: The hypothesis that up‐regulation of bronchial constrictor endothelin receptors in airway smooth muscle cells may contribute to hyperreactivity during airway inflammation was tested in the present study by quantitative endothelin receptor mRNA analysis and functional responses in ring segments of rat trachea and bronchi. Real time reverse transcription polymerase chain reaction was used to quantify endothelin receptor expression in rat airway smooth muscle cells following Sephadex‐induced inflammation. Compared with controls, Sephadex‐induced airway inflammation caused a significant increase (3.9 times P<0.05) of endothelin receptor type B mRNA expression in bronchial smooth muscle cells, but not in tracheal smooth muscle cells. Functional myograph studies of bronchial and tracheal ring segments without epithelium (mechanically denuded) revealed an increase of the maximum contractile effects of endothelin‐1 (a dual agonist for both endothelin type A and B receptors) and sarafotoxin 6c (a selective agonist for endothelin B receptors) in bronchial smooth muscle cells in Sephadex‐induced inflammation, but not in tracheal smooth muscle cells. The enhanced maximal responses of bronchial smooth muscle cells to endothelin‐1 and sarafotoxin 6c in Sephadex‐induced inflammation support our molecular findings and hence imply a role for endothelin B receptors in airway hyperreactivity during airway inflammation.

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Aims and Methods:  The pulmonary and vascular effects of endothelin‐1 receptor activation were studied in isolated perfused and ventilated lung preparations from rat. The responses to endothelin‐1 (ET‐1) and the endothelin B (ETB) receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A (ETA)‐receptor antagonist FR 139317, the ETB‐receptor antagonist BQ 788 and the combined ETA/ETB‐receptor antagonist Bosentan. The respiratory parameter airway conductance (Gaw) and the vascular parameter perfusion flow were analysed simultaneously. Results:  Concentration–response curves for ET‐1 administered intra‐arterially revealed that its most potent effect was on the vascular side while S6c had a more potent effect on airway conductance. ET‐1, given as a bolus dose intra‐arterially (100 μL of 0.2 nm), induced a strong‐ and long‐lasting contraction of the vasculature while only a less pronounced contraction was seen in the airways. Neither of the antagonists had a significant effect per se on Gaw or perfusion flow. FR 139317 reduced the effect of ET‐1 on perfusion flow by about 50%, while airway conductance was augmented. BQ 788 enhanced the decrease in perfusion flow by ET‐1 while Gaw was not influenced. The combined ETA/ETB antagonist Bosentan powerfully prevented the ET‐1‐induced decrease in Gaw but did not alter its reduction in perfusion flow. Conclusions:  The potent effect of ET‐1 on the vascular side of the lung is mediated mainly through ETA receptors, whereas both ETA and ETB receptors are involved in Gaw in the rat lung.

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