Endothelium-Derived Vasoactive Factors, Platelets and Coronary Disease

  • P. M. Vanhoutte


Endothelial cells can release both relaxing and contracting substances. The former include prostacyclin, endothelium-derived relaxing factor (EDRF, which most likely is nitric oxide, or a nitrosoderivative releasing nitric oxide, derived from 1-arginine), and endothelium-derived hyperpolarizing factor (EDHF, which possibly is a labile metabolite of arachidonic acid formed through the P-450 pathway). Possible endothelium-derived contracting factors (EDCF) include superoxide anions, thrombox-ane A2, and the peptide endothelin. Endothelium-derived relaxing factor causes relaxation of vascular smooth muscle by activation of the soluble form of guanylate cyclase, which leads to an accumulation of cyclic GMP; it also reduces platelet adhesion and aggregation. The latter effect is synergistic with the inhibition evoked by prostacyclin. The release of endothelium-derived relaxing factor and prostacyclin plays a key role in the protective role of the endothelium against vasospasm and unwanted coagulation of blood. Indeed, thrombin and aggregating platelets are potent stimuli for the release of endothelium-derived relaxing factor. The platelet products responsible are the adenine nucleotides, ADP and ATP, which activate P2-purinegic receptors on the endothelial cells, and 5-hydroxytryptamine (serotonin) which stimulates 5HT1-like serotonergic receptors. The response to serotonin, but not to the adenine nucleotides, is mediated by a pertussis toxin-sensitive mechanism. When endothelial cells regenerate, or are cultured, they selectively lose the pertussis toxin-sensitive mechanism of release, which results in a marked decrease in sensitivity to exogenous and platelet-released serotonin. As a consequence, the endothelial cells exhibit a considerably reduced response to aggregating platelets. This phenomemon, which can be exacerbated by hypercholesterolemia, favors ongoing platelet aggregation and vasospasm, and constitutes a first step toward atheroscerosis.


Nitric Oxide Methylene Blue Leave Anterior Descend Adenine Nucleotide Pertussis Toxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 299: 373–376CrossRefGoogle Scholar
  2. 2.
    Furchgott RF (1983) Role of the endothelium in responses of vascular smooth muscle. Circ Res 53: 557–573PubMedGoogle Scholar
  3. 3.
    Furchgott RF (1984) Role of endothelium in the responses of vascular smooth muscle to drugs. Ann Rev Pharmacol Toxicol 24: 175–197CrossRefGoogle Scholar
  4. 4.
    Vanhoutte PM, Rubanyi GM, Miller VM, Houston DS (1986) Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol 48: 307–320PubMedCrossRefGoogle Scholar
  5. 5.
    Bassenge E, Busse R (1987) Endothelial modulation of coronary tone. Prog Cardiovasc Dis 30: 349–380CrossRefGoogle Scholar
  6. 6.
    Furchgott RF, Vanhoutte PM (1989) Endothelium-derived relaxing and contracting factors. FASEB J 3: 2007–2018PubMedGoogle Scholar
  7. 7.
    Lüscher TF, Vanhoutte PM (1990) The endothelium: Modulator of cardiovascular function. CRC, Boca Raton pp 1–228Google Scholar
  8. 8.
    Vanhoutte PM, Cohen RA (1983) The elusory role of serotonin in vascular function and disease. Biochem Pharmacol 32: 3671–3674PubMedCrossRefGoogle Scholar
  9. 9.
    Vanhoutte PM, Houston DS (1985) Platelets, endothelium and vasospasm. Circulation 72: 728–734PubMedCrossRefGoogle Scholar
  10. 10.
    Vanhoutte PM, Shimokawa H (1989) Endothelium-derived relaxing factor(s) and coronary vasospasm. Circulation 80: 1–9PubMedCrossRefGoogle Scholar
  11. 11.
    Cohen RA, Shepherd JT, Vanhoutte PM (1983) Inhibitory role of the endothelium in the response of isolated coronary arteries to platelets. Science 221: 273–274PubMedCrossRefGoogle Scholar
  12. 12.
    Houston DS, Shepherd JT, Vanhoutte PM (1985) Adenine nucleotides, serotonin and endothelium-dependennt relaxations to platelets. Am J Physiol 248: H389–H395PubMedGoogle Scholar
  13. 13.
    Houston DS, Shepherd JT, Vanhoutte PM (1986) Aggregating human platelets cause direct contraction and endothelium-dependent relaxation in isolated canine coronary arteries. J Clin Invest 78: 539–544PubMedCrossRefGoogle Scholar
  14. 14.
    Shimokawa H, Aazhus LL, Vanhoutte PM (1987) Porcine Coronary arteries with regenerated endothelium have a reduced endothelium-dependent respartiveness to aggregating platelets and serotonin Circulation Res 61: 256–270PubMedGoogle Scholar
  15. 15.
    Forstermann U, Mugge A, Alheid U, Haverich A, Frolich JC (1988) Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. Circ Res 62: 185–190PubMedGoogle Scholar
  16. 16.
    Houston DS, Vanhoutte PM (1988) Comparison of serotonergic receptor subtypes on the smooth muscle and endothelium of the canine coronary artery. J. Pharmacol Exp Ther 244: 1–10PubMedGoogle Scholar
  17. 17.
    Houston DS, Burnstock G, Vanhoutte PM (1987) Different P2-purinergic receptor subtypes on endothelium and smooth muscle in canine blood vessels. J Pharmacol Exp Ther 241: 501–506PubMedGoogle Scholar
  18. 18.
    Flavahan NA, Shimokawa H, Vanhoutte PM (1989) Pertussis toxin inhibits endothelium-dependent relaxations to certain agonists in porcine coronary arteries. J Physiol 408: 549–560PubMedGoogle Scholar
  19. 19.
    Shimokawa H, Aarhus LL, Vanhoutte PM (1989) Dietary polyunsaturated fatty acids augment endothelium-dependent relaxation to bradykinin in porcine coronary microvessels. Br J Pharmacol 95: 1191–1196Google Scholar
  20. 20.
    Moncada S, Vane JR (1979) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 30: 293–331Google Scholar
  21. 21.
    Furchgott RF (1988) Studies on relaxation of rabbit aorta by sodium nitrite: The basis for the proposal that acid-activatable inhibitory factor from bovine retractor penis is inorganic nitrite and the endothelium derived relaxing factor is nitric oxide. In: Vanhoutte PM (ed) Vasodilatation: Vascular smooth muscle, peptides, autonomic nerves and endothelium. Raven, New York, pp 401–414Google Scholar
  22. 22.
    Ignarro LJ, Byrns RE, Wood KS (1988) Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical. In: Vanhoutte PM (ed) Vasodilatation: Vascular smooth muscle, peptides, autonomic nerves and endothelium. Raven, New York, pp 427–436Google Scholar
  23. 23.
    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
  24. 24.
    Palmer RMJ, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333: 664–666PubMedCrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Moncada S, Palmer RMJ, Higgs A (1988) The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 12: 365–372PubMedGoogle Scholar
  27. 27.
    Feletou M, Vanhoutte PM (1988) Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 93: 515–524PubMedGoogle Scholar
  28. 28.
    Hoeffner U, Feletou M, Flavahan NA, Vanhoutte PM (1989) Canine arteries release two different endothelium-derived relaxing factors. Am J Physiol 257: H330–H333PubMedGoogle Scholar
  29. 29.
    Boulanger C, Hendrickson H, Lorenz RR, Vanhoutte PM (1989) Release of different relaxing factors by cultured porcine endothelial cells. Circ Res 64: 1070–1078PubMedGoogle Scholar
  30. 30.
    Radomski MW, Palmer RMJ, Moncada S (1987) The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun 148: 1482–1489PubMedCrossRefGoogle Scholar
  31. 31.
    Sneddon JM, Vane JR (1988) Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells. Proc Natl Acad Sci USA 85: 2800–2804PubMedCrossRefGoogle Scholar
  32. 32.
    Radomski MW, Palmer RMJ, Moncada S (1987) The anti-aggregating properties of vascular endothelium: Interaction between prostacyclin and nitric oxide. Br J Pharmacol 92: 639–646PubMedGoogle Scholar
  33. 33.
    De Mey JG, Claeys M, Vanhoutte PM (1982) Endothelium-dependent inhibitory effects of acetylcholine, adenosine diphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharm Exp Ther 222: 166–173Google Scholar
  34. 34.
    Lüscher TF, Cooke JP, Houston DS, Neves R, Vanhoutte PM (1987) Endothelium-dependent relaxations in human peripheral and renal arteries. Mayo Clin Proc 62: 601–606PubMedGoogle Scholar
  35. 35.
    Vanhoutte PM (1989) State of the art lecture: Endothelium and control of vascular function. Hypertension 13 (6): 658–667PubMedGoogle Scholar
  36. 36.
    Shimokawa H, Flavahan NA, Vanhoutte PM (1990) Natural Course of the impairment of endothelium-dependent relaxations after balloon endothelium-removal in porcine coronary arteries. Circ Res 65: 740–753Google Scholar

Copyright information

© Springer-Verlag Tokyo 1991

Authors and Affiliations

  • P. M. Vanhoutte
    • 1
  1. 1.Department of Medicine, Center for Experimental TherapeuticsBaylor College of MedicineHoustonUSA

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