that spread along the longitudinal axis of individual cells in the intact human bronchial smooth muscle strips. These Ca²⁺ waves display no apparent synchronization between neighboring cells, and their generation precedes force development. Comparison of the ACh concentration dependence of tissue contraction and selected parameters of the asynchronous Ca²⁺ waves (ACW) reveals that the graded force generation by ACh-stimulated human bronchial muscle strips is achieved by differential recruitment of cells to initiate Ca²⁺ waves and by enhancement of the frequency of ACW once the cells are recruited. Furthermore, pharmacologic characterization shows that the ACW are produced by repetitive cycles of SR Ca²⁺ release via ryanodine-sensitive channels followed by SR Ca²⁺ reuptake by sarco(endo)plasmic reticulum Ca²⁺ ATPase. Extracellular Ca²⁺ entry involving receptor-operated channels/store-operated channels, reverse-mode Na⁺/Ca²⁺ exchange, and to a lesser extent L-type voltage-gated Ca²⁺ channels is required to maintain the ACW. These findings for the first time demonstrate the occurrence and the role of ACW in excitation–contraction coupling in adult human ASM.

Key Words: simultaneous [Ca²⁺]_i imaging and isometric force measurement • confocal microscopy • excitation-contraction coupling • human airway smooth muscle

CLINICAL RELEVANCE Our study provides insight into our understanding of Ca2+ regulation of airway smooth muscle contraction in health. This is important for the investigation of potential abnormalities in the Ca2+ signaling underlying airway hyperresponsiveness.