Coronary Vasomotor Responses: Role of Endothelium and Nitrovasodilators

  • E. Bassenge


The endogenous nitrovasodilator endothelium-derived nitric oxide (EDNO) is continuously synthetized enzymatically by NO synthase from L-arginine and is released from endothelial cells. Enhanced, superimposed EDNO release can be stimulated by various local and circulating factors, such as bradykinin, ATP, etc., but also most importantly by viscous drag-induced shear stress of the blood-stream acting on the endothelial lining. Thus luminal release suppresses leukocyte adhesion (expression of adhesion molecules), platelet activation, platelet adhesion, and platelet aggregation, and abluminal release counteracts myogenic and neurogenic coronary constrictor tone, thereby increasing myocardial perfusion and dilating large coronary artery calibers. Thus endothelial impairment and denudation (hypercholesterolemia, atheromatosis, balloon catheter interventions) favor excessive constrictor tone and myocardial ischemia. Under these conditions EDNO can be supplemented by compounds (e.g., nitroglycerin, isosorbide dinitrate) converted by biological systems into NO. In addition, it can be supplemented by compounds that even spontaneously release NO (e.g., sydnonimines such as SIN-1 and sodium nitroprusside). EDNO and exogenously supplemented NO stimulate soluble guanylyl cyclase, increase cGMP levels, and bring about vascular relaxation, particularly in those still compliant sections in which EDNO production is impaired and cGMP levels are thus diminished. Exogenous nitrovasodilators are preferentially converted (in the presence of cysteine) enzymatically in large coronary arteries, improving coronary conductance, and in the venous bed (preload reduction), resulting in an improved O2 supply/demand ratio. During chronic, continuous application, neurohormonal counterregulation and diminished enzymatic biotransformation into NO may reduce their effectiveness, resulting in tolerance, particularly in the most sensitive vascular sections, such as veins and coronary arteries. This drawback can be overcome by spontaneously applying NO-releasing compounds, intermittent therapy, or intermittent interposition of other vasodilator principles.


endothelium derived NO nitrovasodilators nitrate tolerance receptor dependent and independent NO release nitric oxide 


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  1. 1.
    Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989;3:2007–2018.PubMedGoogle Scholar
  2. 2.
    Bassenge E, Heusch G. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev Physiol Biochem Pharmacol 1990;116:77–165.PubMedGoogle Scholar
  3. 3.
    Rubanyi GM, Freay AD, Kauser K, Johns A, Harder DR. Mecha-noreception by the endothelium—mediators and mechanisms of pressure-induced and flow-induced vascular responses. Blood Vessels 1990;27:246–257.PubMedGoogle Scholar
  4. 4.
    Halbrugge T, Lutsch K, Thyen A, Graefe KH. Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline. Naunyn Schmiedebergs Arch Pharmacol 1991;344:720–727.PubMedCrossRefGoogle Scholar
  5. 5.
    Zeiher AM, Drexler H, Wollschlager H, Just HJ. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391–401.PubMedGoogle Scholar
  6. 6.
    Pohl U, Lamontagne D, Bassenge E, Busse R. EDRF augments coronary conductivity through attenuation of myogenicmyogenic autoregulation (abstr). Pflügers Arch 1990;415(Suppl 1):R62.Google Scholar
  7. 7.
    Pohl U, Lamontagne D, Bassenge E, Busse R. Attenuation of coronary autoregulation in the isolated rabbit heart by endothelium derived nitric oxide. Cardiovasc Res 1994;28:414–419.PubMedCrossRefGoogle Scholar
  8. 8.
    Quyyumi AA, Cannon RO, Panza JA, Diodati JG, Epstein SE. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992;86:1864–1871.PubMedGoogle Scholar
  9. 9.
    Zeiher AM, Drexler H, Saurbier B, Just H. Endiothelium-mediated coronary blood flow modulations in humans: Effects of age, atherosclerosis, hypercholesterolemia, and hypertension, J Clin Invest 1993;92:652–662.PubMedCrossRefGoogle Scholar
  10. 10.
    Huckstorf C, Zanzinger J, Bassenge E. Reduced nitric oxide formation causes coronary vasoconstriction and impaired dilator responses to endogenous agonists and hypoxia in dogs. Naunyn-Schmiedebergs Arch Pharmacol 1994,349:367–373.PubMedGoogle Scholar
  11. 11.
    Bassenge E. Endothelium-mediated regulation of coronary tone. Basic Res Cardiol 1991;86:69–76.PubMedGoogle Scholar
  12. 12.
    Toda N, Okamura T. Regulation by nitroxidergic nerve of arterial tone. News Physiol Sci 1992;7:148–152.Google Scholar
  13. 13.
    Sakuma I, Togashi H, Yoshioka M, et al. NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo—A role for nitric oxide in the central regulation of sympathetic tone. Circ Res 1992;70:607–611.PubMedGoogle Scholar
  14. 14.
    Boulanger C, Luscher TF. Release of endothelin from the porcine aorta—inhibition by endothelium-derived nitric oxide. J Clin Invest 1990;85:587–590.PubMedCrossRefGoogle Scholar
  15. 15.
    Pohl U, Busse R, Kuon E, Bassenge E. Pulsatile perfusion stimulates the release of endothelial autacoids. J Appl Cardiol 1986;1:215–235.Google Scholar
  16. 16.
    Olesen SP. An electrophysiological study of microvascular permeability and its modulation by chemical mediators. Acta Physiol Scand 1989;136:7–28.CrossRefGoogle Scholar
  17. 17.
    Shen J, Luscinskas FW, Connolly A, Dewey CF, Gimbrone MA. Fluid shear stress modulates cystolic free calcium in vascular endothelial cells. Am J Physiol 1992;262:C384-C390.PubMedGoogle Scholar
  18. 18.
    Nishida K, Harrison DG, Navas JP, et al. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 1992;90:2092–2096.PubMedCrossRefGoogle Scholar
  19. 19.
    Uematsu M, Navas JP, Nishida K, et al. Mechanisms of endothelial cell NO synthase induction by shear stress. Circulation 1993;88:I184.Google Scholar
  20. 20.
    Forstermann U, Pollock JS, Nakane M. Nitric oxide synthases in the cardiovascular system. Trends Cardiovasc Med 1993;3:104–110.PubMedCrossRefGoogle Scholar
  21. 21.
    Hecker M, Mülsch A, Bassenge E, Busse R. Vasoconstriction and increased flow: Two principal mechanisms of shear stress-dependent endothelial autacoid release. Am J Physiol 1993;265:H828–H833.PubMedGoogle Scholar
  22. 22.
    Lefer AM, Siegfried MR, Ma X. Protection of ische-miareperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction. J Cardiovasc Pharmacol 1993;22(Suppl):S27–S33.PubMedCrossRefGoogle Scholar
  23. 23.
    Weyrich AS, Buerke M, Albertine KH, Lefer AM. Time course of endothelial adhesion molecule expression during reper-fusion of ischemic feline myocardium. Circulation 1993; 88:12372.Google Scholar
  24. 24.
    Kubes P, Suzuki M, Granger DN. Nitric oxide—An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–4655.PubMedCrossRefGoogle Scholar
  25. 25.
    Dzau VJ, Gibbons GH. Introduction-Vascular remodeling: Mechanisms and implications. J Cardiovasc Pharmacol 1993;21(Suppl 1):S1–S5.PubMedGoogle Scholar
  26. 26.
    Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase—An FAD-containing and FMN-contain-ing flavoprotein. Proc Natl Acad Sci USA 1991;88:7773–7777.PubMedCrossRefGoogle Scholar
  27. 27.
    Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991; 3:65–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Moncada S, Palmer RMJ, Higgs EA. Nitric oxide—physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43:109–142.PubMedGoogle Scholar
  29. 29.
    Pentros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991;338:1557–1558.CrossRefGoogle Scholar
  30. 30.
    Kilbourn RG, Jubran A, Gross SS, et al. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis Biochem Biophys Res Commun 1990; 172:1132–1138.PubMedCrossRefGoogle Scholar
  31. 31.
    Freudenberg H, Lichtlen PR. The normal wall segment in coronary stenoses—a postmortal study. Z Kardiol 1981;70:863–869.PubMedGoogle Scholar
  32. 32.
    Rubanyi GM. Reversal of hypercholesterolemia-induced endothelial dysfunction by L-arginine. Circulation 1991; 83:1118–1120.PubMedGoogle Scholar
  33. 33.
    Cooke J, Andon N, Girerd X, Hirsch A, Creager M. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991;83:1057–1062.PubMedGoogle Scholar
  34. 34.
    Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hyper-cholesterolaemic patients by L-arginine. Lancet 1991;338: 1546–1550.PubMedCrossRefGoogle Scholar
  35. 35.
    Bassenge E, Stewart DJ. Effects of nitrates in various vascular sections and regions. Z Kardiol 1986;75:1–7.PubMedGoogle Scholar
  36. 36.
    Kurz MA, Lamping KG, Bates JN, Eastham CL, Marcus ML, Harrison DG. Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin. Circ Res 1991;68:847–855.PubMedGoogle Scholar
  37. 37.
    Bassenge E, Stewart DJ. Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy. Cardiovasc Drugs Ther 1988;2:27–34.PubMedCrossRefGoogle Scholar
  38. 38.
    Busse R, Pohl U, Mülsch A, Bassenge E. Modulation of the vasodilator action of SIN-1 by the endothelium. J Cardiovasc Pharmacol 1989;14:S81–S85.PubMedGoogle Scholar
  39. 39.
    Moncada S, Rees DD, Schulz R, Palmer RMJ. Development and mechanism of a supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci 1991;88:2166–2170.PubMedCrossRefGoogle Scholar
  40. 40.
    Rafflenbeul W, Bassenge E, Lichtlen P. Competition between endothelium-dependent and nitroglycerin-induced coronary vasodilation (Konkurrenz zwischen endothelabhangiger und Nitroglycerin-induzierter koronarer Vasodilation) Z Kardiol 1989;78:45–57.PubMedGoogle Scholar
  41. 41.
    Jackson WF, Busse R. Elevated guanosine 3′–5′-cyclic monophosphate mediates the depression of nitrovasodilator reactivity in endothelium-intact blood vessels. Naunyn Schmiedebergs Arch Pharmacol 1991;344:345–350.PubMedCrossRefGoogle Scholar
  42. 42.
    Bassenge E, Zanzinger J. Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function. Am J Cardiol 1992;70:23b–29b.PubMedCrossRefGoogle Scholar
  43. 43.
    Bassenge E, Mülsch A. Anti-ischemic actions molsidomine by venous and large coronary dilatation in combination with antiplatelet effects. J Cardiovasc Pharmacol 1989;14:S23–S28.PubMedGoogle Scholar
  44. 44.
    Bassenge E, Zanzinger J. Effectiveness of an NO-releasing pirsidomine derivative on coronary conductance during long-term administration. J Cardiovasc Pharmacol 1993;22(Suppl 7):S22–S26.PubMedGoogle Scholar
  45. 45.
    Feelisch M, Schönafinger K, Noack E. Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans. Biochemical Pharmacology 1992;44, No.6:1149–1157.PubMedCrossRefGoogle Scholar
  46. 46.
    Stewart DJ, Eisner D, Sommer O, Holtz J, Bassenge E. Altered spectrum of nitroglycerin action in long term treatment: Nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency. Circulation 1986;74:573–582.PubMedCrossRefGoogle Scholar
  47. 47.
    Rudolph W, Dirschinger J, Kraus F, Reiniger G, Hall D. Nitrate therapy in patients with coronary artery disease, preparation and doses with and without development of tolerance. Z Kardiol 1990;79(Suppl):III57–65.Google Scholar
  48. 48.
    Elkayam U. Tolerance to organic nitrates: Evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991;114:667–677.PubMedGoogle Scholar
  49. 49.
    Fung HL. Solving the mystery of nitrate tolerance. A new scent on the trail? Circulation 1993;88:322–324.PubMedGoogle Scholar
  50. 50.
    Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO. Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation 1991;84:2336–2345.PubMedGoogle Scholar
  51. 51.
    Meszaros L, Bak J, Chu A. Cyclic ADP ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca2+ channel. Nature 1993;364:76–79.PubMedCrossRefGoogle Scholar
  52. 52.
    Watanabe H, Kakihana M, Ohtsuka S, Enomoto T, Yasui K, Sugishita Y. Platelet cyclic GMP: A potentially useful indicator to evaluate the effects of nitroglycerin and nitrate tolerance. Circulation 1993;88:29–36.PubMedGoogle Scholar
  53. 53.
    Bassenge E, Busse R, Pohl U. Freisetzung von EDRF aus Arterien: Ein neues antiaggregatorisches Prinzip. Cor Vas 1988;2:113–117.Google Scholar
  54. 54.
    Waldman SA, Rapoport RM, Ginsburg R, Murad F. Desensitiza-tion to nitroglycerin in vascular smooth muscle from rat and human. Biochem Pharmacol 1986;35:3525–3531.PubMedCrossRefGoogle Scholar
  55. 55.
    Kowaluk EA, Seth P, Fung H-L. Metabolic activation of sodium nitroprusside to nitric oxide in vascular smooth muscle. J Pharmacol Exp Ther 1992;262:916–922.PubMedGoogle Scholar
  56. 56.
    Fishman AP. Endothelium: A distributed organ with diverse capabilities. Ann NY Acad Sci 1982;401:l–8.Google Scholar
  57. 57.
    Jeserich M, Munzel T, Just H, Drexler H. Reduced plasma L-arginine in hypercholesterolaemia. Lancet 1992;338:561.CrossRefGoogle Scholar
  58. 58.
    Minor RL, Myers PR, Guerra R, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest 1990;86:2109–2116.PubMedCrossRefGoogle Scholar
  59. 59.
    Mugge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG. Chronic treatment with polyethyleneglycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991;69:1293–1300.PubMedGoogle Scholar
  60. 60.
    Holtz J, Giesler M, Bassenge E. Two dilatory mechanisms of anti-anginal drugs on epicardial coronary arteries in vivo: Indirect, flow-dependent, endothelium-mediated dilation and direct smooth muscle relaxation. Z Kardiol 1983;72:98–106.PubMedGoogle Scholar
  61. 61.
    Clozel JP, Veniant M, Hess P, Sprecher U. Effects of two angiotensin coverting enzyme inhibitors and hydralazine on coronary circulation in hypertensive rats. Hypertension 1991;18:118–1114.Google Scholar
  62. 62.
    Lefer AM, Aoki N. Leukocyte-dependent and leukocyte-independent mechanisms of impairment of endothelium-mediated vasodilation. Blood Vessels 1990;27:162–168.PubMedGoogle Scholar
  63. 63.
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774–1777.PubMedCrossRefGoogle Scholar
  64. 64.
    von der Leyen H, Gibbons GH, Morishita R, Lewis NP, Zhang Y, Cooke JP, Dzau VJ. In vivo gene transfer to prevent neointima hyperplasia after vascular injury: Effect of overexpression of constitutive nitric oxide synthase (abstract). FASEB J 1994;8(5):A802.Google Scholar

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© Kluwer Academic Publishers 1997

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  • E. Bassenge

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