Summary
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 applying spontaneously NO-releasing compounds, intermittent therapy, or intermittent interposition of other vasodilator principles.
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References
Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors.FASEB J 1989;3:2007–2018.
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.
Rubanyi GM, Freay AD, Kauser K, Johns A, Harder DR. Mechanoreception by the endothelium—mediators and mechanisms of pressure-induced and flow-induced vascular responses.Blood Vessels 1990;27:246–257.
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.
Zeiher AM, Drexler H, Wollschläger 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.
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.
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.
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.
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.
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.
Bassenge E. Endothelium-mediated regulation of coronary tone.Basic Res Cardiol 1991;86:69–76.
Toda N, Okamura T. Regulation by nitroxidergic nerve of arterial tone.News Physiol Sci 1992;7:148–152.
Sakuma I, Togashi H, Hoshioka 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.
Boulanger C, Luscher TF. Release of endothelin from the porcine aorta—inhibition by endothelium-derived nitric oxide.J Clin Invest 1990;85:587–590.
Pohl U, Busse R, Kuon E, Bassenge E. Pulsatile perfusion stimulates the release of endothelial autacoids.J Appl Cardiol 1986;1:215–235.
Olesen SP. An electrophysiological study of microvascular permeability and its modulation by chemical mediators.Acta Physiol Scand 1989;136:7–28.
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.
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.
Uematsu M, Navas JP, Nishida K, et al. Mechanisms of endothelial cell NO synthase induction by shear stress.Circulation 1993;88:1184.
Förstermann U, Pollock JS, Kakane M. Nitric oxide synthases in the cardiovascular system.Trends Cardiovasc Med 1993;3:104–110.
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.
Lefer AM, Siegfried MR, Ma X. Protection of ischemia-reperfusion injury by syndnonimine NO donors via inhibition of neutrophil-endothelium interaction.J Cardiovasc Pharmacol 1993;22(Suppl):S27-S33.
Weyrich AS, Buerke M, Albertine KH, Lefer AM. Time course of endothelial adhesion molecule expression during reperfusion of ischemic feline myocardium.Circulation 1993;88:I2372.
Kubes P, Suzuki M, Granger DN. Nitric oxide—An endogenous modulator of leukocyte adhesion.Proc Natl Acad Sci USA 1991;88:4651–4655.
Dzau VJ, Gibbons GH. Introduction-Vascular remodeling: Mechanisms and implications.J Cardiovasc Pharmacol 1993;21(Suppl 1):S1-S5.
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-containing flavoprotein.Proc Natl Acad Sci USA 1991;88:7773–777.
Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity.Curr Opin Immunol 1991;3:65–70.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide—physiology, pathophysiology and pharmacology.Pharmacol Rev 1991;43:109–142.
Pentros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock.Lancet 1991;338:1557–1558.
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.
Freudenberg H, Lichtlen PR. The normal wall segment in coronary stenoses—a postmortal study.Z Kardiol 1981;70:863–869.
Rubanyi GM. Reversal of hypercholesterolemia-induced endothelial dysfunction by L-arginine.Circulation 1991;83:1118–1120.
Cooke J, Andon N, Girerd X, Hirsch A, Creager M. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta.Circulation 1991;83:1057–1062.
Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine.Lancet 1991;338:1546–1550.
Bassenge E, Stewart DJ. Effects of nitrates in various vascular sections and regions.Z Kardiol 1986;75:1–7.
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.
Bassenge E, Stewart DJ. Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy.Cardiovasc Drugs Ther 1988;2:27–34.
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.
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.
Rafflenbeul W, Bassenge E, Lichtlen P. Competition between endothelium-dependent and nitroglycerin-induced coronary vasodilation (Konkurrenz zwischen endothelabhängiger und Nitroglycerin-induzierter koronarer Vasodilation).Z Kardiol 1989;78:45–57.
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.
Bassenge E, Zanzinger J. Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function.Am J Cardiol 1992:70:23b-29b.
Bassenge E, Mülsch A. Anti-ischemic actions of molsidomine by venous and large coronary dilatation in combination with antiplatelet effects.J Cardiovasc Pharmacol 1989;14:S23-S28.
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.
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.
Stewart DJ, Elsner 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.
Rudolph W, Dirschinger J, Kraus F, Reiniger G, Hall D. Nitrate therapy in patients with coronary artery disease, preparations and doses with and without development of tolerance.Z Kardiol 1990;79(Suppl):III57–65.
Elkayam U. Tolerance to organic nitrates: Evidence, mechanisms, clinical relevance, and strategies for prevention.Ann Intern Med 1991;114:667–677.
Fung HL. Solving the mystery of nitrate tolerance. A new scent on the trail?Circulation 1993;88:322–324.
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.
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.
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.
Bassenge E, Busse R, Pohl U. Freisetzung von EDRF aus Arterien: Ein neues antiaggregatorisches Prinzip.Cor Vas 1988;2:113–117.
Waldman SA, Rapoport RM, Ginsburg R, Murad F. Desensitization to nitroglycerin in vascular smooth muscle from rat and human.Biochem Pharmacol 1986;35:3525–3531.
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.
Fishman AP. Endothelium: A distributed organ with diverse capabilities.Ann NY Acad Sci 1982;401:1–8.
Jeserich M, Munzel T, Just H, Drexler H. Reduced plasma L-arginine in hypercholesterolaemia.Lancet 1992;339:561.
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.
Mügge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.Circ Res 1991;69:1293–1300.
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.
Clozel JP, Veniant M, Hess P, Sprecher U. Effects of two angiotensin converting enzyme inhibitors and hydralazine on coronary circulation in hypertensive rats.Hypertension 1991;18:II8-II14.
Lefer AM, Aoki N. Leukocyte-dependent and leukocyte-independent mechanisms of impairment of endothelium-mediated vasodilation.Blood Vessels 1990;27:162–168.
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.
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.
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Bassenge, E. Coronary vasomotor responses: Role of endothelium and nitrovasodilators. Cardiovasc Drug Ther 8, 601–610 (1994). https://doi.org/10.1007/BF00877414
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DOI: https://doi.org/10.1007/BF00877414