TY - JOUR T1 - Evidence for Endothelin Involvement in the Pulmonary Vasoconstrictor Response to Systemic Hypoxia in the Isolated Rat Lung JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 419 LP - 425 VL - 283 IS - 2 AU - R. M. Smith AU - T. J. Brown AU - A. G. Roach AU - K. I. Williams AU - B. Woodward Y1 - 1997/11/01 UR - http://jpet.aspetjournals.org/content/283/2/419.abstract N2 - 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 μM), BQ788 (3 μM) and bosentan (1.5 and 5 μM) all attenuated the hypoxia-induced increases in LW and PPP. In addition, phosphoramidon (1 μM), 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 μM) 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. The American Society for Pharmacology and Experimental Therapeutics ER -