Analysis of ET-A and ET-B receptors using an isolated perfused rat lung preparation

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 (ET(B)) receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A (ET(A))-receptor antagonist FR 139317, the ET(B)-receptor antagonist BQ 788 and the combined ET(A)/ET(B)-receptor antagonist Bosentan. The respiratory parameter airway conductance (G(aw)) 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 microL 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 G(aw) 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 G(aw) was not influenced. The combined ET(A)/ET(B) antagonist Bosentan powerfully prevented the ET-1-induced decrease in G(aw) 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 ET(A) receptors, whereas both ET(A) and ET(B) receptors are involved in G(aw) in the rat lung.