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Endothelin-1 receptor density, distribution, and function in human isolated asthmatic airways.

The potent bronchoconstrictor and mitogenic actions of the peptide endothelin-1 (ET-1) on airway smooth muscle may contribute significantly to the bronchial obstruction observed in asthma. However, the status of the receptor-effector systems that mediate these actions of ET-1 in asthmatic airways is currently unknown. Thus, we have used quantitative autoradiographic and isometric-tension recording techniques to evaluate the density, distribution, and function of the specific receptors that mediate the actions of ET-1 in both asthmatic and nonasthmatic airways. Here, we report that similar numbers of specific binding sites for [125I]-ET-1 exist in asthmatic and nonasthmatic airways, with the greatest densities located in airway smooth muscle in both tissue types. The ETB-receptor subtype constituted approximately 82% and 88% of these receptors for ET-1 in asthmatic and nonasthmatic human bronchial smooth muscle, respectively, and mediated contraction in response to this peptide. In addition, a component of ET-1-induced contraction appeared to be mediated by a non-ETB, BQ-123-resistant mechanism. Furthermore, a small population of ETA sites was identified that did not mediate contraction, but which may have a role in ET-1-induced prostanoid release and airway smooth-muscle proliferation. Interestingly, bronchial smooth muscle from asthmatic lung was significantly less sensitive to the contractile effects of ETB receptor activation, consistent with desensitization of this receptor subtype in response to the increased production and release of ET-1 that occurs in this disease.