Abstract
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.
Similar content being viewed by others
References
Abaitey AK, Parrat JR, Jr (1976) Cardiovascular effects of diethylcarbamizine citrate. Br J Pharmacol 56:219–227
Aharony D, Stein RL, Redkar-Brown DG, Hubbs SJ, Kusner EJ, Krell RD (1986) The mechanism of leukotriene inhibition of REV 5901. Fed Proc 45:659
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 131:554–558
Ahmed T, Oliver W, Jr (1983) Does slow-reacting substance of anaphylaxis mediate hypoxic pulmonary vasoconstriction? Am Rev Respir Dis 127:566–571
Anderson DL, Fleisher LN, Olson NC (1987) Effect of sulfidopeptide leukotrienes on pulmonary hemodynamics in pigs. Fed Proc 46:1113
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 57:131–141
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 229:105–112
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 627–637
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 56:533–539
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 233:148–157
Garrett RC, Thomas HM, III (1983) Meclofenamate uniformly decreases shunt fraction in dogs with lobar atelectasis. J Appl Physiol 54:284–289
Garrett RC, Foster S, Thomas HM, III (1987) Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction. J Appl Physiol 62:129–133
Harvey RM, Enson Y (1969) Pulmonary vascular resistance. In: Stollerman GH (ed) Advances in internal medicine. Year Book, Chicago, pp 73–93
Higgs GA, Flower RJ, Vane JR (1979) A new approach to anti-inflammatory drugs. Biochem Pharmacol 28:1959–1961
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 81:2890–2892
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 64:1535–1542
Kadowitz PJ, Hyman AL (1984) Analysis of responses to leukotriene D4 in the pulmonary vascular bed. Circ Res 55:707–717
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 72:717–724
Lewis RA, Austen KF (1984) The biologically active leukotrienes biosynthesis, metabolism, receptors, functions, and pharmacology. J Clin Invest 73:889–897
Morganroth ML, Reeves JT, Murphy RC, Voelkel NF (1984) Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction. J Appl Physiol 56:1340–1346
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 131:488–492
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 10:398–406
Mullane K, Salmon JA, Kraemer R (1987) Leukocyte-derived metabolites of arachidonic acid in ischemia-induced myocardial injury. Fed Proc 46:2422–2433
Naeije R, Leeman M, Lejeune P (1986) Effects of diethylcarbamazine and cromolyn sodium on hypoxic pulmonary vasoconstriction in dogs. Bull Eur Physiopathol Respir 22:75–80
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:A128
Piper PJ, Letts LG, Galton SA (1983) Generation of a leukotriene-like substance from porcine vascular and other tissues. Prostaglandins 25:591–599
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 132:93–98
Shuster DP, Dennis DR (1987) Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs. J Appl Physiol 62:1808–1813
Snedecor GW, Cochran WD (1967) Statistical methods. Iowa State University Press, Ames, IA
Thomas HM, III, Garrett RC (1983) Relation of shunt fraction in lobar atelectasis to strength of hypoxic vasoconstriction. Am Rev Respir Dis 127:A3000
Thomas HM, III, Garrett RC (1982) Strength of hypoxic vasoconstriction determines shunt fraction in dogs with atelectasis. J Appl Physiol 53:44–51
Unger M, Atkins M, Briscoe WA, King TKC (1977) Potentiation of pulmonary vasoconstrictor response with repeated intermittent hypoxia. J Appl Physiol 43:662–667
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 241:117–123
Voelkel NF, Stenmark KR, Reeves JT, Mathias MM, Murphy RC (1984) Actions of lipoxygenase metabolites in isolated rat lungs. J Appl Physiol 57:860–867
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 54:54–68
Wagner PD, Naumann PF, Laravuso PB (1974) Simultaneous measurements of eight foreign gases in blood by gas chromatography. J Appl Physiol 36:600–605
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 227:700–705
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thomas, H.M., Sourour, M.S., Lopez, D. et al. Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction. Lung 167, 187–198 (1989). https://doi.org/10.1007/BF02714947
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02714947