, Volume 169, Issue 1, pp 185–202 | Cite as

Endothelium-derived relaxing factor and the pulmonary circulation

  • G. Cremona
  • A. T. Dinh Xuan
  • T. W. Higenbottam


Endothelium-derived relaxing factor (EDRF) is probably identical to nitric oxide (NO) and is released by the vascular endothelium both in the basal unstimulated state and in response to a wide range of physical and chemical stimuli. Since it was first described 10 years ago, evidence is accumulating that it is an important modulator of vascular smooth muscle tone. EDRF acts on the pulmonary vascular bed as on the systemic circulation. EDRF release to pharmacologic stimuli is impaired in pulmonary arteries from patients with chronic hypoxemia. This impairment is associated with severity of respiratory failure and of structural change of vessel walls. Disturbance of EDRF activity may be important in the pathophysiology of pulmonary vascular disease. This brief review describes the current status of experimental studies concerning the possible role of EDRF on the pulmonary circulation in normal conditions and in the pathogenesis of pulmonary hypertension.

Key words

Pulmonary circulation Endothelium-derived relaxing factor Hypoxic pulmonary vasoconstriction Pulmonary hypertension 


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  1. 1.
    Abacioglu N, Ercan ZS, Kanzik L, Zengil H, Demiryurek T, Turker RK (1987) Endothelium-dependent relaxing effect of histamine on the isolated guinea pig main pulmonary artery strips. Agents Action 22:30–35CrossRefGoogle Scholar
  2. 2.
    Adelstein RS, Hathaway DR (1979) Role of calcium and cyclic adenosine 3′5′-monophosphate in regulatory smooth muscle contraction. Am J Cardiol 44:783–787PubMedCrossRefGoogle Scholar
  3. 3.
    Adnot S, Raffestin B, Eddahibi S, Braquet P, Chabrier P-E (1991) Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest 87:155–162PubMedGoogle Scholar
  4. 4.
    Altura BT, Altura BM (1987) Endothelium-dependent relaxation in coronary arteries requires magnesium ions. Br J Pharmacol 91:449–451PubMedGoogle Scholar
  5. 5.
    Altura BM, Chand N (1981) Bradykinin-induced relaxation of renal and pulmonary arteries is dependent on intact endothelial cells. Br J Pharmacol 74:10–11PubMedGoogle Scholar
  6. 6.
    Bhardwaj R, Moore PK (1989) The effect of arginine and nitric oxide on resistance blood vessels of the perfused rat kidney. Br J Pharmacol 97:739–744PubMedGoogle Scholar
  7. 7.
    Bolton TB, Clapp LH (1986) Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle. Br J Pharmacol 87:713–723PubMedGoogle Scholar
  8. 8.
    Borland CDR, Chamberlain AT, Higenbottam TW, Barber RW, Thrush BA (1985) A comparison between the rates of reaction of nitric oxide in the gas phase and in whole cigarette smoke. Beitr Tabakforsch Int 13:67–73Google Scholar
  9. 9.
    Borland CDR, Harmes K, Cracknell N, Mack D, Higenbottam TW (1985) Methaemoglobin levels in smokers and non-smokers. Arch Environ Health 40:330–333PubMedGoogle Scholar
  10. 10.
    Borland CDR, Higenbottam TW (1989) A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide. Eur Respir J 2:56–63PubMedGoogle Scholar
  11. 11.
    Boulanger C, Henderikson H, Lorenz RR, Vanhoutte PM (1989) Release of different relaxing factors by cultured porcine endothelial cells. Circ Res 64:1070–1078PubMedGoogle Scholar
  12. 12.
    Brain SD, Williams TJ, Tippins JR, Morris H, MacIntyre I (1985) Calitonin gene-related peptide is a potent vasodilator. Nature 313:54–56PubMedCrossRefGoogle Scholar
  13. 13.
    Brashers VL, Peach MJ, Rose CE Jr (1988) Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation. J Clin Invest 82:1495–1502PubMedGoogle Scholar
  14. 14.
    Bredt DS, Hwang PM, Snyder SH (1990) Localization of nitric oxide synthetase indicating a neural role for nitric oxide. Nature 437:768–770CrossRefGoogle Scholar
  15. 15.
    Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685PubMedCrossRefGoogle Scholar
  16. 16.
    Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG (1990) Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 345:346–347PubMedCrossRefGoogle Scholar
  17. 17.
    Busse R (1987) Stimulation of soluble guanylate cyclase activity by endothelium-derived relaxing factor: a general principle of its vasodilator and anti-aggrgatory properties. Thromb Res Suppl VII:3–13Google Scholar
  18. 18.
    Chand N, Altura BM (1981) Acetylcholine and bradykinin relax intrapulmonary arteries by acting on endothelial cells: role in lung vascular disease. Science 213:1376–1379PubMedCrossRefGoogle Scholar
  19. 19.
    Chand N, Altura BM (1981) Bradykinin and arachidonic acid, but not beta adrenergic or histaminergic vasorelaxation is mediated by intact endothelial cells. Clin Res 29:443–447Google Scholar
  20. 20.
    Chen GF, Suzuki H (1989) Direct and indirect actions of acetylcholine and histamine on intra pulmonary artery and vein muscles of the rat. Jpn J Physiol 39:51–65PubMedGoogle Scholar
  21. 21.
    Chen GF, Suzuki H (1990) Calcium dependency of the endothelium-dependent hyperpolarization in smooth muscle cells of the rabbit carotid artery. J Physiol (Lond) 421:521–534Google Scholar
  22. 22.
    Cherry PD, Gillis CN (1987) Evidence for the role of endothelium-derived relaxing factor in acetylcholine-induced vasodilatation in the intact lung. J Pharmacol Exp Ther 241:516–520PubMedGoogle Scholar
  23. 23.
    Chester AH, O’Neil GS, Moncada S, Tadjkarimi, Yacoub MH (1990) Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries. Lancet 336:897–900PubMedCrossRefGoogle Scholar
  24. 24.
    Christie MI, Griffith TM, Lewis MJ (1989) A comparison of basal and agonist-stimulated release of endothelium-derived relaxing factor from different arteries. Br J Pharmacol 98:397–406PubMedGoogle Scholar
  25. 25.
    Cocks TM, Angus JA, Campbell JH, Campbell GR (1985) Release and properties of endothelium-derived relaxing factor (EDRF) from endothelial cells in culture. J Cell Physiol 123:310–320PubMedCrossRefGoogle Scholar
  26. 26.
    Coene M-C, Herman AG, Jordaens F, Van Hove C, Verbeuren TJ, Zamekeyn LL (1985) Endothelium-dependent relaxations in isolated arteries of control and hypercholesterolemic rabbits. Br J Pharmacol 85:267pGoogle Scholar
  27. 27.
    Cohen RA, Shepherd JT, Vanhoutte PM (1983) Inhibitory role of the endothelium in the response of isolated coronary arteries to platelets. Science 22:273–274CrossRefGoogle Scholar
  28. 28.
    Collins P, Griffith TM, Henderson AH, Lewis MJ (1986) Endothelium-derived relaxing factor alters calcium fluxes in rabbit aorta: a cyclic guanosine monophosphate-mediated effect. J Physiol (Lond) 381:427–437Google Scholar
  29. 29.
    Craven PA, DeRubertis FR (1978) Restoration of the responsiveness of purified guanylate cyclase to nitroguanidine, nitric oxide and related activators by heme and heme proteins: evidence for the involvement of the paramagnetic nitrosyl-heme complex in enzyme activation. J Biol Chem 253:8433–8443PubMedGoogle Scholar
  30. 30.
    Cremona G, Higenbottam TW, Dinh Xuan AT, Wells FC, Large S, Stewart S, Wallwork J (1991) Influence of endothelium-derived relaxing factor (EDRF) on basal vascular resistance in isolated perfused human lungs. Thorax 46:283P (abstract)Google Scholar
  31. 31.
    Davies PF (1989) How do vascular endothelial cells respond to flow? NIPS 4:22–25.Google Scholar
  32. 32.
    De Mey JG, Claeys M, Vanhoutte PM (1982) Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther 222:166–173PubMedGoogle Scholar
  33. 33.
    De Mey JG, Vanhoutte PM (1982) Heterogenous behaviour of the canine arterial and venous wall. Circ Res 51:439–447PubMedGoogle Scholar
  34. 34.
    Dinh Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland C, Wallwork J (1989) Reduced endothelium-dependent relaxation of cystic fibrosis pulmonary arteries. Eur J Pharmacol 163:401–403PubMedCrossRefGoogle Scholar
  35. 34.
    Dinh Xuan AT, Higenbottam TW, Clelland C, Pepke-Zaba J, Cremona G, Wallwork J (1990) Impairment of pulmonary endothelium-dependent relaxation in patients with Eisenmenger’s syndrome. Br J Pharmacol 99:9–10PubMedGoogle Scholar
  36. 36.
    Dinh Xuan AT, Higenbottam TW (1989) Non-prostanoid endothelium-derived vasoactive factors. J Int Med Res 17:305–315PubMedGoogle Scholar
  37. 37.
    Dinh Xuan AT, Higenbottam TW, Clelland C, Pepke-Zaba J, Wells FC, Wallwork J (1990) Acetylcholine and adenosine disphosphate cause endothelium-dependent relaxation of isolated human pulmonary arteries. Eur Respir J 3:633–638PubMedGoogle Scholar
  38. 38.
    Dinh Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland CA, Wells FC, Wallwork J (1990) The L-arginine analogue, NG-monomethyl-arginine, inhibits endothelium-dependent relaxation of human pulmonary arteries. Am Rev Respir Dis 141(4):A350 (abstract)Google Scholar
  39. 39.
    Dinh Xuan AT, Higenbottam TW, Wallwork J (1991) Relationship between chronic hypoxia and in vitro relaxation mediated by endothelium-derived relaxing factor in human chronic obstructive lung disease. Angiology 41: (in press)Google Scholar
  40. 40.
    D’Orleans-Juste P, Dione S, Mizrahe J, Regoli D (1985) Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium. Eur J Pharmacol 114:9–21PubMedCrossRefGoogle Scholar
  41. 41.
    Doyle MP, Hoekstra JW (1981) Oxidation of nitrogen oxides by bound dioxygen in haemoproteins. J Inorg Biochem 14:351–358PubMedCrossRefGoogle Scholar
  42. 42.
    Durand J, Leroy Ladurie M, Ranson-Bitker B (1970) Effects of hypoxia and hypercapnia on the repartition of pulmonary blood flow in supine subjects. Prog Respir Res 5:156.Google Scholar
  43. 43.
    Ehrasam RE, Perruchoud A, Oberholzer M, Burkhart F, Herzog H (1983) Influence of age on pulmonary haemodynamics at rest and during supine exercise. Clin Sci 65:653–660.Google Scholar
  44. 44.
    Fishman AP (1976) Hypoxia on the pulmonary circulation: how and where it acts. Circ Res 38:221–231PubMedGoogle Scholar
  45. 45.
    Forstermann U, Dudel C, Frolich JC (1987) Endothelium-derived relaxing factor is likely to modulate the tone of resistance arteries in rabbit hindlimb in vivo. J Pharmacol Exp Ther 243:1055–1061PubMedGoogle Scholar
  46. 46.
    Freiman PC, Kitchell GG, Heistod DD, Armstrong ML, Harrison DG (1986) Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates. Circ Res 58:783–789PubMedGoogle Scholar
  47. 47.
    Fritts AW, Harris P, Clauss H, Odell JE, Cournand A (1958) The effect of acetylcholine on the human pulmonary circulation under normal and hypoxic condition. J Clin Invest 37:99–108PubMedGoogle Scholar
  48. 48.
    Furchgott RF (1983) Role of endothelium in responses of vascular smooth muscle. Circ Res 53:557–573PubMedGoogle Scholar
  49. 49.
    Furchgott RF (1984) The role of the endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 24:175–197PubMedCrossRefGoogle Scholar
  50. 50.
    Furchgott RF (1988) Studies on the relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from bovine retractor penis factor is inorganic nitric oxide and endothelium-derived relaxing factor is nitric oxide. In: Vanhoutte PM (ed). Vasodilatation, vascular smooth muscle, peptides, autonomic nerves and endothelium. Raven Press, New York, pp 401–404Google Scholar
  51. 51.
    Furchgott RF, Carvalho MH, Khan MT, Matsunaga K (1987) Evidence for endothelium-dependent vasodilatation of resistance vessels by acetylcholine. Blood Vessels 24:145–9PubMedGoogle Scholar
  52. 52.
    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376PubMedCrossRefGoogle Scholar
  53. 53.
    Gerrard W (1980) In: Gas solubilities: widespread applications. Pergamon Press, Oxford, Chap. 15, pp. 347–358Google Scholar
  54. 54.
    Grasen T, Leisner H, Tiedt N (1986) Absence of role of endothelium in response of isolated porcine coronary arteries to acetylcholine. Cardiovasc Res 20:299–302Google Scholar
  55. 55.
    Griffith TM, Edwards DH, Lewis MJ, Newby AC, Henderson AH (1984) The nature of endothelium-derived relaxing factor. Nature 308:645–647PubMedCrossRefGoogle Scholar
  56. 56.
    Griffith TM, Edwards DH, Davies RL, Harrison TJ, Evans KT (1987) EDRF coordinates the behaviour of vascular resistance vessels. Nature 329:442–445.PubMedCrossRefGoogle Scholar
  57. 57.
    Griffith TM, Henderson AH, Edwards OH, Lewis MJ (1984) Isolated perfused rabbit coronary artery and aortic strip preparations: the role of endothelium-derived relaxant factor. J Physiol (Lond) 351:13–24Google Scholar
  58. 58.
    Gruetter CA, Barry BK, McNamara DB, Gruetter DY, Kadowitz PJ, Ignarro LJ (1979) Relaxation of bovine coronary artery and activation of coronary arery guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine. J Cyclic Nucleotide Protein Morph Res 5:211–224Google Scholar
  59. 59.
    Gryglewski RJ, Palmer RMJ, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456PubMedCrossRefGoogle Scholar
  60. 60.
    Hakim TS, Michel RP, Minami H, Chang HK (1983) Site of pulmonary hypoxic vasoconstriction studied with arterial and venous occlusion. J Appl Physiol 54:1298–1302PubMedGoogle Scholar
  61. 61.
    Hakim TS, Kelly S (1989) Occlusion vs micropipette pressures in the pulmonary circulation. J Appl Physiol 67:1277–1185PubMedGoogle Scholar
  62. 62.
    Harris P, Heath D (1986) Pulmonary haemodynamics in chronic bronchitis and emphysema. In: The human pulmonary circulation. Churchill Livingstone, Edinburgh, pp 522–544Google Scholar
  63. 63.
    Harrison DG, Armstrong ML, Freiman PC, Heistod DD (1987) Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest 80:1808–1811PubMedGoogle Scholar
  64. 64.
    Higenbottam TW, Pepke-Zaba J, Scott J, Wallwork J (1988) Inhaled endothelium-derived relaxing factor in primary pulmonary hypertension. Am Rev Respir Dis 137:A107 (abstract)Google Scholar
  65. 65.
    Hoeffner U, Boulanger C, Vanhoutte PM (1989) Proximal and distal dog coronary arteries respond differently to basal EDRF but not to NO. Am J Physiol 256:H828-H831.PubMedGoogle Scholar
  66. 66.
    Holden WE, McCall E (1984) Hypoxia-induced contraction of porcine pulmonary artery strips depend on intact endothelium. Exp Lung Res 7:101–112PubMedGoogle Scholar
  67. 67.
    Holtz J, Forstermann U, Pohl U, Giesler M, Bassenge E (1984) Flow-dependent endotheliummediated dilatation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibitor. J Cardiovasc Pharmacol 6:1161–1169PubMedGoogle Scholar
  68. 68.
    Hutter JA, Despins P, Higenbottam TW, Stewart S, Wallwork J (1988) Heart-lung transplantation: better use of resources. Am J Med 85:4–11PubMedCrossRefGoogle Scholar
  69. 69.
    Hyman AL, Kadowitz PJ (1989) Influence of tone on responses to acetylcholine in the rabbit pulmonary vascular bed. J Appl Physiol 67:1388–1394PubMedGoogle Scholar
  70. 70.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269PubMedCrossRefGoogle Scholar
  71. 71.
    Ignarro LJ, Byrns RE, Buga GM, Wood KS (1987) Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP. Am J Physiol 253:H1074-H1082PubMedGoogle Scholar
  72. 72.
    Ignarro LJ, Harbison RG, Wood KS, Kadowitz PJ (1986) Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J Pharmacol Exp Ther 237:893–900PubMedGoogle Scholar
  73. 73.
    Johns RA, Linden JM, Peach MJ (1989) Endothelium-dependent relaxation and cyclic GMP accumulation in rabbit pulmonary artery are selectively impaired by moderate hypoxia. Circ Res 65:1508–1515PubMedGoogle Scholar
  74. 74.
    Kadowitz PG, Hyman AL (1984) Analysis of leukotriene D4 in the pulmonary vascular bed. Circ Res 55:707–717PubMedGoogle Scholar
  75. 75.
    Katsuki S, Arnold W, Mittal C, Murad F (1977) Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerine and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 3:23–35.PubMedGoogle Scholar
  76. 76.
    Kiese M (1973) Ferrihemoglobin in normal blood. In: Methaemoglobinemia. A comprehensive test. CRC Press, Cleveland, Chap 3, p 12Google Scholar
  77. 77.
    Knowles RG, Palacios M, Palmer RMJ, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 86:5159–5162PubMedCrossRefGoogle Scholar
  78. 78.
    Komori K, Suzuki H (1987) Heterogenous distribution of muscarinic receptors in the rabbit saphenous artery. Br J Pharmacol 92:657–664PubMedGoogle Scholar
  79. 79.
    Komori K, Suzuki H (1987) Electrical responses of smooth muscle cells during cholinergic vasodilatation in the rabbit saphenous artery. Circ Res 61:586–593PubMedGoogle Scholar
  80. 80.
    Ku DD, Ann HS (1987) Magnesium deficiency produces endothelium-dependent vasorelaxation in canine coronary arteries. J Pharmacol Exp Ther 241:961–966PubMedGoogle Scholar
  81. 81.
    Lloyd TC (1968) Hypoxic pulmonary vasoconstriction: role of perivascular tissue. 25:560–565Google Scholar
  82. 82.
    Luscher TF, Diederich D, Siebenmann R, Lehmann K, Stulz P, von Segesser L, Yang Z, Turina M, Gradel E, Weber E, Buhler FR (1988) Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med 319:462–467PubMedCrossRefGoogle Scholar
  83. 83.
    Luscher TF, Vanhoutte PM (1986) Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8:344–348PubMedGoogle Scholar
  84. 84.
    Martin W, Furchgott RF, Villani GM, Jothianandan D (1986) Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J Pharmacol Exp Ther 237:539–547PubMedGoogle Scholar
  85. 85.
    Martin W, Villani GM, Jothianandan D, Furchgott RF (1985) Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:708–716PubMedGoogle Scholar
  86. 86.
    Mazmanian GM, Baudet B, Brink C, Cerrina J, Kirkiacharian S, Weiss M (1989) Methylene blue potentiates vascular reactivity in isolated rat lungs. J Appl Physiol 66:1040–1045PubMedGoogle Scholar
  87. 87.
    McMurty IF, Petrum MD, Reeves JT (1978) Lungs from chronically hypoxic rats have decreased pressor response to acute hypoxia. Am J Physiol 235:H104-H109Google Scholar
  88. 88.
    Melkumyants AM, Balashov SA, Khayutin VM (1989) Endothelium dependent control of arterial diameter by blood viscosity. Cardiovasc Res 23:741–747PubMedCrossRefGoogle Scholar
  89. 89.
    Meyer M, Schuster KD, Schulz H, Mohr M, Piiper J (1990) Pulmonary diffusing capacities for nitric oxide and carbon monoxide determined by rebreathing in dogs. J Appl Physiol 68:2344–2357PubMedGoogle Scholar
  90. 90.
    Miller VM, Aarhus LL, Vanhoutte PM (1986) Modulation of endothelium-dependent responses by chronic alteration of blood flow. Am J Physiol 251:H520-H527PubMedGoogle Scholar
  91. 91.
    Miller VM, Vanhoutte PM (1986) Endothelium-dependent responses in isolated blood vessels of lower vertebrates. Blood Vessels 23:225–235PubMedGoogle Scholar
  92. 92.
    Moncada S, Gryglewski RJ, Bunting S, Vane JR (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263:663–665PubMedCrossRefGoogle Scholar
  93. 93.
    Moncada S, Palmer RMJ, Higgs EA (1989) Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol 38:1709–1715PubMedCrossRefGoogle Scholar
  94. 94.
    Myers PR, Minor RL, Guerra R, Bates JN, Harrison DG (1990) Vasorelaxant properties of the endothelium-derived relaxing factor more closely resembles S-nitrosocysteine than nitric oxide. Nature 345:161–163PubMedCrossRefGoogle Scholar
  95. 95.
    Nandiwada PA, Hyman AL, Kadowitz PJ (1983) Pulmonary vasodilator response to vagal stimulation and acetylcholine in the cat. Circ Res 53:86–95PubMedGoogle Scholar
  96. 96.
    Nemery B, Wijns W, Piret L, Cauwe F, Brasseur L, Frans A (1983) Pulmonary vascular tone is a determinant of basal lung perfusion in normal seated subjects. J Appl Physiol 54:262–266PubMedGoogle Scholar
  97. 97.
    Ohlstein EH, Wood KS, Ignarro LJ (1982) Purification and properties of heme-deficient hepatic soluble guanylate cyclase: effects of heme and other factors on enzyme activation by NO, HO-heme and protoporphyrin IX. Arch Biochem Biophys 218:187–198PubMedCrossRefGoogle Scholar
  98. 98.
    Orton EC, Reeves JT, Stenmark KR (1988) Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension. J Appl Physiol 65:2459–2467PubMedGoogle Scholar
  99. 99.
    Palmer RMJ, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666PubMedCrossRefGoogle Scholar
  100. 100.
    Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  101. 101.
    Palmer RMJ, Moncada S (1989) A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun 158:348–352PubMedCrossRefGoogle Scholar
  102. 102.
    Peach MJ, Singer HA, Izzo NJ, Loeb AL (1987) Role of calcium in endothelium-dependent relaxation of arterial smooth muscle. Am J Cardiol 59:35A-43APubMedCrossRefGoogle Scholar
  103. 103.
    Pinto A, Abraham NG, McKane KM (1986) Cytochrome P450-dependent mono-oxygenase activity and endothelial-dependent relaxations induced by arachidonic acid. J Pharmacol Exp Ther 236:445–451PubMedGoogle Scholar
  104. 104.
    Radomski MW, Palmer RMJ, Moncada S (1987) Endogenous nitric oxide inhibits human platelets adhesion to vascular endothelium. Lancet 2:1057–1058PubMedCrossRefGoogle Scholar
  105. 105.
    Rapoport RM (1986) Cyclic guanosine monophosphate inhibition of contraction may be mediated through inhibition of phosphatidyl-inositol hydrolysis in rat aorta. Circ Res 58:407–410PubMedGoogle Scholar
  106. 106.
    Rees DD, Palmer RMJ, Hodson HF, Moncada S (1989) A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 96:418–424PubMedGoogle Scholar
  107. 107.
    Robin ED, Theodore J, Burke CM, Oesterle SN, Fowler MB, Jamieson SW, Baldwin JL, Morris AJ, Hunt SA, Vankessel A, Stimson EB, Shumway NE (1987). Hypoxic pulmonary vasoconstriction persists in the human transplanted lungs. Clin Sci 72:283–287PubMedGoogle Scholar
  108. 108.
    Rodman DM, Yamaguchi T, Hasunuma K, O’Brien RF, McMurtry IF (1990) Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery. Am J Physiol 258:L207-L214PubMedGoogle Scholar
  109. 109.
    Rodman DM, Yamaguchi T, O’Brien RF, McMurtry I (1988) Methylene blue enhances hypoxic contraction in isolated rat pulmonary arteries. Chest 93:93s-94s (abst):1278PubMedGoogle Scholar
  110. 110.
    Rubanyi GM, Romero JC, Vanhoutte PM (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250:H1145-H1149PubMedGoogle Scholar
  111. 111.
    Rubanyi GM, Vanhoutte PM (1986) Superoxide anion and hyperoxia inactivate endothelium derived relaxing factor. Am J Physiol 250:H222-H227Google Scholar
  112. 112.
    Rubanyi GM, Vanhoutte PM (1988) Heterogeneity of endothelium-dependent responses to acetycholine in canine femoral arteries and veins. Separation of the role played by endothelial and smooth muscle cells. Blood Vessels 25:75–81PubMedGoogle Scholar
  113. 113.
    Rudolph AM, Kurland MD, Auld PAM, Paul MH (1959) Effects of vasodilator drugs on normal and serotonin-constricted pulmonary vessels of the dog. Am J Physiol 197:617–623PubMedGoogle Scholar
  114. 114.
    Sakuma I, Gross SS, Levi R (1987) Peptidoleukotrienes induce an endothelium-dependent relaxation of guinea pig main pulmonary artery and thoracic aorta. Prostaglandins 34:685–696PubMedCrossRefGoogle Scholar
  115. 115.
    Liu S, Crawley DE, Barnes PJ, Evans TW (1991) Endothelium-derived relaxing factor inhibits hypoxic vasoconstriction in rats. Am Rev Respir Dis 143:32–37PubMedGoogle Scholar
  116. 116.
    Springall DR, Polak JM, Howard L, Power RF, Krausz T, Manickom S, Bamien NR, Khagani A, Rose M, Yacoub MH (1990) Persistence of intrinsic neurones and possible phenotypic changes after extrinsic denervation of human respiratory tract by heart-lung transplantation. 141:1538–1546Google Scholar
  117. 117.
    Standen NB, Quayle JM, Davies NW, Brayden JE, Huang T, Nelson MT (1989) Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245:177–180PubMedCrossRefGoogle Scholar
  118. 118.
    Tare M, Parkington HC, Coleman HA, Neild TO, Dusting GJ (1990) Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium. Nature 346:69–71PubMedCrossRefGoogle Scholar
  119. 119.
    Taugner R, Kirckheim H, Forssmann WG (1984) Myoendothelial contacts in glomerular arterioles and in renal interlobular arteries of rat, mouse and Tupaia belangeri. Cell Tissue Res 235:319–325.PubMedCrossRefGoogle Scholar
  120. 120.
    Taylor SG, Southerthon JS, Weston AH, Baker JRJ (1988) Endothelium-dependent effects of acetylcholine in rat aorta: a comparison with sodium nitroprusside and cromakalim. Br J Pharmacol 94:853–863.PubMedGoogle Scholar
  121. 121.
    Thulesius O, Ugaily-Thulesius L, Neglen P, Shuhaiber H (1988) The role of the endothelium in the control of venous tone: studies on isolated human veins. Clin Physiol 8:359–366PubMedGoogle Scholar
  122. 122.
    Vallance P, Collier J, Moncada S (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2:997–1000PubMedCrossRefGoogle Scholar
  123. 123.
    Vane JR, Angaard EE, Botting RM (1990) Regulatory functions of the vascular endothelium N Engl J Med 323:27–36PubMedCrossRefGoogle Scholar
  124. 124.
    Verbeuren TJ, Jordaens FH, Zammeheyn LL, Van Hove CE, Coene M-C, Herman AG (1986) Effect of hypercholesterolemia on vascular reactivity in the rabbit: endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58:552–564PubMedGoogle Scholar
  125. 125.
    Von Euler U, Liljestrand G (1946) Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 12:301–320CrossRefGoogle Scholar
  126. 126.
    Warren JB, Maltby NH, McCormack D, Barnes PJ (1989) Pulmonary endothelium-derived relaxing factor is impaired in hypoxia. Clin Sci 77:671–676PubMedGoogle Scholar
  127. 127.
    Weinheimer G, Oswald H (1986) Inhibition of endothelium-dependent smooth muscle relaxation by calmodulin antagonists. Arch Pharmacol 332:391–397CrossRefGoogle Scholar
  128. 128.
    Weir EK (1978) Does normoxic pulmonary vasodilatation rather than hypoxic vasoconstriction account for the pulmonary pressor response to hypoxia. Lancet 1:476–477PubMedCrossRefGoogle Scholar
  129. 129.
    Weir EK (1984) In: Weir EK, Reeves JT (eds) Pulmonary hypertension. Futura, New York, p 251Google Scholar
  130. 130.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415PubMedCrossRefGoogle Scholar
  131. 131.
    Zellers TM, VanHoutte PM (1989) Heterogeneity of endothelium-dependent and independent responses among large and small pulmonary arteries. Pulmon Pharmacol 2:201–208CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • G. Cremona
    • 1
  • A. T. Dinh Xuan
    • 1
  • T. W. Higenbottam
    • 1
  1. 1.Department of Respiratory PhysiologyPapworth HospitalCambridgeUK

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