We investigated the effect of systemic
hypoxia (
Krebs-Henseleit solution gassed with 5% CO2/95% N2) on an isolated, perfused rat lung.
Hypoxia resulted in a slowly developing sustained increase in pulmonary perfusion pressure (PPP) accompanied by an increase in lung weight (LW). The
endothelin (ET) receptor antagonists
BQ123 (3 and 10 microM),
BQ788 (3 microM) and
bosentan (1.5 and 5 microM) all attenuated the
hypoxia-induced increases in LW and PPP. In addition,
phosphoramidon (1 microM), an ET-converting
enzyme inhibitor, also significantly attenuated the
hypoxia-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 microM) all significantly attenuated the
hypoxia-induced increases in PPP and LW. The increase in PPP and LW after the onset of
hypoxia was accompanied by an increase in perfusate levels of ET-1 compared with normoxic time-matched 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 synthesis and secretion, together with the increase in perfusate levels of ET-1, suggests that ET production and release contribute to the changes seen.