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

1 Endothelin (ET) receptors within the vasculature and airways were st udied in a rat perfused lung model in which pulmonary perfusion pressu re (PPP), pulmonary inflation pressure (PIP) and lung weight were cont inuously monitored. 2 The vascular potencies of ETs (ET-1>ET-2>ET-3) s uggest an action via ET(A) receptors. This was confirmed by use of the antagonist, BQ123 (2 mu M). The vasoconstrictor effects of sarafotoxi n 6c (SX6C) also indicated the presence of ET(B) receptors. 3 Lung wei ght increases induced by ETs appeared to be a consequence of their vas oconstrictor potencies. The mixed ET receptor antagonist, bosentan (5 mu M), markedly attenuated the responses of ET-1 and SX6C on PPP and l ung weight, further implicating activation of both ET(A) and ET(B) rec eptors in these responses. 4 Endothelin-1 (ET-1) induced an accumulati on of albumin-bound Evans blue dye in orthogradely perfused lungs. Ret rograde perfusion attenuated the extravasation and increase in lung we ight 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 sugges t this is an ET(B)-mediated response. However SX6C was more potent tha n ETs and the dose-response curve was significantly steeper and achiev ed a higher maximum. 6 Indomethacin did not affect the vascular or bro nchial responses to ET-1 or SX6C. 7 These findings indicate that rat p ulmonary vasculature contains both ET(A) and ET(B) receptors. Retrogra de perfusion suggests that ET(B) receptors are located arterially wher eas ET(A) receptors are predominantly venous in distribution. Differen ces in the bronchoconstrictor potency of SX6C (compared to ETs) and th e antagonism by bosentan may indicate ET(B) receptor heterogeneity in the airways.