title: Hypoxic pulmonary vasoconstriction in isolated blood-perfused rat lung; modulation by thromboxane A2, platelet-activating factor, cysteinyl leukotrienes and endothelin-1.
abstract: Recent evidence suggests that hypoxic pulmonary vasoconstriction (HPV) is mediated by hypoxia-induced closure of voltage-gated potassium channels in pulmonary vascular smooth muscle cells. It is also claimed that various vasoconstrictor mediators such as thromboxane A2 (TXA2), platelet activating factor (PAF), cysteinyl leukotrienes (cys-LTs) or endothelin-1 (ET-1) contribute to HPV. Their role, however, has not been unequivocally accepted. On the contrary, it is well known that endothelium-derived nitric oxide negatively modulates HPV. Since NO counteracts action of vasoconstrictor mediators, we tested the hypothesis that modulatory role of TXA2 PAF, cys-LTs and ET-1 in HPV would become apparent in absence of endogenous NO. For that purpose we assessed contribution of these mediators to HPV in the isolated blood-perfused rat lung pretreated with a non-selective NOS inhibitor, L-NAME. HPV, which was greatly augmented by L-NAME (300 microM) alone, was inhibited neither by a TXA2 synthase inhibitor (Camonagrel, 300 pM), nor by a PAF receptor antagonist (WEB 2170, 100 microM), nor by an inhibitor of five-lipooxygenase-activating protein (MK 886, 10 microM), nor by a non-selective ET-1 receptor antagonist (LU 302872, 30 pM). In summary, in isolated blood-perfused rat lung, TXA2, PAF, cys-LTs and ET-1 seem not to be involved in HPV, whereas we confirm the dominant role of endogenous NO in blunting HPV.
authors.affiliation: Department of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, PL 31-531, Kraków, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chłopicki
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Bartuś
authors.forename: Ryszard J
authors.initials: RJ
authors.lastname: Gryglewski
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled; D013928:Thromboxane A2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548594:Alox5ap protein, rat; D002352:Carrier Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D015289:Leukotrienes; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D044022:Receptor, Endothelin A; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D013928:Thromboxane A2; D019001:Nitric Oxide Synthase; D013930:Thromboxane-A Synthase; D019331:NG-Nitroarginine Methyl Ester