Endothelium — Influenced Vasomotion: Models and Measurements

  • T. M. Griffith
Part of the NATO ASI Series book series (volume 166)


The chance discovery by Furchgott and colleagues in 1980 that acetylcholine relaxes isolated arterial strips only if their endothelium is carefully preserved has now clarified the mechanism of action of a wide variety of pharmacological agents and the physiology of flow regulation. “Sandwich” experiments in which an endothelium-intact aortic strip relaxed a closely apposed endothelium-denuded strip, suggested that the phenomenon was mediated by a diffusible vasodilator (Furchgott and Zawadzki, 1980; Furchgott, 1983) and this was confirmed by bioassay experiments (Griffith et al., 1984). This short review will focus on the properties and physiological significance of this agent, endothelium derived relaxing factor (EDRF). Endothelium-dependent relaxation is associated with hyperpolarization of underlying smooth muscle (Bolton et al., 1984) but recent evidence suggests that this is mediated by a separate factor (Komori and Suzuki, 1987; Feletou and Vanhoutte, 1988). Endothelium also produces an endothelium-derived contracting factor or EDCF, (Hickey et al., 1985; Gillespie et al., 1986) and a peptide, endothelin, which is one of the most potent vasoconstrictor agents yet discovered has now been sequenced and cloned (Yanagisawa et al., 1988). In addition to modulating the action of pharmacological agents, EDRF and EDCF, by responding to mechanical forces, may together account for the complementary homeostatic phenomena of flow-dependent dilatation and the so-called “myogenic” response. The former, an endothelium-dependent mechanism whereby the arterial lumen adjusts dynamically to alterations in flow rate (Schretzenmayr, 1933; Gerova et al, 1981; Holtz et al, 1983; Pohl et al, 1986a) seems to be mediated by EDRF release stimulated by shear stress. The “myogenic” response (Bayliss, 1902) is the mechanism whereby quick stretch or a rise in transmural pressure induces vasoconstriction, limits flow and thus contributes to autoregulation. There is evidence that this also depends on an intact endothelium in some (Harder, 1987; Katusic et al., 1987), although not all (Hwa and Bevan, 1986), artery types so that it is not always strictly “myogenic”. The specific involvement of endothelin, whilst likely, remains to be confirmed.


Diameter Ratio Soluble Guanylate Cyclase Geometrical Similarity Endothelium Derive Relaxing Factor Individual Junction 
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  1. Angus, J.A., Campbell, G.R., Cocks, T.M., and Manderson, J.A., 1983, Vasodilatation by acetylcholine is endothelium-dependent: A study by sonomicrometry in canine femoral artery in vivo, J. Physiol. (Lond), 344: 209.Google Scholar
  2. Azuma, H., Ishikawa, M., Sekizaki, S., 1986, Endothelium-dependent inhibition of platelet aggregation, Br. J. Pharmac., 88: 411.CrossRefGoogle Scholar
  3. Bayliss, W.M., 1902, On the local reaction of the arterial wall to changes of internal pressure, J. Physiol. (Lond.), 28: 220.Google Scholar
  4. Bolton, T.B., Lang, R.J., and Takewaki, T., 1984, Mechanisms of action of noradrenaline and carbachol on smooth muscle of guinea pig anterior mesenteric artery, J. Physiol. (Lond), 351: 549.Google Scholar
  5. Cocks, T.M., Angus, J.A., Campbell, J.H., and Campbell, G.R., 1985, Release and properties of endothelium-derived relaxing factor (EDRF) from endothelial cells in culture, J. Cell. Physiol., 123: 310.PubMedCrossRefGoogle Scholar
  6. Colden-Standfield, M., Schilling, W.P., Ritchie, A.K., Eskin, S.G., Navarro, L.T., and Kunze, D.L. 1987, Bradykinin-induced increases in cytosolic calcium and ionic currents in cultured bovine aortic endothelial cells, Circ. Res., 61: 632.CrossRefGoogle Scholar
  7. Collins, P., Griffith, T.M., Henderson, A.H., and Lewis, M.J., 1986, Endothelium-derived relaxing factor alters calcium fluxes in rabbit aorta: A cyclic guanosine monophosphate-mediated phenomenon, J. Physiol. (Lond.), 381: 427.Google Scholar
  8. Craven, P.A., and De Rubertis, F.R., 1978, Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemoproteins, J. Biol. Chem., 253: 8433.PubMedGoogle Scholar
  9. De Mey, J.G., and Gray, S.D., 1985, Endothelium-dependent reactivity in resistance vessels, Prog. Appl. Microcirc., 8: 181.Google Scholar
  10. De Mey, J.G., and Vanhoutte, P.M., 1983, Anoxia and endothelium-dependent reactivity of the canine femoral artery, J.Physiol. (Lond.), 335: 65.Google Scholar
  11. Edwards, D.H., Griffith, T.M., Ryley, H.C., and Henderson, A.H., 1986, Haptoglobin-hemoglobin complex in human plasma inhibits endothelium dependent relaxation: evidence that endothelium derived relaxing factor acts as a local autocoid, Cardiovasc. Res., 20: 549.PubMedCrossRefGoogle Scholar
  12. Feletou, M., and Vanhoutte, P.M., 1988, Endothelium-dependent hyperpolarization of canine coronary smooth muscle, Br. J. Pharmac., 93: 515.CrossRefGoogle Scholar
  13. Fiscus, R.R., Rapoport, R.M., and Murad, F., 1983, Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta, J. Cyclic Nucleotide Protein Phosphor. Res., 9: 415.PubMedGoogle Scholar
  14. Forstermann, U., Trogisch, G., and Busse, R., 1985, Species-dependent differences in the nature of endothelium-derived vascular relaxing factor, Eur. J. Pharmacol., 106: 639.CrossRefGoogle Scholar
  15. Forstermann, U., Goppelt-Strube, M., Frohlich, J.C., Busse, R., 1986a, Inhibitors of acyl-coenzyme A:lysolecithin acyltransferase activates the production of endothelium-derived relaxing factor, J. Pharmacol. Exp. Ther., 238: 352.PubMedGoogle Scholar
  16. Forstermann, U., Mulsch, A., Bohme, E., Busse, R., 1986b, Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries, Circ Res., 58: 531.PubMedCrossRefGoogle Scholar
  17. Forstermann, U., Dudel, C. and Frolich, C., 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.PubMedGoogle Scholar
  18. Forstermann, U., Alheid, U., Frolich, J.C., and Mulsch, A., 1988, Mechanisms of action of lipoxygenase and cytochrome P 450 mono-oxygenase inhibitors in blocking endothelium-dependent vasodilatation, Br. J. Pharmacol., 93: 569.PubMedCrossRefGoogle Scholar
  19. Furchgott, R.F., and Zawadzki, J.V., 1980, The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine, Nature, 288: 373.PubMedCrossRefGoogle Scholar
  20. Furchgott, R.F., 1983, Role of endothelium in responses of vascular smooth muscle, Circ.Res., 53: 557.PubMedCrossRefGoogle Scholar
  21. Furchgott, R.F., 1988, Studies on relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from bovine retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide, in:“Mechanisms of Vasodilatation”, Vol IV, Vanhoutte, P.M., Ed., Raven press, New York (in press).Google Scholar
  22. Gerova, M., Gero, J., Barta, E., Dolezel, S., Smiesko, V., and Levicky, V., 1981, Neurogenic and myogenic control of conduit coronary artery: A possible interference, Bas. Res. Cardiol., 76: 503.CrossRefGoogle Scholar
  23. Gillespie, M.N., Owasoyo, J.O., McMurtry, I.F., O Brien, R.F., 1986, Sustained coronary constriction provoked by a peptidergic substance released from endothelial cells in culture, J. Pharmac. Exp. Ther., 236: 339.Google Scholar
  24. Gore, R.W., 1972, Wall stress: a determinant of regional differences in response of frog microvessels to norepinephrine, Am. J. Physiol., 222: 82.PubMedGoogle Scholar
  25. Griffith, T.M., Edwards, D.H., Lewis, M.J., Newby, A.C., and Henderson, A.H., 1984, The nature of endothelium-derived relaxant factor, Nature, 308: 645.PubMedCrossRefGoogle Scholar
  26. Griffith, T.M., Edwards, D.H., Lewis, M.J., and Henderson A.H., 1985, Evidence that cyclic guanosine monophosphate (cGMP) mediates endothelium-dependent relaxation, Eur. J. Pharmacol., 112: 195.PubMedCrossRefGoogle Scholar
  27. Griffith, T.M., Edwards, D.H., Lewis, M.J., Newby, A.C., and Henderson, A.H., 1986, Production of endothelium-derived relaxant factor is dependent on oxidative phosphorylation and extracellular calcium, Cardiovasc. Res., 20: 7.PubMedCrossRefGoogle Scholar
  28. Griffith, T.M, Edwards, D.H., and Henderson, A.H., 1987a, Unstimulated release of endothelium derived relaxing factor is independent of mitochondrial ATP generation, Cardiovasc. Res., 21: 565–568.PubMedCrossRefGoogle Scholar
  29. Griffith, T.M., Edwards, D.H., Davies, R. Ll., Harrison, T.J., Evans, K.T., 1987b, EDRF coordinates the behaviour of vascular resistance vessels, Nature, 329: 442.PubMedCrossRefGoogle Scholar
  30. Griffith, T.M., Edwards, D.H., Davies, R. Ll., Harrison, T.J., Evans, K.T., 1988, Endothelium-derived relaxing factor (EDRF) and resistance vessels in an intact vascular bed: a microangiographic study of the rabbit isolated ear, Br. J. Pharmacol., 93: 6542.CrossRefGoogle Scholar
  31. Gryglewski, R.J., Palmer, R.M.J., and Moncada, S., 1986, Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxinng factor, Nature, 320: 454.PubMedCrossRefGoogle Scholar
  32. Guyton, A.C., cited in Koch, A.R., 1964, Some mathematical forms of autoregulating models, Circ. Res., 15 (suppl 1): 269.Google Scholar
  33. Harder, D.R., 1987, Pressure-induced myogenic activation of cat cerebral arteries is dependent on intact endothelium, Circ. Res., 60: 102.PubMedCrossRefGoogle Scholar
  34. Hickey, K.A., Rubanyi, G.M., Paul, R.J., Highsmith, R.F., 1985, Characterisation of a coronary vasoconstrictor produced by cultured endothelial cells, Am. J. Physiol., 248: C550.PubMedGoogle Scholar
  35. Holtz, J., Giesler, M., and Bassenge, E., 1983, Two dilatory mechanisms of antianginal drugs on epicardial coronary arteries in vivo: Indirect flow-dependent endothelium-mediated dilation and direct smooth muscle relaxation, Z. Kardiol., 75 (Suppl. 3): 98.Google Scholar
  36. Holzmann, S., 1982, Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips, J. Cyclic Nucl. Res., 8: 409.Google Scholar
  37. Hwa, J.J., Bevan, J.A., 1986, Stretch-dependent (myogenic) tone in rabbit ear resistance arteries, Am. J. Physiol., 250: H87.PubMedGoogle Scholar
  38. Ignarro, L.J., Byrns, R.E., Buga, G.M., and Wood, K.S., 1987, Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical, Circ. Res., 61: 866.PubMedCrossRefGoogle Scholar
  39. Kamiya, A., and Togawa, T., 1980, Adaptive regulation of wall shear stress to flow change in the canine carotid artery, Am. J. Physiol., 239: H14.PubMedGoogle Scholar
  40. Katusic, Z.S., Shepherd, J.T., and Vanhoutte, P.M., 1987, Endothelium-dependent contraction to stretch in canine basilar arteries, Am. J. Physiol., 252: H671.PubMedGoogle Scholar
  41. Komori, K. and Suzuki,H., 1987, Heterogeneous distribution of muscarinic receptors in the rabbit saphenous artery, Br. J. Pharmacol., 92: 657PubMedCrossRefGoogle Scholar
  42. Long, C.J. and Stone, T.W., 1985, The release of endothelium-derived relaxant factor is calcium dependent, Blood Ves., 22: 205.Google Scholar
  43. Luckhoff, A., Pohl,U., Mulsch,A. and Busse, R., 1988, Differential role of extra and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells, Br. J. Pharmacol.,in press.Google Scholar
  44. Martin, W., Villani, G.M., Jothianandan, D., and Furchgott, R.F., 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.PubMedGoogle Scholar
  45. Melkumyants, A.M., Balashov, S.A., Veselova, E.S., and Khayutin, V.M., 1987, Continuous control of the lumen of feline conduit arteries by blood flow rate, Cardiovasc. Res., 21: 863.PubMedCrossRefGoogle Scholar
  46. Moncada, S., Palmer, R.M.J. and Gryglewski, R.J., 1986, Mechanisms of action of some inhibitors of endothelium-derived relaxing factor, Proc. Natl. Acad. Sci. U.S.A., 83: 9164.PubMedCrossRefGoogle Scholar
  47. Murray, C.D., 1926, The physiological principle of minimum work applied to the angle of branching of arteries, J. Gen. Physiol., 9: 835.PubMedCrossRefGoogle Scholar
  48. Nakache, M. and Gaub, H.E., 1988, Hydrodynamic hyperpolarization of endothelial cells, Proc Natl. Acad. Sci. U.S.A., 85: 1841.Google Scholar
  49. Olesen, S-P., Clapham, D.E., and Davies, P.F., 1988, Haemodynamic shear stress activates a K’ current in vascular endothelial cells, Nature, 331: 168.PubMedCrossRefGoogle Scholar
  50. Owen, M.P., and Bevan, J.A., 1985, Acetylcholine induced endothelial-dependent vasodilatation increases as artery diameter decreases in the rabbit ear, Experentia, 41: 1057.CrossRefGoogle Scholar
  51. Palmer, R.M.J., Ferrige, A.G., and Moncada, S., 1987, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor, Nature, 327: 524.PubMedCrossRefGoogle Scholar
  52. Palmer, R.M.J., Ashton, D.S. and Moncada, S., 1988, Vascular endothelial cells synthesise nitric oxide from L-arginine, Nature, 333: 664.PubMedCrossRefGoogle Scholar
  53. Pohl, U., and Busse, R., 1988, Reduced nutritional blood flow in autoperfused rabbit hindlimbs following inhibition of endothelial vasomotor function, in: W. Halpern, J. Brayden, M. McLaughlin, G. Osol, B.L. Pegram, and K. Mackey, eds., “Proc 2nd international symposium on resistance arteries”, Perinatology Press, Ithaca (in press)Google Scholar
  54. Pohl, U., Holtz, J., Busse, R. and Bassenge, E., 1986a, Crucial role of endothelium in the vasodilator response to increased flow in vivo, Hypertension. 8: 37.PubMedCrossRefGoogle Scholar
  55. Pohl, U., Busse, R., Kuon, E., and Bassenge, E., 1986b, Pulsatile perfusion stimulates the release of endothelial autocoids, J. Appl. Cardiol., 1: 215.Google Scholar
  56. Pohl, U., Dersi, L., Simon, B., Busse, R., 1987, Selective inhibition of endothelium-dependent dilation in resistance vessels in vivo, Am. J. Physiol., 253: H234.PubMedGoogle Scholar
  57. Rapoport, R.M. and Murad, F., 1983, Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cyclic GMP, Circ. Res., 52: 352.PubMedCrossRefGoogle Scholar
  58. Rapoport, R.M., Draznin, M.B., and Murad, F., 1983, Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation, Nature, 306: 174.PubMedCrossRefGoogle Scholar
  59. Rapoport, R.M., Draznin, M.B., Murad. F., 1984, Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta, Circ. Res., 55: 468.Google Scholar
  60. Rubanyi, G.M., Lorenz, R.R., and Vanhoutte, P.M., 1985a, Bioassay of endothelium-derived relaxing factor(s): inactivation by catecholamines, Am. J. Physiol., 249: H95.PubMedGoogle Scholar
  61. Rubanyi, G.M., Schwartz, A., and Vanhoutte, P.M., 1985b, The calcium antagonists Bay K 8644 and (+) 202, 791 stimulate the release of endothelial relaxing factor from canine femoral arteries, Eur. J. Pharmacol., 117: 143.PubMedCrossRefGoogle Scholar
  62. Rubanyi, G.M., Romero, J.C. and Vanhoutte, P.M., 1986a, Flow-induced release of endothelium-derived relaxing factor, Am. J. Physiol., 250: H1145.PubMedGoogle Scholar
  63. Rubanyi, G.M. and Vanhoutte, P.M., 1986b, Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor, Am. J. Physiol., 250: H822.PubMedGoogle Scholar
  64. Schretzenmayr, A., 1933, Uber kreislaufregulatorische Vorgange an den grossen Arterien bei der Muskelarbeit, Pfluegers Arch., 232: 743.CrossRefGoogle Scholar
  65. Schmidt, H.H.H.W., Klein, M.M., Niroomand, F., Bohme, E., 1988, Is arginine a physiological precursor of endothelium-derived nitric oxide? Eur. J. Pharmacol., 148: 293.PubMedCrossRefGoogle Scholar
  66. Shikano, K. and Berkowitz, B.A., 1987, Endothelium-derived relaxing factor is a selective relaxant of vascular smooth muscle, J. Pharm. Exp. Ther., 243: 55.Google Scholar
  67. Singer, H.A. and Peach, M.J., 1982, Calcium-and endothelial-mediated vascular smooth muscle relaxation in rabbit aorta, Hypertension 4 (suppl. II):II-19-II-25.Google Scholar
  68. Winquist, R.J., Bunting, P.B. and Schofield, T.L., 1985, Blockade of endothelium-dependent relaxation by the amiloride analog dichlorobenzamil: Possible role of Na+/Ca++ exchange in the release of endothelium-derived relaxant factor, J. Pharmacol. Exp. Ther., 235: 644.PubMedGoogle Scholar
  69. Woldenburg, M.J. and Horsfield, K., 1983, Finding the optimal lengths for three branches at a junction, J. Theor. Biol., 104: 301.CrossRefGoogle Scholar
  70. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui Y., Yazaki, Y., Goto, K., and Masaki, T., 1988, A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature, 332: 441.CrossRefGoogle Scholar
  71. Zamir, M., 1976, Optimality principles in arterial branching, J. Theor. Biol., 62: 227.PubMedCrossRefGoogle Scholar
  72. Zamir, M., and Bigelow, D.C., 1984, Cost of departure from optimality in arterial branching, J Theor. Biol., 109: 401.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • T. M. Griffith
    • 1
  1. 1.Department of Diagnostic RadiologyUniversity of Wales College of MedicineHeath Park, CardiffUK

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