Hyperreactive airway diseases such as asthma are characterized by severe bronchospasm. Considerable controversy exists as to whether an intrinsic defect in the control of airway smooth muscle tone is directly implicated in the pathogenesis of these disorders. While some investigators suggest a basic muscle disorder, other theories place greater emphasis on inflammatory processes and the release of bronchoactive autacoids within the airways. In either case, mechanisms that mediate the contractile response of ASM cells to exogenous agents play a pivotal role in the disorder. Moreover, effective treatment of this disorder almost always involves modulation of airway smooth muscle tone as a key component of the therapeutic strategy. This proposal seeks to determine the role of specific plasmalemmal potassium channels in the regulation of the contractile state of airway smooth muscle. The central hypothesis of the application is that membrane potassium channels play a key role in the regulation of muscle tone. This hypothesis will be tested by examining the alteration in the function of specific potassium channel proteins at the single-channel, whole-cell, and tissue levels. Patch-clamp techniques will be used to examine the effect of contractile and relaxant agents on channel function, and these experiments will be correlated with microelectrode recordings from tissue strips. The availability of precise information about the role of these channels in contraction and relaxation of airway smooth muscle may provide important insights into ways in which contraction can be regulated by pharmacologic agents.
| Adda, S; Fleischmann, B K; Freedman, B D et al. (1996) Expression and function of voltage-dependent potassium channel genes in human airway smooth muscle. J Biol Chem 271:13239-43 |
