Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Abstract

Background/Aims: Tetraethylammonium chloride (TEA) induces oscillatory contractions in mouse airway smooth muscle (ASM); however, the generation and maintenance of oscillatory contractions and their role in ASM are unclear. Methods: In this study, oscillations of ASM contraction and intracellular Ca 2+ were measured using force measuring and Ca 2+ imaging technique, respectively. TEA, nifedipine, niflumic acid, acetylcholine chloride, lithium chloride, KB-R7943, ouabain, 2-Aminoethoxydiphenyl borate, thapsigargin, tetrodotoxin, and ryanodine were used to assess the mechanism of oscillatory contractions. Results: TEA induced depolarization, resulting in activation of L-type voltage-dependent Ca 2+ channels (LVDCCs) and voltage-dependent Na + (V Na ) channels. The former mediated Ca 2+ influx to trigger a contraction and the latter mediated Na + entry to enhance the contraction via activating LVDCCs. Meanwhile, increased Ca 2+ -activated Cl - channels, inducing depolarization that resulted in contraction through LVDCCs. In addition, the contraction was enhanced by intracellular Ca 2+ release from Ca 2+ stores mediated by inositol (1,4,5)-trisphosphate receptors (IP 3 Rs). These pathways together produce the contractile phase of the oscillatory contractions. Furthermore, the increased Ca 2+ activated the Na + -Ca 2+ exchanger (NCX), which transferred Ca 2+ out of and Na + into the cells. The former induced relaxation and the latter activated Na + /K + -ATPase that induced hypopolarization to inactivate LVDCCs causing further relaxation. This can also explain the relaxant phase of the oscillatory contractions. Moreover, the depolarization induced by V Na channels and NCX might be greater than the hypopolarization caused by Na + /K + -ATPase alone, inducing LVDCC activation and resulting in further contraction. Conclusions: These data indicate that the TEA-induced oscillatory contractions were cooperatively produced by LVDCCs, V Na channels, Ca 2+ -activated Cl - channels, NCX, Na + /K + ATPase, IP 3 Rs-mediated Ca 2+ release, and extracellular Ca 2+ .