Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction

Menthol, known as a cold receptor agonist, has widely been used in the relief of respiratory symptoms such as coughing and chest congestion. Previous studies have demonstrated that menthol reduces bronchoconstriction and airway hyperresponsiveness. The aim of this study was to examine the effects of menthol and icilin, another cold receptor agonist, on airway smooth muscle contraction. Isometric force was monitored using epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. Intracellular Ca²⁺ concentrations were assessed by fura-2 fluorescence. (-)Menthol (0.01-1 mM) inhibited contraction induced by methacholine (MCh, 0.01-10 μM) and high extracellular K⁺ concentrations (20-60 mM) in a concentration-dependent manner. Moreover, the increases of intracellular Ca²⁺ concentrations induced by MCh or high K⁺ were significantly reduced by (-)menthol. Icilin (100 μM) also significantly attenuated contraction induced by MCh or high K⁺. The inhibitory effect of 1 mM (-)menthol on MCh-induced contraction was significantly higher at cool temperature (24-26 °C) than at 37 °C. The present results demonstrate that inhibition of Ca²⁺ influx plays an important role in the menthol-mediated inhibition of contraction in airway smooth muscle. Furthermore, our findings indicate that stimulation of unknown cold receptors may be involved in these mechanisms. These findings suggest that the use of menthol is beneficial for reducing respiratory symptoms because of its inhibitory effects on airway smooth muscle contraction.