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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.
AuthorsStefan Chłopicki, Joanna B Bartuś, Ryszard J Gryglewski
JournalPolish journal of pharmacology (Pol J Pharmacol) 2002 Sep-Oct Vol. 54 Issue 5 Pg. 433-41 ISSN: 1230-6002 [Print] Poland
PMID12593530 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • 5-Lipoxygenase-Activating Proteins
  • Alox5ap protein, rat
  • Carrier Proteins
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Leukotrienes
  • Membrane Proteins
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptor, Endothelin A
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • Thromboxane A2
  • Nitric Oxide Synthase
  • Thromboxane-A Synthase
  • NG-Nitroarginine Methyl Ester
Topics
  • 5-Lipoxygenase-Activating Proteins
  • Animals
  • Carrier Proteins (antagonists & inhibitors)
  • Endothelin Receptor Antagonists
  • Endothelin-1 (metabolism)
  • Hypoxia (metabolism, physiopathology)
  • In Vitro Techniques
  • Leukotrienes (metabolism)
  • Lung (metabolism, physiopathology)
  • Membrane Proteins (antagonists & inhibitors)
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide Synthase (antagonists & inhibitors)
  • Perfusion
  • Platelet Activating Factor (metabolism)
  • Platelet Membrane Glycoproteins (antagonists & inhibitors)
  • Pulmonary Artery (physiopathology)
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin A
  • Receptors, Cell Surface (antagonists & inhibitors)
  • Receptors, G-Protein-Coupled
  • Thromboxane A2 (metabolism)
  • Thromboxane-A Synthase (antagonists & inhibitors)
  • Vasoconstriction

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