RELATIONSHIP BETWEEN ENDOTHELIN-1 BINDING-SITE DENSITIES AND CONSTRICTOR ACTIVITIES IN HUMAN AND ANIMAL AIRWAY SMOOTH-MUSCLE

Endothelin-1 (ET-1) binding site densities and constrictor activities were compared in airway smooth muscle preparations of human, guinea-pig, rat and mouse. The mean contractile response to 0.3 μM ET-1 (measured as the % maximum response to 10 μM carbachol, % C(max) ± s.e. mean) and the mean concentration of ET-1 producing 30% C(max) (95% confidence limits) were respectively; 85.9 ± 5.4% and 3.4 nM (2.4 - 5.0) for mouse trachea (n = 11), 88.8 ± 4.7% and 18.2 nM (11.2 - 25.2) for rat trachea (n = 6), 71.0 ± 7.1% and 35.2 nM (5.4 - 231) for human bronchus (n = 3), and 32.3 ± 3.0% and 241 nM (125 - 460) for guinea-pig trachea (n = 6). Light microscopic autoradiography revealed specific [125I]-ET-1 binding sites localized to the smooth muscle band, with very low levels of binding associated with cartilage, submucosal and epithelial cells. Quantitative autoradiographic analyses of the concentration-dependence of specific [125I]-ET-1 binding (0.1 - 2 nM) to smooth muscle revealed similar dissociation constants but markedly different specific binding site densities for the various animal species. The order of densities of specific [125I]-ET-1 binding sites was rat trachea (69.0 ± 11.2 amol mm-2) > human bronchus (42.7 ± 17.5 amol mm-2) > mouse trachea (28.7 ± 2.6 amol mm-2) > guinea-pig trachea (8.3 ± 1.8 amol mm-2). A positive relationship between [125I]-ET-1 binding site density and ET-1 constrictor activity was observed in airway smooth muscle preparations from rat, human and guinea-pig. The greater sensitivity of mouse trachea to the constrictor actions of ET-1 was not dependent on the release of cyclo-oxygenase- or epithelium-derived constrictor substances, but may have been due to an inter-species difference in the receptor-effector system for ET-1.