ACTIONS OF ENDOTHELINS AND SARAFOTOXIN 6C IN THE RAT ISOLATED-PERFUSED LUNG

1 Endothelin (ET) receptors within the vasculature and airways were studied in a rat perfused lung model in which pulmonary perfusion pressure (PPP), pulmonary inflation pressure (PIP) and lung weight were continuously monitored. 2 The vascular potencies of ETs (ET-1>ET-2>ET-3) suggest an action via ET(A) receptors. This was confirmed by use of the antagonist, BQ123 (2 mu M). The vasoconstrictor effects of sarafotoxin 6c (SX6C) also indicated the presence of ET(B) receptors. 3 Lung weight increases induced by ETs appeared to be a consequence of their vasoconstrictor potencies. The mixed ET receptor antagonist, bosentan (5 mu M), markedly attenuated the responses of ET-1 and SX6C on PPP and lung weight, further implicating activation of both ET(A) and ET(B) receptors in these responses. 4 Endothelin-1 (ET-1) induced an accumulation of albumin-bound Evans blue dye in orthogradely perfused lungs. Retrograde perfusion attenuated the extravasation and increase in lung weight due to ET-1 but significantly augmented those induced by SX6C. 5 The bronchoconstrictor actions of ETs (ET-1=ET-2=ET-3) and SX6C suggest this is an ET(B)-mediated response. However SX6C was more potent than ETs and the dose-response curve was significantly steeper and achieved a higher maximum. 6 Indomethacin did not affect the vascular or bronchial responses to ET-1 or SX6C. 7 These findings indicate that rat pulmonary vasculature contains both ET(A) and ET(B) receptors. Retrograde perfusion suggests that ET(B) receptors are located arterially whereas ET(A) receptors are predominantly venous in distribution. Differences in the bronchoconstrictor potency of SX6C (compared to ETs) and the antagonism by bosentan may indicate ET(B) receptor heterogeneity in the airways.