, Volume 167, Issue 1, pp 187–198 | Cite as

Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction

  • Henry M. Thomas
  • Magdi S. Sourour
  • Deborah Lopez
  • Steven H. Foster


The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 µg/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41±17% (SD), left atrial pressure rose 3.5±1.5 mmHg, and cardiac output fell 18±8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25±7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5±3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4±1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26±4%; p=0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9±2.8 mmHg; p<0.05; the increase in PVR was +1.8±1.2 mmHg/L/min, p<0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5±8.1% before and 27.0±7.4% after RG 5901 (p>0.05). The pressor response to hypoxia was + 8.9±2.1 mmHg before and +8.7±3.7 mmHg after RG 5901 (p>0.05).

We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.

Key words

Pulmonary shunt Atelectasis Normoxia 


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  1. 1.
    Abaitey AK, Parrat JR, Jr (1976) Cardiovascular effects of diethylcarbamizine citrate. Br J Pharmacol 56:219–227PubMedGoogle Scholar
  2. 2.
    Aharony D, Stein RL, Redkar-Brown DG, Hubbs SJ, Kusner EJ, Krell RD (1986) The mechanism of leukotriene inhibition of REV 5901. Fed Proc 45:659Google Scholar
  3. 3.
    Ahmed T, Marchette B, Wanner A, Yerger L (1985) Direct and indirect effects on leukotriene D4 on the pulmonary and systemic circulations. Am Rev Respir Dis 131:554–558PubMedGoogle Scholar
  4. 4.
    Ahmed T, Oliver W, Jr (1983) Does slow-reacting substance of anaphylaxis mediate hypoxic pulmonary vasoconstriction? Am Rev Respir Dis 127:566–571PubMedGoogle Scholar
  5. 5.
    Anderson DL, Fleisher LN, Olson NC (1987) Effect of sulfidopeptide leukotrienes on pulmonary hemodynamics in pigs. Fed Proc 46:1113Google Scholar
  6. 6.
    Bednar M, Smith B, Pinto A, Mullane KM (1985) Nafazatrom-induced salvage of ischemic myocardium in anesthetized dogs is mediated through inhibition of neutrophil function. Circ Res 57:131–141PubMedGoogle Scholar
  7. 7.
    Berkowitz BA, Zabko-Potapovich B, Valocik R, Gleason JG (1983) Effects of the leukotrienes on the vasculature and blood pressure of different species. J Pharmacol Exp Ther 229:105–112Google Scholar
  8. 8.
    Coutts SM, Khandwala A, Van Inwegen RG, Chakraborty U, Musser J, Bruens J, Jariwala N, Dally-Meade V, Ingram R, Pruss T, Jones H, Neiss E, Weinryb I (1985) Arylmethyl phenyl ethers: a new class of specific inhibitors of 5-lipoxygenase. In: Bailey JM (ed) Prostaglandins, leukotrienes and lipoxins. Plenum, New York, pp 627–637Google Scholar
  9. 9.
    Enson Y, Wood JA, Mantaras NB, Harvey RM (1977) The influence of heart rate on pulmonary arterial-left ventricular pressure relationships at end-diastole. Circulation 56:533–539PubMedGoogle Scholar
  10. 10.
    Fleisch JH, Rinkema LE, Haisch KD, Swanson-Bean D, Goodson T, Ho PPK, Marshall WS (1985) LY171883, 1-<2-hydroxy-3-propyl-<4-(1h-tetrazol-5-yl) butoxy>phenyl>ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Ther 233:148–157PubMedGoogle Scholar
  11. 11.
    Garrett RC, Thomas HM, III (1983) Meclofenamate uniformly decreases shunt fraction in dogs with lobar atelectasis. J Appl Physiol 54:284–289PubMedGoogle Scholar
  12. 12.
    Garrett RC, Foster S, Thomas HM, III (1987) Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction. J Appl Physiol 62:129–133PubMedGoogle Scholar
  13. 13.
    Harvey RM, Enson Y (1969) Pulmonary vascular resistance. In: Stollerman GH (ed) Advances in internal medicine. Year Book, Chicago, pp 73–93Google Scholar
  14. 14.
    Higgs GA, Flower RJ, Vane JR (1979) A new approach to anti-inflammatory drugs. Biochem Pharmacol 28:1959–1961PubMedCrossRefGoogle Scholar
  15. 15.
    Higgs GA, Mugridge KG, Moncada S, Vane JR (1984) Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW 755C. Proc Natl Acad Sci USA 81:2890–2892PubMedCrossRefGoogle Scholar
  16. 16.
    Jones TR, Guindon Y, Young R, Champion E, Charette L, Denis D, Ethier D, Hamel R, Ford-Hutchinson AW, Fortin R, Letts G, Masson P, McFarlane C, Piechuta H, Rokach J, Yoakim C, DeHaven RN, Maycock A, Pong SS (1986) L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propylsulfonyl]-γ-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist. Can J Physiol Pharmacol 64:1535–1542PubMedGoogle Scholar
  17. 17.
    Kadowitz PJ, Hyman AL (1984) Analysis of responses to leukotriene D4 in the pulmonary vascular bed. Circ Res 55:707–717PubMedGoogle Scholar
  18. 18.
    Leeman M, Naeije R, Lejeune P, Melot C (1987) Influence of cyclo-oxygenase inhibition and of leukotriene receptor blockade on pulmonary vascular pressure/cardiac index relationships in hyperoxic and in hypoxic dogs. Clin Sci 72:717–724PubMedGoogle Scholar
  19. 19.
    Lewis RA, Austen KF (1984) The biologically active leukotrienes biosynthesis, metabolism, receptors, functions, and pharmacology. J Clin Invest 73:889–897PubMedGoogle Scholar
  20. 20.
    Morganroth ML, Reeves JT, Murphy RC, Voelkel NF (1984) Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction. J Appl Physiol 56:1340–1346PubMedGoogle Scholar
  21. 21.
    Morganroth ML, Stenmark KR, Morris KG, Murphy RC, Mathias M, Reeves JT, Voelkel NF (1985) Diethylcarbamazine inhibits acute and chronic hypoxic pulmonary hypertension in awake rats. Am Rev Respir Dis 131:488–492PubMedGoogle Scholar
  22. 22.
    Mullane K, Hatala MA, Kraemer R, Sessa W, Westlin W (1987) Myocardial salvage induced by REV-5901, an inhibitor and antagonist of the leukotrienes. J Cardiovasc Pharmacol 10:398–406PubMedCrossRefGoogle Scholar
  23. 23.
    Mullane K, Salmon JA, Kraemer R (1987) Leukocyte-derived metabolites of arachidonic acid in ischemia-induced myocardial injury. Fed Proc 46:2422–2433PubMedGoogle Scholar
  24. 24.
    Naeije R, Leeman M, Lejeune P (1986) Effects of diethylcarbamazine and cromolyn sodium on hypoxic pulmonary vasoconstriction in dogs. Bull Eur Physiopathol Respir 22:75–80PubMedGoogle Scholar
  25. 25.
    Ovetsky RS, Sprague AH, Stephenson TE, Dahms TE, Lonigro AJ (1987) Inhibition of leukotriene synthesis does not attenuate the pulmonary pressor response to alveolar hypoxia. Am Rev Respir Dis 135:A128Google Scholar
  26. 26.
    Piper PJ, Letts LG, Galton SA (1983) Generation of a leukotriene-like substance from porcine vascular and other tissues. Prostaglandins 25:591–599PubMedCrossRefGoogle Scholar
  27. 27.
    Rubin LJ, Hughes JD, Lazar JD (1985) The effects of eicosanoid inhibitors on normoxic and hypoxic pulmonary vascular tone in dogs. Am Rev Respir Dis 132:93–98PubMedGoogle Scholar
  28. 28.
    Shuster DP, Dennis DR (1987) Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs. J Appl Physiol 62:1808–1813CrossRefGoogle Scholar
  29. 29.
    Snedecor GW, Cochran WD (1967) Statistical methods. Iowa State University Press, Ames, IAGoogle Scholar
  30. 30.
    Thomas HM, III, Garrett RC (1983) Relation of shunt fraction in lobar atelectasis to strength of hypoxic vasoconstriction. Am Rev Respir Dis 127:A3000Google Scholar
  31. 31.
    Thomas HM, III, Garrett RC (1982) Strength of hypoxic vasoconstriction determines shunt fraction in dogs with atelectasis. J Appl Physiol 53:44–51PubMedGoogle Scholar
  32. 32.
    Unger M, Atkins M, Briscoe WA, King TKC (1977) Potentiation of pulmonary vasoconstrictor response with repeated intermittent hypoxia. J Appl Physiol 43:662–667PubMedGoogle Scholar
  33. 33.
    Van Inwegan RG, Khandwala A, Gordon P, Coutts S, Jolly S (1987) REV-5901: an orally effective peptidoleukotriene antagonist, detailed biochemical/pharmacological profile. J Pharmacol Exp Ther 241:117–123Google Scholar
  34. 34.
    Voelkel NF, Stenmark KR, Reeves JT, Mathias MM, Murphy RC (1984) Actions of lipoxygenase metabolites in isolated rat lungs. J Appl Physiol 57:860–867PubMedGoogle Scholar
  35. 35.
    Wagner PD, Laravuso RB, Uhl RR, West JB (1974) Continuous distributions of ventilation perfusion ratios in normal subjects breathing air and 100% O2. J Clin Invest 54:54–68PubMedCrossRefGoogle Scholar
  36. 36.
    Wagner PD, Naumann PF, Laravuso PB (1974) Simultaneous measurements of eight foreign gases in blood by gas chromatography. J Appl Physiol 36:600–605PubMedGoogle Scholar
  37. 37.
    Weichman BM, Wasserman MA, Holden DA, Osborn RR, Woodward DF, Ku TW, Gleason JG (1983) Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog. J Pharmacol Exp Ther 227:700–705PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc 1989

Authors and Affiliations

  • Henry M. Thomas
    • 1
  • Magdi S. Sourour
    • 1
  • Deborah Lopez
    • 1
  • Steven H. Foster
    • 1
  1. 1.Will Rogers Pulmonary Research LaboratoryCornell University Medical CollegeWhite PlainsUSA

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