Publications

VERZEICHNIS DER WISSENSCHAFTLICHEN ARBEITEN

1. 1. Nguyen-Duong, Hoang, Versuche zum Nachweis von 3,4-Dehydro-tropolon. Diplomarbeit, Universität Heidelberg, 1964.
2. 2. Nguyen-Duong, Hoang, Über das intermediäre Auftreten von 3,4-Dehydro-tropolon und 5,4-Dehydro-dibenzooxepin. Dissertation, Universität Heidelberg, 1966.
3. 3. Tochtermann W., K.Oppenländer und Nguyen-Duong, Hoang, Untersuchungen an Siebenringsystemen, III: Über das intermediäre Auftreten von 4,5-Dehydro-(b,f)-oxepin. Liebigs Ann. Chem. 701, 117-125 (1967).
4. 4. Schnizer W. und H.Nguyen-Duong, Transmitter in der Froschlunge. Pflügers Arch., 300, R16 (1968).
5. 5. Gebert G., E.Voigt, A.Blazevic und Nguyen-Duong Hoang, Das Verhalten der energiereichen Phosphate und des O₂-Verbrauches des Froschsartorius beim Übergang von in vivo- zu in-vitro Bedingungen. Pflügers Arch., 303, 375-385 (1968).
6. 6. Schnizer W., Nguyen-Duong Hoang und K.Brecht, Transmitter in der Froschlunge. Pflügers Arch., 304, 271-283 (1968).
7. 7. Betz E., U.Knebel, L.Neumann und H.Nguyen-Duong, Die Wirkung von hohen CO₂-Konzentrationen auf energiereiche Substrate und EEG-Aktivität des Cortex. Pflügers Arch., 307, R117 (1969).
8. 8. Konold P., G.Gebert, H.Nguyen-Duong und K.Brecht, Der Einfluss von Milieuänderung, Temperatur und Präparation auf den Ionengehalt und die Kalium-Dilatation muskulärer Arterien in vitro. Pflügers Arch., 310, 86-94 (1969).
9. 9. Betz E., U.Knebel, L.Neumann and H.Nguyen-Duong, Effect of high concentrations of CO₂ on cerebral Metabolism and EEG Activity. In: Cerebral Blood Flow: Clinical and experimental results, herausgegeben von M. Brock, C.Fieschi, D.H.Ingwar, N.­A.Lassen, K.Schürmann, Springer Verlag, Berlin (1969).
10. 10. Gebert G., Hoang Nguyen-Duong, W.Schnizer, P.Konold, F.Hillenbrand, H.Yabu and K.Brecht, The response of isolated arteries and veins to potassium, osmolarity and drugs ( Die Reaktion isolierter Arterien und Venen auf Kalium, osmotischer Druck and Pharmaka). Ärztliche Forschung, 23, 391-8 (1969).
11. 11. Brecht K., H.Nguyen-Duong, R.Fischer, F.Hillenbrand, P.Matis, H.J.Schneider und W.Schnizer, Über die Wirkung von Trasylol und anderen vasoaktiven Substanzen auf isolierten Arterien und Venen. Ärztliche Forschung, 24, 86-92 (1970).
12. 12. Schlote W., E.Betz, U.Knebel und H.Nguyen-Duong, EEG-Veränderungen und Dendriten-Schwellung bei schwerer respirato­rischer Acidose. Pflügers Arch., 316, R74 (1970).
13. 13. Schlote, W., Betz, E., Knebel, U. and Nguyen-Duong, H., EEG-Veränderungen und Dendritenschwellung bei schwerer respiratorischer Acidose. Wien.Klin.Wochenschr., 82, 667 (1970).
14. 14. Kissling G., H.Nguyen-Duong, H.F.Kienzle, G.Sieber, Negative Inotropie von Acetylcholin aus intramuralen parasympathischen Nervenendigungen des Säugerventrikels. Pflügers Arch., 319, R18-19 (1970).
15. 15. Rieckert H., H.J.Schneider, W.Schnizer und H.Nguyen-Duong, Die Gefäßwandfunktion des kaudalen Venensystems unter dem Einfluss von Kontrazeptiva: Eine in vivo- und in vitro-Untersuchung. In: Sexualhormone und Blutgerinnung (1971), Schattauer-Verlag.
16. 16. Nguyen-Duong, H. and K.Brecht, The Influence of Potassium on the Adenosin 3′, 5’-monophosphate content of the vascular muscle. Pflügers Arch., 40. Tagung der Dtsch.Physiol.Gesellschaft (Düsseldorf), R55 (1972).
17. 17. Nguyen-Duong Hoang und K.Brecht, cAMP and the Potassium Relaxation of Arterial Smooth Muscle. Pflügers Arch., 347, R15 (1974).
18. 18. Schnizer, W., H.Piechowiak, Hoang Nguyen-Duong, M.Schiebe und G.Gebert, Postischemic Edema of Skeletal Muscle: Ion, Water and osmotic Shifts during and after Ischemia. Pflügers Arch., 347, R48 (1974).
19. 19. Gebert, G., W.Schnizer, H.Piechowiak, H.Nguyen-Duong und M.Schiebe, Mechanismus der Ödembildung im Skelettmuskel nach Ischämie. “Gewebsischämie und Mikrozirkulation”; Hrsg.: Breddin K. und Eisenbach, Schattauer Verlag, Stuttgart (1974).
20. 20. Nguyen-duong, Hoang, K.Brecht und G.Gebert, Cyclic AMP and the Potassium-induced Vasodilation. Pflügers Archiv, 356, 3-8 (1975).
21. 21. Kissling G., K.Reutter, G.Sieber, H.Nguyen-Duong und R.Jacob, Negative Inotropie von endogenem Acetylcholin beim Katzen-und Hühnerventrikel-myokard. Pflügers Arch., 333, 35-50 (1972).
22. 22. Nguyen-Duong Hoang, Coupling and uncoupling of vascular smooth muscle of arteries and veins after electrical stimulation. Pflügers Arch., 355, R58 (1975).
23. 23. Gebert, G. and H.Nguyen-Duong, Effects of ions, electrical stimulation and catecholamines on vascular smooth muscle. Arzneimittel-Forschung (Drug.Res.) 25, 1667-8 (1975).
24. 24. Brecht K., G.Gebert, H.Nguyen-Duong, Über Wirkungen von elektrischen, ionalen, hormonalen und pharmakologischen Reizen auf die Mechanik von Arterien und Venen und ihre Beeinflussung durch Nifedipin (Adalat). Med.Welt, 26, 1602-09 (1975).
25. 25. Nguyen-Duong H., G.Gebert und K.Brecht, The effect of drugs and electrical stimulation on the mechanical response of bovine arteries and veins. Pflügers Arch., 359, R140 (1975).
26. 26. Nguyen-Duong Hoang, G.Gebert und K.Brecht, Electrical stimulation of isolated bovine arteries and veins: mechanical response and interaction with drugs. Second international symposium on vascular neuroeffector mechanisms, Uni. of Odense, Denmark, Jul. 29-Aug.1 1975, Blood vessels, 12, 372 (1975).
27. 27. Schlote, W., Betz, E., Nguyen-Duong, H., Reversible apical swelling of dendrites in the cerebral cortex of cats during respiratory acidosis. Adv. Neurol., 12, 483-95 (1975).
28. 28. Nguyen-Duong, H., K.Brecht und G.Gebert, Vascular Effects of Potassium in Physiologic Concentration Range, in Ionic Actions on Vascular Smooth Muscle with Special Regard to Brain Vessels, S.61-4 Editor: E. Betz, Springer-Verlag, Berlin-Heidelberg-New York, 1976.
29. 29. Nguyen-Duong Hoang und G.Gebert, Evidence for dopamine receptors in the bovine facial vein. Pflügers Arch., 365, R30 (1976).
30. 30. Gebert, G. and H.Nguyen-Duong, Mechanism of K⁺-induced Vasodilatation, Pflügers Arch, 365, R31 (1976).
31. 31. Gebert, G. and H.Nguyen-Duong, Adrenergic and noradrenergic transmitter systems in vascular smooth muscle. Arzneimittel-Forschung (Drug Res.) 26, 1234-5 (1976).
32. 32. Gebert G., M.Schiebe, W.Schnizer, H.Nguyen-Duong, Effect of an enzyme inhibitor on the oedema formation in rat skeletal muscle after tourniquet ischemia. Arzneimittel-Forschung (Drug.Res.) 26, 1237-8 (1976).
33. 33. Nguyen Duong Hoang, Ulrich Voss, Karl Brecht, Functional characterization of different, isolated human blood vessels. Proceedings of the International Union of Physiological Sciences, Vo. XIII, 548 (1977).
34. 34. Nguyen-Duong H. und K.Brecht, Untersuchungen über Mechanismen der Kontraktionsauslösung am glatten Gefäßmuskel und ihre Beeinflussung durch Kalzium-Antagonisten. Münch.med. Wschr., 119, Suppl. 1, 12-18 (1977).
35. 35. Nguyen Duong Hoang and K.Brecht, Different levels of uncoupling contraction in vascular muscles. Pflügers Arch., 373, R50 (1978).
36. 36. Nguyen Duong H. and K.Brecht, The influence of magnesium ions on the reactivity of bovine facial vessels. Pflügers Arch., 377, R37 (1978).
37. 37. Nguyen Duong H, W.Schüle and K.Brecht, Influence of variable Mg_o on basal tone and drug-induced contractions of bovine facial vessels. Pflügers Arch., 379, R32 (1979).
38. 38. Nguyen Duong H. and K.Brecht, Reactivity of isolated bovine facial vessels to electrical stimulation and to drugs. Pharmacology, 19, 23-35 (1979).
39. 39. Nguyen Duong Hoang, Die Beziehungen zwischen Energiestoffwechsel und Mechanik beim glatten Gefäßmuskel. Phlebol. und Proktol., 8, 221-227 (1979).
40. 40. Nguyen Duong H., K.Brecht and M.Weil, Effects of extracellular magnesium ions on the vascular smooth muscle. Pflügers Arch., 382, R25 (1979).
41. 41. Nguyen Duong H., und K.Brecht, Die Wirkung von Magnesiumionen auf Rinderfacialgefäße. 3. Hohenheimer Magnesium-Symposium; Universität Hohenheim 28./29. September 1979. Gesellschaft für Magnesium-Forschung e.V., Tutzing.
42. 42. Nguyen Duong Hoang, Mitwirkung an der Redaktion des Kapitels: Muskelphysiologie, des “Kurzgefassten Lehrbuchs der Physiologie”. Herausgegeben von W.D.Keidel, 5.Auflage, Georg Thieme Verlag Stuttgart, 1979.
43. 43. Nguyen Duong H., U.Voss and K.Brecht, Effect of potassium on isolated bovine facial and human saphenous veins. Experientia, 36, 975-976 (1980).
44. 44. Nguyen Duong Hoang, Differential alpha-and beta-adrenergic sensitivity of veins: possible significance for the venous return. Proceedings of the International Union of Physiological Sciences, Vol. XIV, 610 (1980).
45. 45. Nguyen Duong H., R.Rüdel and U.Voss, Effects of AR-L 115 on Arterial and Venous muscle Tone in vitro. Arzneimittelforschung (Drug.Res.), 31, 197-199 (1980).
46. 46. Nguyen Duong H., K.Brecht und K.Schulz, Die Wirkungen von extracellulären Magnesium-Ionen auf isolierte Blutgefäße. 4.Hohenheimer Magnesium-Symposium, Universität Hohenheim 26. und 27.September 1980. Gesellschaft für Magnesium-Forschung e.V.Tutzing.
47. 47. Nguyen Duong H. und K.Brecht, Experimentelle Studien über die Wirkung von Magnesium auf isolierte Blutgefäße und ihre therapeutischen Aspekte. Magnesium-Bulletin, 2, 33-41 (1980).
48. 48. Nguyen Duong H., Differentiation between relaxing effects of various vasodilators. Pflügers Arch., 391, R36 (1981).
49. 49. Nguyen Duong H. und K.Brecht, Über die Wirkung von Magnesium-Ionen auf isolierte Blutgefäße und ihre therapeutische Bedeutung bei Koronarspasmen. Med.Welt, 32, 964-6 (1981).
50. 50. Brecht K. und Nguyen Duong H., Auch Magnesium kann Koronarspasmen lösen, Ärztl. Praxis, 34, 119-1110 (1982).
51. 51. Nguyen Duong H. and K.Brecht, Magnesium as the physiologic calcium antagonist: Its vascular effects and therapeutic use. International Erwin Riesch Symposium; Tübingen Sept. 19-22, 1982, in Cardiac Adaptation to hemodynamic Overload, Training and Stress. Eds. R.Jacob, R.W.Gülch, G.Kissling. Dr.D.Steinkopff Verlag Darmstadt, 1983, S.288-294.
52. 52. Nguyen Duong Hoang, Etiology and treatment of coronary spasms: Role of Magnesium as the physiologic Calcium Antagonist. Magnesium-Bulletin, 4, 204 (1982).
53. 53. Nguyen Duong H., Inability of some Vasodilators to Block Fluoride induced Contractions of Vascular smooth Muscle in Calcium-free solutions. Pflügers Arch., 394, R43 (1982).
54. 54. Nguyen Duong Hoang, Unterschiedliche adrenerge Reaktivität entlang der Rinderfacialvenen und mögliche Bedeutung für den venösen Rückstrom. In Gefäßwandelemente in vivo und in-vitro. Erwin-Riesch-Symposium (3./4.Juni 1983). Herausgegeben von H.Fischer und E.Betz. Wissenschaftliche Verlagsgesellschaft GmbH, Stuttgart, 1984.
55. 55. Nguyen Duong Hoang und S.Sebaldt, Ätiologie von Koronarspasmen und Rolle der Magnesium Ionen. 86. Hohenheimer Magnesium-Symposium, Universität Hohenheim, 23.Sept. 1983.
56. 56. Nguyen-Duong H., Ineffectiveness of some Vasodilators to antagonize Fluoride Contractions of Bovine Facial Vessels induced in Calcium-free Solutions. Pflügers Arch., 400, R12 (1984).
57. 57. Nguyen Duong H., Spontaneous rhythmic contractions as a possible trigger mechanism of coronary spasms. Pflügers Arch., 402, R45 (1984).
58. 58. Nguyen Duong H., Koronarspasmen: Ursache, Therapie und Prophylaxe mit Magnesium Ionen. 7. Hohenheimer Magnesium-Symposium. Universität Hohenheim, 28. /29. September 1984.
59. 59. Nguyen Duong Hoang, Mechanism of Contractions Induced by Ergometrin in isolated porcine coronary arteries: Role of Magnesium ions as the physiologic Calcium-Antagonists. Magnesium-Bulletin, 7, 70-78 (1985).
60. 60. Nguyen Duong Hoang, Effects of Vasoactive Drugs on Fluoride-induced Contractions of Vascular Smooth Muscle in Calcium-Free Solution, Arzneimittelforschung/Drug Research, 235 (II) 1246-1250 (1985).
61. 61. Nguyen-Duong H. and P.Sick, Overactivity of isolated porcine coronary arteries to Histamine after pretreatment with Tetraaethylammonium and Barium Ions. Pflügers Arch., 403, R29 (1985).
62. 62. Nguyen Duong H., Cholinergic-induced contractions of epicardial coronary arteries: possible role for the parasympathetic system in the aetiology of coronary spasms. Pflügers Arch., 405, R60 (1985).
63. 63. Nguyen Duong Hoang, Ätiologie der Koronarspasmen, prophylaktische und therapeutische Bedeutung der Magnesium-Ionen. In Magnesium in der Frauenheilkunde. H.Weidinger (Heraus­geber). Bayreuther Gespräch 10.-12.Mai 1985. Münchner Wissenschaftliche Publikationen, 1985.
64. 64. Nguyen Duong H., Rolle der Magnesium Ionen bei der Ätiologie und der Therapie von Koronarspasmen. 8. Hohenheimer Magnesium-Symposium (27./28.September 1985).
65. 65. Nguyen Duong H., Spontaneous phasic contractions of isolated coronary arteries and hyperactivity to pharmacologic stimuli: possible relationship to pathogenetic mechanisms underlying coronary spasms, European Conference on Muscle and Motility 14th Europ. Congress on Muscle and Motility, 1985, 11.-15.Sept.Ulm 1985. J. of Muscle Research and Cell Motility.
66. 66. Nguyen Duong Hoang, Mögliche Bedeutung des parasympathischen Nervensystems bei der Ätiologie von Koronarspasmen. Med. Welt, 38, 748-754 (1987).
67. 67. Nguyen Duong Hoang, Mechanisms of the inhibitory action of various vasodilators on acetylcholine-induced contractions of porcine coronary arteries incubated in Ca-free solutions. Pflügers Arch., 406, R40 (1986).
68. 68. Nguyen Duong Hoang, Untersuchungen über möglichen den Koronarspasmen zugrundeliegenden Pathomechanismen. Deutsche Arbeitsgemeinschaft Arterioskleroseforschung am 30./31.Mai, 1986 in Blaubeuren.
69. 69. NGUYEN DUONG Hoang, Spontaneous phasic contractions of isolated coronary arteries and hyperactivity to pharmacological stimuli: possible relationship to pathogenetic mechanisms underlying coronary spasms. J.of muscle Res. and Cell Motility 7, 85 (1986).
70. 70. Nguyen Duong Hoang, Effects of vasodilators on acetylcholine-induced contractions of porcine coronary arteries incubated in Ca-free solutions;  1987 unveröffentlich.
71. 71. Nguyen Duong Hoang and P.Sick, Amplification of serotonin-induced con-tractions of isolated porcine coronary arteries after pretreatment with therapeutic doses of ß-methyldigoxin. Europ.J.of Pharmacology, 135, 89-91 (1987).
72. 72. Nguyen Duong Hoang, Dual effect of lithium ions on isolated porcine coronary arteries. Pflügers Arch., Europ.J.of Physiol., 408, R79 (1987).
73. 73. Nguyen Duong Hoang, Die Wirkungen von Änderungen der Magnesium-Ionen Konzentration auf epikardialen Koronararterien und ihre Bedeutung für Prophylaxe und Therapie der Koronarspasmen. 10.Hohenheimer Mg-Symposium 25./26.Sept. 1987.
74. 74. Nguyen Duong Hoang, Die Rolle von Magnesium-Ionen bei der Ätiologie und Therapie von Koronarspasmen. Magnesium in Klinik und Forschung, Bayreuther Gespräch 22.- 24.Mai 1987, Münchner Wissenschaftliche Publikationen, 131-139 (1987).
75. 75. Nguyen Duong Hoang, Effects of intracellular pH changes induced by propionate and ammonium ions on the tone of porcine coronary arteries. Pflügers Arch., Europ.J.of Physiol., 411, R203 (1988).
76. 76. Nguyen Duong Hoang, In vitro study on muscarinic receptors mediating contractions in pig coronary smooth muscle. Pflügers Arch., Europ.J.of Physiol., 412, R87 (1988).
77. 77. Nguyen Duong Hoang, Therapeutic role in the treatment and prophylaxis of coronary spasms. Proc. of the 5th Int.Magnesium Symposium. Aug.8-12, 1988, Kyoto Int. Conf. Hall, Kyoto, Japan.p.136 (1988).
78. 78. Nguyen Duong Hoang, Mechanisms of the relaxing effect of Magnesium Acetylsalicylate and possible therapeutic role in treatment and prophylaxis of coronary spasms. Magnesium Research, 2, 108 (1989).
79. 79. Nguyen-Duong Hoang, Bamosa, A.O., Spurway, N.C., Effects of variations of intracellular pH, induced by exposure to weak acids or bases, on vascular smooth muscle contractility, Proc. of the Int. Union of Physiol. Sciences, XXXI Int. Congress of Physiol. Sciences, Helsinki, Finnland, 9-14 July, 1989.p.398 (1989).
80. 80. Nguyen Duong Hoang, Die Eignung von Magnesium als Adjuvens zu synthetischen Calcium-Antagonisten bei der Behandlung von Herzkoronar-Erkrankungen. 11. Hohenheimer Magnesium-Symposium. Uni. Hohenheim 29./30.September 1989.
81. 81. Nguyen Duong Hoang, The use of Magnesium as an adjuvant to synthetic Calcium antagonists for prophylaxis and therapy of coronary diseases, Magnesium Bulletin, 11, 159-165 (1989).
82. 82. Nguyen Duong Hoang, Mechanical responses of isolated porcine coronary arteries after intracellular alkaline or acid loading, Pflügers Arch, 415, R 76 (1990).
83. 83. Nguyen Duong Hoang, Effets de manipulations du pH intracellulaire sur la contractilité d’artères coronaires isolées de porc, Comptes rendus de la réunion commune des associations de physiologistes français et tchécoslovaques, Prague 2.-5- 7. 1990. S. 114.
84. 84. Mundl H., A.Mannschedel, A.Kässbohrer, H.Nguyen-Duong and H.Pelzer, Inhibition of KCl and Phorbolester induced contractions of coronary arteries by both activators and inhibitors of protein kinases. Naunyn-Schmiedebergs Arch. Pharmacol., 342, R27 (1990).
85. 85. Nguyen Duong H., Untersuchungen über Regelmechanismen des intrazellulären pH bei der Glattgefäßmuskulatur, Jahrestagung der Gesellschaft der Physiologen der DDR, Neu-Brandenburg, 6.-8. Feb. 1991 (ausgefallen).
86. 86. Nguyen Duong Hoang, Mechanisms of intracellular pH regulation in vascular smooth Muscle, LXV. Fyziologické Dny 5.-7. února 1991, Brno.
87. 87. Nguyen Duong Hoang, Effects of Lithium and of Fluoride ions on Acetylcholine-induced contractions of porcine coronary arteries, Pflügers Arch., 418, R52 (1991).
88. 88. Nguyen Duong H., Mechanisms of coronarospastic hypercontractility and its inhibition by magnesium ions, 13. Hohenheimer Magnesium-Symposium; Uni. Hohenheim 13. /14. September 1991.
89. 89. Nguyen Duong H., Mechanisms of the contractions induced by Fluoride ions in rabbit aorta and in porcine coronary arteries. Pflügers Arch., 419, R85 (1991).
90. 90. Nguyen Duong H., Untersuchungen über die Wirkung von Fluorid-Ionen auf die Kontraktilität der Glattgefäßmuskulatur; In Mengen- und Spurenelemente; 11. Arbeitstagung; 12. und 13. Dezember 1991 in Leipzig. Herausgeber: M. Anke, B. Groppel, H. Gürtler, M. Grün, I. Lombeck, H.J. Schneider, Friedrich-Schiller-Universität Jena, 1991.
91. 91. Nguyen Duong H., Mechanisms of Fluoride-induced contractions in vascular smooth muscle in presence and absence of external Calcium, Pflügers Arch. Europ.J.of Physiol., 420, R31 (1992).
92. 92. Nguyen Duong Hoang, Effects of manipulations of cytoplasmic pH on the mechanical responses of isolated porcine coronary arteries. Arch. Int. Physiol. Biochem. et de Biophys. 101, 207-216 (1992).
93. 93. Nguyen Duong Hoang, Genetic predisposition and essential Hypertension, Mendel-Forum July 20-22, 1992 BRNO Czechoslovakia.
94. 94. Nguyen Duong Hoang, Uncoupling of G-protein mediated fluoride-contractions of vascular smooth muscle by pH_i perturbations; Arzneimittelforschung / Drug Research, 44, 1013-1020 (1994).
95. 95. Nguyen Duong H., Spezifische Beeinflussung unterschiedlicher Stufen der chemomechanischen Koppelung in der Glattgefäßmuskulatur durch Fluorid- und Lithium-Ionen; In Mengen- und Spurenelemente, 12.Arbeitstagung; 10. und 11.Dezember 1992 in Jena. Herausgeber: M.Anke, B.Groppel, H.Gürtler, M.Grün, I.Lombeck, H.J.Schneider. Friedrich-Schiller-Universität Jena. Biologische Fakultät, 1992.
96. 96. Nguyen Duong H., Mechanical responses of vascular smooth muscle to perturbations of the signal transduction system at different non-receptor levels; Pflügers Arch., 422, R81 (1993).
97. 97. Nguyen Duong H., Effects of perturbing cytoplasmic pH in vascular smooth muscle precontracted with fluoride ions in Ca-free medium; XXXII nd International congress of Physiological Sciences Glasgow 1 – 6 August 1993.
98. 98. Nguyen Duong H., Effets de perturbations du pH cytoplasmique sur la contractilité d’artères isolées; 61ème Réunion Annuelle de l’Association des Physiologistes, Université de Bordeaux II; 14 – 17 Septembre 1993. Arch. Int. Physiol. Biochem. et de Biophys. 101, A103 (1993).
99. 99. Nguyen Duong H., Effects of manipulating Calcium influx on the phasic and tonic components of agonist-induced vascular contractions. Pflügers Arch., 426, R92 (1994).
100. 100. Nguyen Duong H., Effets d’altérations de l’influx calcique sur les composantes phasiques et toniques des contractions vasculaires induites par l’acétylcholine. Arch. Int. Physiol. Biochim. Biophys. 102, A104 (1994).
101. 101. Nguyen Duong H., Coordinated receptor stimulation and decreased potassium conductance as a possible primary cause of coronary spasms. Pflügers Arch., 429, R71 (1995).
102. 102. Nguyen Duong H., Modulation of the spasmolytic effect of potassium channel openers by intracellular magnesium, 5^th European Magnesium Congress Vienna Austria June 15- 18, 1995. Magnesium Research, 8, Suppl.1 58 (1995).
103. 103. Nguyen Duong H., Mechanisms of the relaxant and the antirhythmic effects of elevated external Magnesium ions on epicardial coronary arteries. 17. Magnesium Symposium Stuttgart-Hohenheim 29./30.September 1995.
104. 104. Nguyen Duong H., Implications des canaux potassiques sensibles à l’ATP dans le couplage chimiomécanique d’artères coronaires isolées de porc. 63ème Congrès de la Société de Physiologie. Strasbourg, 20-22 Décembre 1995. Arch. of Physiol. Biochem., 103, D83 (1995).
105. 105. Nguyen Duong H., K_ATP channels switch on in relaxation, and off in contraction of vascular smooth muscle 5th International Symposium on Resistance Arteries September 25-29, 1996. J. Vasc. Res. 33 (Suppl.2) 17 (1996).
106. 106. Nguyen Duong H., Role of ATP-regulated K channels in the mechanisms of anti-rhythmic effects of elevated external magnesium ions on epicardial coronary arteries. Advances in Magnesium Research: Magnesium in Cardiology; Ed. R.Smetana, John Libbey & Company Ltd, 121-131 (1997).
107. 107. Nguyen Duong H., Dual role of K_ATP channels in contraction and relaxation mechanisms of vascular smooth muscle, 76.Jahrestagung der Deutschen Physiologischen Gesellschaft 11.-15. März 1997 in Rostock. Pflügers Arch., 433, R84 (1997).
108. 108. Nguyen Duong H., Involvement of K_ATP channels in tone responses of histamine-stimulated porcine coronary arteries to perturbations of pH_i at constant pH_o. XXXIII International Congress of Physiological Sciences. S^t.Petersburg June 30- July 5 1997, P037.32.
109. 109. Nguyen Duong H., Analyse des réponses contractiles d’artères coronaires isolées de porc stimulées par agonistes à des perturbations du pH_i induites par addition externe de NH₄⁺; 65^ème Réunion annuelle de la Société de Physiologie, 17 – 19 Septembre 1997, Prague, République Tchèque.
110. 110. Nguyen-Duong H. et U. Jäger, Effet relaxant du trans-resveratrol sur des artères coronaires isolées de porc,  66ème Congrès de la Société de Physiologie, Lyon, 16-18 Septembre 1998). Archives of Physiology and Biochemistry, 106, Supplement A. VI.132. (1998).
111. 111. Jäger U. and Nguyen-Duong H. Relaxant Effect of trans-Resveratrol on Isolated Porcine Coronary arteries. Arzneimittel-Forschung/Drug Research. 49 (I), 3, 207-211 (1999).
112. 112. Nguyen-Duong H. and Jäger U., Multiple Mechanisms of Action of Trans-Reseveratrol and its protective Role in Cardiovascular diseases. 67ème Congrès de la Société de Physiologie (Paris. Faculté de Médecine Cochin-Port Royal-Univversité Paris V). 13-16 Septembre 1999. (Résumés des Communications).
113. 113. Nguyen-Duong Hoang, Modulation of the Pattern of Contractile responses of Porcine Coronary Arteries to pHi Perturbations induced by the “Acid-Load Technique“. 78^th Annual Meeting of the Deutsche Physiologische Gesellschaft. 14-17 March 1999, Bonn. Pflügers Arch. 437, R147 (1999).
114. 114. Jäger Ulrich and Nguyen-Duong Hoang, Analysis of Vascular Rhythmicity as a cause of Coronary Spasms and Possible Role of Defective Potassium Conductance. Pflügers Arch., 437, R147 (1999).
115. 115. Nguyen-Duong H., Mechanism of the NMDA-receptor mediated vasodilatation induced by glutamate in vascular smooth muscle.  79^th Annual Meeting (19-22 March 2000, Ulm) of the Deutsche Physiologische Gesellschaft. Pflügers Arch., 439, R341 (2000).
116. 116. Jäger U, Nguyen-Duong H., Multiple mechanisms of action of trans-resveratrol and its protective role in cardiovascular diseases. Pflügers Arch., 439, R341 (2000).
117. 117. Nguyen-Duong H., “Depressotoxic” effect induced by L-glutamate in isolated porcine coronary arteries stimulated by fluoride ions. 68^th Annual Meeting 19-22 September 2000, Liège, Belgium. Pflügers Arch., 439, R234 (2000).
118. 118. Nguyen-Duong H., Vasorelaxation induced by L-glutamate in porcine coronary arteries, Journal of Toxicology and Environmental Health, Part A, 62, 643-653 (2001).
119. 119. Nguyen-Duong H. and Jäger U., NMDA-receptor-mediated relaxation induced by glutamate in vascular smooth muscle. 69^th Annual Meeting of the Société de Physiologie. 5-7 September 2001, Montpellier, France, Pflügers Arch. 442, R90 (2001).
120. 120. Nguyen-Duong H. and Jäger U., Glycine-dependence and toxicity of the effects induced by glutamic acid and related substances on vascular smooth muscle. Cor et Vasa, The Czech society of Cardiology, 2002, Suppl. 44 (4).
121. 121. H.Nguyen-Duong and U. Jäger. Zinc ions relax porcine coronary artery preparations stimulated by depolarization and by agonists. Pflügers Archiv/European Journal of Physiology; Physiome 2002 Société de Physiologie. Abstracts of the 70^th Annual Meeting 18-20 September 2002, Québec, Canada. 444, R41-R77 Affiche No 9, 2002.
122. 122. Nguyen-Duong H., The neuroprotective role of Mg ions in the central nervous system. 24. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung e.V., Klinikum Fulda, 10.- 11.Oktober 2003.
123. 123. Nguyen-Duong H., The possible role of Mg ions in the treatment of tinnitus caused by direct damages of hair cells, 25. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung e.V. Klinikum recht der Isar der TU München, 08.-09.Oktober 2004.
124. 124. Nguyen-Duong H., Durch defekte Transduktionsmechanismen verursachter Tinnitus lässt sich mit Magnesium und mit spezifischen Glutamatrezeptoren-Antagonisten rational therapieren. 26. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung e.V., Klinikum am Biederstein, 05.- 07. Oktober 2006.
125. 125. Nguyen-Duong H., Antihypertensive Treatment may be optimized by chronotherapy supplemented with Mg ions, 27. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung e.V. München, 18.- 20. Oktober 2007.
126. 126. Nguyen-Duong H., Effects of Zinc ions on the contractility of vascular smooth muscle preparations (Wpływ jonów cynku na kurczliwość praparatów gładkich mięśni naczyń). X Symposium. Trace elements in the environment-Ecological and methodical problems. Trace elements in food chain. 11-14 May 2008. Koszalin-Mielno (Poland).
127. 127. Nguyen-Duong H., The efficiency of antihypertensive therapy with Ca-antagonists and Mg ions may depend on “Vasomotion” of the arterioles and their medullary control.  28. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung Klinikum Fulda, 10.-11. Oktober 2008.
128. 128. Nguyen-Duong H., Role of magnesium ions in the treatment of cardiovascular diseases caused by failure of the „vasomotion“ function. 29. Magnesium-Symposium der Gesellschaft für Magnesium-Forschung e.V. Klinikum Fulda, 16.-17 Oktober 2009.

EFFECTS OF GLUTAMATE AND OF ZINC IONS ON THE CONTRACTILITY OF VASCULAR SMOOTH MUSCLE PREPARATIONS.

EFFECTS OF GLUTAMATE AND OF ZINC IONS ON THE CONTRACTILITY OF VASCULAR SMOOTH MUSCLE PREPARATIONS.

Hoang Nguyen-Duong

Formerly Department of General Physiology of the University of Ulm, Ulm (Germany).

Summary

It was shown in this study that isolated porcine coronary arteries (PCA) contracted by depolarization with high K_o or by histamine are dose-dependently relaxed by glutamic acid, aspartic acid, N-methyl-asparate (NMDA) and γ-aminobutyric acid (GABA). Zn²⁺ was also shown to relax dose-dependently PCA contractions induced by 50 mM KCl with an ED₅₀ value of about 1.5 mM and to inhibit dose-dependently histamine-induced contractions, shifting ED₅₀ values from 6µM to 40 µM, not affecting however corresponding cumulative concentration-response (CCR) curves established for acetylcholine-induced contractions. Furthermore, since Zn²⁺ ions are co-localized in many glutamatergic synapses of the central nervous system, it has been postulated in analogy to glutamate neurotoxicity that perturbations of the synaptic zinc concentrations might be a triggering factor in several cerebral diseases, such as ischemic strokes and sustained seizures. Unfortunately little is known so far about effects of glutamate and of zinc ions on the vascular tone. Although the nature of the glutamatergic receptors occurring in the blood vessels investigated in this study remains unclear, the results suggest nevertheless that glutamate and Zn²⁺ ions interact with voltage-gated as well with ligand-operated Ca-channels. An interesting aspect might be the putative role of glutamate and of zinc as long-term toxic agents in the early steps of the pathomechanisms leading to degenerative vascular lesions.

Key words. Monosodium glutamate; aspartate, N-methyl-D-aspartate (NMDA), GABA; zinc ions; blood vessels.

1. Introduction

Glutamate receptors, exhaustively investigated in the central nervous system (CNS), are classified according to the nature of the signal transduction mechanism, with ionotropic receptors acting as ligand-gated cation channels and metabotropic receptors operating via second messengers [1, 2]. Ionotropic receptors gated by L-glutamate are distinguished on the basis of pharmacological criteria into three main subtypes: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors. NMDA receptors are characterized by high Ca permeability and a voltage-dependent Mg²⁺ block. The gating of the associated ion channels is modulated by glycine (acting as a co-agonist to glutamate) and by Zn²⁺ ions. Zn²⁺ ions are also present in synaptic glutamatergic vesicles and co-released with glutamate.  NMDA receptors have been shown to play an important role in several cerebral functions endowed with high synaptic plasticity, such as learning and memory; however, they have also been implicated in neuronal injury and death caused by massive release of L-glutamate, which might take place in several types of traumatic lesions, such as head injury, stroke, epilepsy and chronic neurodegenerative diseases [3 - 6]. A quite similar neurotoxicity has been postulated for zinc ions [7]. However notwithstanding the ambiguous role played by glutamate and zinc in the cerebral neurotransmission, both substances are widely present in daily life, with a reputation of being “virtually nontoxic” [7, 8]. Aims of the present study were a. to investigate the effects of glutamate and other related substances with transmitter function and of Zn²⁺ ions on the contractility of arterial preparations activated by different stimuli and b. to detect a putative deleterious effect of excess glutamate on the vascular cells similar to the excitotoxicity observed in neurons, whereby a possible implication as triggering factors in pathological lesions of the vascular wall might also be discussed.

2. Materials and methods

Large branches of epicardial coronary arteries (right, anterior descen­ding and circum­flex arteries; outside diameter 2.5 mm – 0.9 mm) were prepared from pig hearts freshly obtained from a nearby slaught­erhouse. The vessel preparations were cut into helical strips (approx. 10 -15 mm in length and 2 mm in width), pierced by two hooks and mounted ver­tically in 6 parallel setups of organ baths each filled with 25 ml of physiologi­cal salt solution (PSS) maintained at 37°C and aerated continu­ously with 95% O₂ and 5 % CO₂. The PSS had the following composition (mM): NaCl 137; KCl 2.7; CaCl₂ 1.4; MgCl₂ 0.5; NaHCO₃ 11.9; NaH₂PO₄ 0.4; Glucose 8. The changes in force or length developed by the prepara­tions were measured isome­trically (Statham In­struments trans­ducers) or isotonically (HF-Modem-Hugo Sachs Elektronik K.G.) and regi­stered on conventio­nal chart recorders. Maximal wall stress (force/cross sectional area; mN/mm²) was approximated by multiply­ing force with the tissue length and dividing through the wet weight. Following chemicals were used: aspartic acid, γ-aminobutyric acid (GABA), 3.4-diaminopyridine (3.4-AP), glutamic acid, glycine, histamine dihydro­chloride, NaF, tetra­ethylammo­nium (TEA), ZnCl₂. The drugs were all purchased from Sigma. The data were expressed as the mean ± S.E.M. and the number of strip prepara­tions excised from the same coronary artery. For statisti­cal analysis, Student’s t-test for paired and unpaired values was used. P values less than 0.05 were considered signifi­cant.

3. Results

3.1 Relaxations induced by glutamate, GABA, NMDA and aspartate in PCA depolarized by high K or stimulated by histamine.

Whereas the basal tone of unstimulated PCA preparations was not affected by application of glutamate or related agonists (GABA, NMDA, aspartate), preparations contracted by depolari­zation with high K_o or after stimulation with 10 mM histamine were strongly relaxed by glutamate (0.1 – 5 mM). However, the relaxing efficacy differed according to the type of activation. The amplitude of the relaxation induced by glutamate (5 mM) in preparations depolarized by high external K⁺ and contracted via Ca influx through L-type Ca channels, was much smaller than that recorded in histamine-stimulated preparations (Table 1).

Table 1: Comparison of the magnitude of relaxations induced by glutamate, aspartate, NMDA and GABA on PCA preparations contracted by KCl (50 mM) and by histamine (10 µM). The values are expressed as percentage of the maximal height of contraction obtained by depolarization with 50 mM KCl and of the tonic component of the biphasic contraction induced by 10 µM histamine, respectively. 100 % correspond to the values in mN/mm² given in the parentheses; n = 6 for each agonist.

Moreover, in the first case the relaxations were transient, whereas in histamine-stimulated preparations the relaxations were sustained. Contrasting with the general observation that histamine characteristically exerts a predominantly dilator effect on vascular smooth muscle, very powerful contractions were recorded when histamine was applied on PCA preparations at all concentrations (Fig. 1 and 2); these contractions are most probably linked to the activation of ligand-operated receptor channels. Fig. 1 summarizes the relaxing effect of several agonists of glutamatergic receptors on PCA preparations stimulated by 50mM KCl or by 10µM histamine. The largest relaxations were those induced by aspartate, NMDA and GABA on preparations stimulated by histamine.

At first sight the finding that glutamate, as well as the other agonists investigated relax contractions induced by histamine or by depolarization with high K⁺ is unexpected, since it is well-known that in the CNS glutamate acts mainly as an excitatory neurotransmitter. If gating of the channels associated with glutamatergic receptors results in Ca entry then contractions would be expected to occur, when glutamate is added to stimulated PCA preparations. The results presented in Fig. 1 show that the contrary is observed and that without exception only relaxations are throughout recorded. Although no experimental evidence is presented here to support following assumption, a rationale explanation for the contradiction encountered in this study may be that stimulation of glutamatergic receptors in the vascular smooth muscle, which have not been investigated until now, is associated with increasing potassium conductance. This point will be further explained in details in the discussion. Fig. 2 shows representative experiments obtained for GABA (A), NMDA (B) and aspartate (C).

3.2. Inhibiting effects of Zn²⁺ ions on depolarization-induced PCA-contractions and on relaxations induced by glutamate in histamine-stimulated preparations.

On the left side of Fig. 3 it is shown that Zn²⁺ ions relax dose-dependently PCA contractions induced by 50 mM external K⁺ with an ED₅₀ value of approx. 1.5 mM. This finding is easily interpreted, if it is assumed that the depolarization induced by high external K⁺ opens Ca-channel of L-type, leading to contraction of the vascular smooth cells. Thus Zn²⁺ ions seem able to inhibit Ca-entry by binding to a specific site of the channel pore.

Fig. 1 Effects of NMDA-agonists on PCA stimulated by 50 mM KCl or by 10 µM histamine. The error bars represent means values ± SEM and n = 6 for each column. See text for further details.

On the right side of the Fig. 3 it can be seen that addition of Zn²⁺ ions reduces the amplitude of the relaxations induced by 5 mM glutamate in histamine-stimulated PCA preparations. They amount to resp. 49.38 ± 5.77 %  with 0.1 mM Zn²⁺ and to 16.82 ± 3.72 %  with 1 mM Zn²⁺ ; n = 12; p < 0.05). The diagram on the left side of the same figure shows relaxations induced by cumulative addition of zinc ions on PCA depolarized by high K⁺. 100 % correspond to the maximal contractions induced by 50 mM K⁺: 17 mN/mm²; n = 6. The results presented in Fig. 3 are consistent with the ability of Zn²⁺ ions to act as modulator of both voltage-sensitive and ligand-gated ion channels. Thus, taken together the results seem to suggest that Zn²⁺ ions modify the kinetics of ion channels by binding to sites located on Ca or K channels.

Fig. 2 Representative mechanograms for the relaxations induced by GABA (A), for NMDA (B) and for aspartic acid (C).

3.3. Effects of Zinc ions on PCA contractions induced by histamine and by acetylcholine.

Fig. 4 shows the effects of ZnCl₂ (0.5 mM) on contractions induced by histamine and by ACh. Whereas CCR-curves for histamine-induced contractions were significantly shifted to the right (ED50 values increased from 0.9 µM to 4 µM), indicating a blockade of Ca entry through ligand-gated channels by Zn²⁺ ions, the same treatment did not affect the corresponding effects induced by ACh.

Fig. 3 The diagram on the left shows the relaxations induced by cumulative addition of zinc ions on PCA depolarized by high K⁺. 100 % correspond to the maximal contractions induced by 50 mM KCl: 17 mN/mm²; n = 6. The diagram on the right shows the effects of two zinc ions concentrations (0.1 and 1 mM) on the relaxations induced by 5 mM glutamate on PCA preparations contracted by 10 µM histamine. The error bars represent means values ± SEM.

Fig. 4 Effects of ZnCl2 (0.5 mM) on contractions induced by histamine and ACh (n = 12).100 % =9.98 ± 1.2 for histamine and 8,1 ± 1.5 mN/mm² for Ach., n = 12. The error bars represent mean values ± SEM.

3.4 Effects of K channel blockers on glutamate-induced relaxations of PCA stimulated by histamine.

In order to test the possibility that the glutamate-induced relaxations are caused by an increased potassium conductance, PCA preparations relaxed by glutamate during a stimulation with histamine were treated with K-channel blockers (3, 4-diaminopyridine and tetraethylammonium). As can be seen in Fig. 5

Fig. 5 Effects of K channel blockers on glutamate-induced relaxations of PCA stimulated by 10 µM histamine. The two columns at the left obtained from parallel experiments which show the height of the contractions induced by high K⁺ and by histamine are included for the purpose of comparison. The error bars represent means values ± SEM and n = 6 for each column).

(third and fourth column from the left) application of 1 mM 3, 4-diaminopyridine reversed completely the relaxations induced by glutamate in the histamine-stimulated preparations. A similar treatment of the preparations with 5 mM TEA was not able to significantly affect the glutamate-induced relaxations. The amplitude of contractions induced by 50 mM K⁺ and 10 µM histamine are shown in the first and second column of Fig. 5 in order to allow a comparison with the glutamate-induced effects.

The representative mechanogram shown in Fig. 6 shows the reversal of glutamate-induced relaxations in contractions after a pre-treatment with 3,4-diaminopyrimidine. By itself 3, 4-diaminopyridine elicited a strong phasic and unsustained contraction.

Fig. 6 Relaxing effect of glutamate (5 mM) on PCA preparations stimulated by histamine (10 µM) and its reversal to contraction after a pre-treatment  with 3, 4-diaminopyrimidine (5 mM). The preparations were contracted at the beginning and at the end of the experiment in order to test their reactivity.

3.5 Effects of glutamate on PCA preparations contracted by histamine in presence and in absence of glycine.

It has been reported that glycine, which represents an essential coagonist, is indispensable for the physiologic activation of NMDA receptors [2]. In agreement with this requirement, the ED₅₀ values of CCR curves obtained for the relaxation induced by L-glutamate in histamine-stimulated PCA preparations were shifted leftward from 0.8 mM to 0.25 µM in presence of 1 mM glycine (Fig. 7).

Fig. 7 Effects of glutamate on PCA preparations contracted by histamine in presence and in absence of glycine. The error bars represent means values ± SEM; n = 12). See text for further details.

3.6 Effects of glutamate on F^--induced PCA contractions and complete loss of contractility elicited by administration of L-glutamate on PCA preparations overactivated by treatment with F^- -ions.

Depending of the level at which it is applied in the signal transduction chain, glutamate might exert quite different effects. CCR curves established for contractions induced by depolarization with K_o (10 – 100 mM) were slightly and significantly shifted to the right in presence of 5 mM glutamate (Fig. 8, diagram at the left), suggesting that glutamate-induced relaxations partly rely on a reduction of Ca entry. By contrast, the effects elicited by glutamate on F^--induced contractions were more complex (Fig. 8, diagram at the right). It has been shown in a previous study [11] that fluoride ions, which form spontaneously [AlF₄]^- (fluoroaluminate) are able to stimulate the signal transduction chain downstream of the receptor site by acting at the level of inositide signalling pathway as a phosphate analogue with G proteins. In keeping with the assumed mechanism, CCR curves obtained for contractions induced by NaF (1.5 – 12 mM) were significantly shifted to the left (ED₅₀ from 6.3 to 3.1 mM), indicating that the sensitivity of contractions triggered by direct activation of the G-proteins was increased in the presence of glutamate. Parallel to the leftwards shift of the CCR curves, a depression of the maximum effect (reflecting a reduced intrinsic efficacy) was also observed at higher F^- concentrations (Fig. 8, diagram at the right). This observation may be explained as follows: since NMDA ion channels are subject to voltage-dependent Mg²⁺ blockade, a moderate depolarization elicited by F^- would displace the channel-bound Mg²⁺ ions, leading in turn to an opening of channels associated with glutamatergic receptors and most probably to increased K⁺ efflux. The ensuing hyperpolarization would lead to a reduced Ca entry and to inhibition of the vascular tone. Consistent with the proposed mechanism, this depression could be reversed by increasing the external Mg²⁺ to 5 mM (Fig. 8 diagram at the right).

When L-glutamate (10 mM) was added to F^--stimulated PCA preparations, within 1 to 2 hours a complete and irreversible loss of contractility and reactivity toward depolarization by 50 mM K⁺ or applied NaF were regularly observed (not shown); control experiments performed in absence of L-glutamate demonstrated that contractility and reactivity of the PCA preparations remained completely intact within the same lapse of time (not shown).

Fig. 8 Comparison of glutamate effects on contractions induced by cumulative increasing concentrations of external KCl (right) and of NaF. Left diagram: 100 % = 24.56 ±1.73 mN/mm², n = 12. Right diagram: 100 % = 14.24 ± 1.52 mN/mm²; n = 12. The errors bars represent means values 24± S.E.M.. See text for further details.

4. Discussion

The results presented in this study suggest that substances known for their ability to activate glutamatergic receptors in the CNS have pronounced relaxing effects on preparations excised from PCA. Although only some sporadic information exist on pharmacological effects of amino acids on the vascular smooth muscle, to my knowledge there is as yet no published report on receptors stimulated by binding of NMDA, GABA or kainate in PCA. Hence it is not possible at the moment to interpret the present results on the basis of available biochemical, molecularbiological or electrophysiological data. The first conspicuous discrepancy encountered in the pharmacological behaviour of the PCA preparations is the relaxation to the application of agonists of glutamatergic receptors, which have been recorded throughout and without exception. This finding is in contrast with the fact, that in the CNS amino acids are excitatory by nature and that stimulation of NMDA receptors regularly leads to Ca entry in the postsynaptic cells. A logical inference is that the glutamatergic receptors involved in PCA are associated with K⁺ channels. This assumption is consistent with the reversal of glutamate-induced PCA-relaxations observed after addition of a specific K⁺ blocker (Fig. 5 and 6). Glutamate seems also to unspecifically interfere with Ca entry through voltage-gated channels; however the effects were transient, whereas the corresponding effects recorded after stimulation of ligand-operated receptors were sustained and of larger amplitude (Table 1 and Fig. 1). An additional hint for the hypothetical occurrence in the vascular wall of glutamatergic receptors of unidentified subtype is the extreme sensibilization of the glutamate-induced effects by glycine, a co-agonist of NMDA-receptors in the CNS (Fig. 7) [12]. It has been postulated that Zn²⁺, a co-factor and structural component of many enzymes, which also plays a role as an intercellular signalling messenger, may be partly responsible for the neuronal death associated with transient global ischemia, with sustained seizures and with some neurological diseases [3]. The different effects of Zn²⁺ described in this study seem to be consistent with its function as an endogenous modulator of ligand- and voltage-gated ion channels (Fig. 3 and 4). A very strong argument for a modulator role of Zn²⁺ ions in ligand-gated receptors is their ability to inhibit histamine-stimulated PCA preparations, whereas the corresponding effects induced by acetylcholine were unaffected (Fig.4). Inside channel proteins Zn²⁺ ions coordinate to histidine, cysteine, aspartate and glutamate residues; since histamine is a derivative of histidine, the finding described in Fig 4 might not be wholly casual.

Because of the vital role played by zinc ions in the metabolism of proteins, carbohydrates, lipids, as well as in gene transcription, immune response, and many other fundamental biological processes, this essential trace element is strongly controlled by various homeostatic mechanisms, regulating their absorption, their cellular uptake and their distribution among intracellular compartments. On account of the extreme efficacy of the underlying homeostatic mechanisms the nontoxicity of even excessive zinc ingestion has been generally taken for granted [8]. However recent research demonstrating that dysregulation of zinc and copper homeostasis in the brain might play an extremely critical role in Alzheimer disease [14] emphasize the necessity of re-evaluating the far too simplistic aforementioned assumption made on the innocuousness of excessive zinc [8] and support precautions to be taken with regard to zinc as an environmental toxicant and as a cerebral neurotoxin. In terms of integrated systems with regulatory functions however the pharmacological and toxicological significance in the organism of copper and zinc ions is only understood when these ions are considered by pairs, as reciprocal antagonists, in the same way as it is done with calcium and magnesium ions.

The relaxing effect of glutamate described in the present study may be linked to the well-known so-called Chinese restaurant syndrome, which manifests itself as headaches and flushing [6]. The ED₅₀, i.e. the dose producing a half-maximum relaxation in PCA preparations amounted to about 0.9 mM. This value is of the same order of magnitude with that reported in plasma of humans after the experimental ingestion of monosodium glutamate, in which the concentration peaked until a value of about 0.5 mM [13].

A “cytotoxic” effect of glutamic acid has been also demonstrated in the isolated rat lung [15] which seems to correspond to that observed in neurones and glial cells and be related to the neurotoxic effect described in the CNS. The observation made in the present study that high concentration of L-glutamate (10 mM) when added to F^--stimulated PCA preparations led to a complete and irreversible loss of contractility and reactivity might be explained as follows: stimulation with fluoride ions takes place downstream of the receptor site and represents a rather unspecific inter­vention, that targets on several classes of G proteins, impinging upon several effector systems; together with an fluoride-induced intracellular Ca overload, this would in turn inevitably lead to an rather indiscriminate stimulation of proteases, protein kinases, and phospholi­pases. An activation of phospholipa­se A₂ and of cyclooxygenase would for example generates free-radical species overwhelming the endogenous scavenging mechanisms and producing lipid per­oxidation and membrane damage.

In conclusion, the data presented in this study, which give a preliminary account of the sensitivity of peripheral blood vessels to glutamate, to zinc ions and to related substances, need undoubtedly further electrophysiological investigations before therapeutic implications could be deduced. Nevertheless the total loss of contractility of hyperstimulated blood vessels after the administration of glutamate reported in the present study let one speculate on initial stages in the pathogenesis of atherosclerotic lesions. It is conceivable that such similar mechanisms might underlie permeability changes of the cell membrane, leading to local oedema of the blood vessels, favouring in turn the accumulation of lipids, the activation of macrophages and provoking eventually an irreversible production of foam cells.

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Correspondence:

Prof. Dr. Hoang Nguyen-Duong, E-Mail: hoang.nguyen-duong@gmx.de