ENDOTHELIN-1 RECEPTOR DENSITY, DISTRIBUTION, AND FUNCTION IN HUMAN ISOLATED ASTHMATIC AIRWAYS

The potent bronchoconstrictor and mitogenic actions of the peptide end othelin-1 (ET-1) on airway smooth muscle may contribute significantly to the bronchial obstruction observed in asthma. However, the status o f the receptor-effector systems th at mediate these actions of ET-1 in asthmatic airways is currently unknown. Thus, we have used quantitati ve autoradiographic and isometric-tension recording techniques to eval uate the density, distribution, and function of the specific receptors that mediate the actions of ET-1 in both asthmatic and nonasthmatic a irways. Here, we report that similar numbers of specific binding sites for [I-125]-ET-1 exist in asthmatic and nonasthmatic airways, with th e greatest densities located in airway smooth muscle in both tissue ty pes. The ET(B)-receptor subtype constituted approximately 82% and 88% of these receptors for ET-1 in asthmatic and nonasthmatic human bronch ial 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-ET(B), BQ-123-resistant mechanism. Fu rthermore, a small population of ET(A) sites was identified that did n ot mediate contraction, but which may have a role in ET-1-induced pros tanoid release and airway smooth-muscle proliferation. Interestingly, bronchial smooth muscle from asthmatic lung was significantly less sen sitive to the contractile effects of ET(B) receptor activation, consis tent with desensitization of this receptor subtype in response to the increased production and release of ET-1 that occurs in this disease.