EVIDENCE FOR ENDOTHELIN INVOLVEMENT IN THE PULMONARY VASOCONSTRICTOR RESPONSE TO SYSTEMIC HYPOXIA IN THE ISOLATED RAT LUNG

We investigated the effect of systemic hypoxia (Krebs-Henseleit soluti on gassed with 5% CO2/95% N-2) on an isolated, perfused rat lung. Hypo xia resulted in a slowly developing sustained increase in pulmonary pe rfusion pressure (PPP) accompanied by an increase in lung weight (LW). The endothelin (ET) receptor antagonists BQ123 (3 and 10 mu M), BQ788 (3 mu M) and bosentan (1.5 and 5 mu M) all attenuated the hypoxia-ind uced increases in LW and PPP. In addition, phosphoramidon (1 mu M), an ET-converting enzyme inhibitor, also significantly attenuated the hyp oxia-induced increases in PPP and LW. The use of two agents that alter peptide secretion, phalloidin (10 and 50 nM) and colchicine (100 nM), and the peptide synthesis inhibitor cycloheximide (5 mu M) all signif icantly attenuated the hypoxia-induced increases in PPP and LW. The in crease in PPP and LW after the onset of hypoxia was accompanied by an increase in perfusate levels of ET-1 compared with normoxic time-match ed controls. The results show that in this model, systemic hypoxia is capable of causing a sustained vasoconstriction and increased LW. The fact that these increases can be attenuated by an ET-converting enzyme inhibitor, ET receptor antagonists and agents that block peptide synt hesis and secretion, together with the increase in perfusate levels of ET-1, suggests that ET production and release contribute to the chang es seen.