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The Pharmacological and Biochemical Interaction of Organic Nitrates with Sulfhydryls: Possible Correlations with the Mechanism for Tolerance Development, Vasodilation, and Mitochondrial and Enzyme Reactions

  • Philip Needleman
  • Eugene M. JohnsonJr.
Chapter
Part of the Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology book series (HEP, volume 40)

Abstract

The known reactivity of organic nitrate vasodilators with reduced glutathione in the presence or absence of liver organic nitrate reductase (Heppel and Hilmoe, 1950; Needleman and Krantz, 1965; Needleman and Hunter, 1965) stimulated an investigation of the mechanism of the pharmacologic action of nitrates and the mechanism of tolerance which appear to involve either direct or enzymatic reactions with sulfhydryl groups. Sulfhydryl-containing compounds play a role in determining mitochondrial structure and are essential for oxidative phosphorylation. Organic nitrates have been demonstrated to uncouple oxidative phosphorylation by liver and heart mitochondria (Needleman and Hunter, 1966; Boime and Hunter, 1971). Nitrates also have been shown to inhibit monoamine oxidase (MAO), a mitochondrial enzyme containing many sulfhydryl groups (Ogawa and Gudbjarnason, 1968; Kalin and Kylin, 1969). The apparent mechanism of MAO-inhibition by nitrates is the result of a concentration-dependent oxidation of SH-groups (Jakschik and Needleman, 1973). Organic nitrates that are potent vasodilator compounds in dogs are substances that are readily denitrated in the presence of the endogenous SH compound, reduced glutathione, and nitrate reductase (Needleman et al., 1969); furthermore, there is a positive correlation between the induction of organic nitrate tolerance and the oxidation of critical tissue sulfhydryl groups in vascular smooth muscle (Needleman and Johnson, 1973).

Keywords

Sodium Nitrite Ethacrynic Acid Isosorbide Dinitrate Organic Nitrate Biochemical Interaction 
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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References

  1. Andersson, R.: Cyclic AMP as a mediator of the relaxing action of papaverine, nitroglycerine, diazoxide, and hydralazine in intestinal and vascular smooth muscle. Acta Pharmacol. Toxicol. 32, 321–336 (1973).CrossRefGoogle Scholar
  2. Baumel, I.P., Pitterman, A., Patel, G., DeFeo, J.J., Harbans, L.: Mechanisms underlying potentiation of barbiturate action by sodium nitrite in the mouse: The role of methemoglobin-induced hypoxia. J. Pharmacol. Exp. Ther. 188, 481–489 (1974).PubMedGoogle Scholar
  3. Blum, S.W., Quinn, J.B., Howe, B.B., Hefner, M.A., Winbury, M.M.: Pharmacologic and biochemical evaluation of organic nitrates: Attempted correlation of activities. J. Pharmacol. Exp. Ther. 176, 684–691 (1971).PubMedGoogle Scholar
  4. Bogaert, M.G.: Tolerance towards glyceryl trinitrate (Trinitrin) in rabbits. Arch. Int. Pharmacodyn. Ther. 172, 228–230 (1968).PubMedGoogle Scholar
  5. Bogaert, M.G., DeSchaepdryver, A.F.: Tolerance towards glyceryl trinitrate (Trinitrin) in dogs. Arch. Int. Pharmacodyn. Ther. 171, 221–224 (1968).PubMedGoogle Scholar
  6. Boime, I., Hunter, F.E., Jr.: Effects of glycerol trinitrate, mannitol hexanitrate and erythritol tetranitrate on electron transport and phosphorylation in liver mitochondria. Biochem. Pharmacol. 20, 533–545 (1971).CrossRefGoogle Scholar
  7. Brahen, S., Krantz, J. C., Jr.: Respiration of coronary arteries and nitrites. Arch. Int. pharmacodyn. 104, 29–32 (1955).PubMedGoogle Scholar
  8. Brody, T.M., Diamond, J.: Blockade of biochemical correlates of contraction and relaxation in uterine and intestinal smooth muscle. Ann. N. Y. Acad. Sci. 139, 772–780 (1967).PubMedCrossRefGoogle Scholar
  9. Carr, C. J., Bell, F.K., Bradyhouse, M. F., Krantz, J. C., Jr.: The effect of vasodilators upon the dephosphorylating enzymes of dogs coronary arteries. J. Pharmacol. exp. Ther. 108, 385–392 (1953).PubMedGoogle Scholar
  10. Clark, D.G.: The supersensitivity of the rat cardiovascular system to epinephrine after repeated injections of ethylene glycol dinitrate. Toxicol. appl. Pharmacol. 17, 433–442 (1970).PubMedCrossRefGoogle Scholar
  11. Clark, D.G.: Effects of ethylene glycol dinitrate on pituitary-adrenocortical function in the rat. Toxicol. appl. Pharmacol. 21, 355–360 (1972).PubMedCrossRefGoogle Scholar
  12. Clark, D.G., Litchfield, M. H.: Metabolism of ethylene glycol dinitrate (ethylene dinitrate) in the rat following repeated administration. Brit. J. Industr. Med. 26, 150–155 (1969).PubMedGoogle Scholar
  13. Clark, D.G., Litchfield, M.H.: Role of inorganic nitrite in methemoglobin formation after nitrate ester administration to the rat. Brit. J. Pharmacol. 48, 162–168 (1973).Google Scholar
  14. Crandall, L.A., Jr., Leake, C.D., Lowenhart, A.S., Muehlberger, C.W.: Acquired tolerance to and cross tolerance between the nitrous and nitric acid esters and sodium nitrite in man. J. Pharmacol. exp. Ther. 41, 103–120 (1931).Google Scholar
  15. Diamond, J., Brody, T.M.: Effect of catecholamines on smooth muscle motility and Phosphorylase activity. J. Pharmacol. exp. Ther. 159, 202–211 (1966).Google Scholar
  16. DiCarlo, F.J., Melger, M.D.: Nitroglycerin biotransformation by rat blood serum. Biochem. Pharmacol. 19, 1371–1379(1970).CrossRefGoogle Scholar
  17. Egashira, T., Takano, K., Shimizu, K., Kurosawa, Y., Kamijo, K.: Effect of sodium nitrite on monoamine oxidase activity in rat liver and brain. Jap. J. Pharmacol. 21, 274–276 (1971).PubMedCrossRefGoogle Scholar
  18. Elbright, G. E.: The effects of nitroglycerin on those engaged in its manufacture. J. Amer. med. Ass. 62, 201–202(1914).Google Scholar
  19. Epstein, S. E.: Angina pectoris: Pathophysiology, evaluation, and treatment. Ann. intern. Med. 75, 263–296(1971).Google Scholar
  20. Fleisch, J.H., Trrus, E.: The prevention of isoproterenol desensitization and isoproterenol reversal. J. Pharmacol. exp. Ther. 181, 425–433 (1972).PubMedGoogle Scholar
  21. Forssman, S., Masreliez, N., Johannson, G., Sundell, G., Wilander, O., Bostrom, G.: Untersuchungen des Gesundheitszustandes von Nitroarbeitern bei drei schwedischen Sprengstoffabriken. Arch. Gewerbepath. Gewerbehyg. 16, 157–177 (1958).CrossRefGoogle Scholar
  22. Gross, E., Bock, M., Helbrung, F.: Zur Toxikologie des Nitroglykols im Vergleich zu der des Nitroglycerins. Arch. exp. Path. Pharmak. 200, 271–304 (1942).CrossRefGoogle Scholar
  23. Haldane, J., Makgill, R.H., Mavrogordato, A.E.: The action as poisons of nitrites and other physiologically related substances. J. Physiol. (Lond.) 21, 160–189 (1897).Google Scholar
  24. Harley, J.D., Robin, H.: The effect of the nitrite ion on intact human erythrocytes. Blood 20, 710–721 (1962).PubMedGoogle Scholar
  25. Hasegawa, H., Sato, M.: Experimental study on nitroglycol poisoning in rabbits. J. Biochem. (Tokyo) 54, 58–64(1963).Google Scholar
  26. Hay, M.: The chemical nature and physiological action of nitroglycerin. Practitioner 30, 422–433 (1883).Google Scholar
  27. Heppel, L.A., Hilmoe, R. J.: Metabolism of inorganic nitrite and nitrate esters. II. The enzymatic reduction of nitroglycerin and erythritol tetranitrate by glutathione. J. biol. Chem. 183, 129–138 (1950).Google Scholar
  28. Herman, A.G., Bogaert, M.G.: Organic nitrates: Tolerance at the level of the vascular smooth muscle. Arch. Int. Pharmacodyn. 192, 200–202 (1971).PubMedGoogle Scholar
  29. Hunter, F.E., Jr., Ford, L.: Nitrite formation by enzymatic reaction of mannitol hexanitrate with glutathione. J. Pharmacol. exp. Ther. 113, 186–191 (1955).PubMedGoogle Scholar
  30. Hunter, F.E., Jr., Kahana, S., Ford L.: Effect of inorganic and organic nitrites and nitrates on aerobic phosphorylation in liver mitochondria. Fed. Proc. 12, 221 (1953).Google Scholar
  31. Jakschik, B.A., Needleman, P.: Sulfhydryl reactivity of organic nitrates: Biochemical basis for inhibition of glyceraldehyde-P-dehydrogenase and monoamine oxidase. Biochem. Biophys. Res. Commun. 53, 539–544 (1973).PubMedCrossRefGoogle Scholar
  32. Kalin, M., Kylin, B.: Organic nitrate explosives as monoamine-oxidase inhibitors. Arch. Environ. Hlth 18, 311–318 (1969).Google Scholar
  33. Kalin, M., Kylin, B., Malmfors, T.: The effect of nitrate explosives on adrenergic nerves. Arch. Environ. Hlth 19, 32–35 (1969).Google Scholar
  34. Keilin, D., Hartree, E.F.: Spectroscopic study of the permeability and lysis of red blood corpuscles. Nature (Lond.) 157, 210–214 (1946).CrossRefGoogle Scholar
  35. Kociba, R.J., Sleight, S.D.: Nitrite toxicosis in the ascorbic acid-deficient guinea pig. Toxicol. appl. Pharmacol. 16, 424–429 (1970).PubMedCrossRefGoogle Scholar
  36. Krantz, J.C., Jr., Carr, C. J., Bryant, H.H.: Alkyl nitrites XIV. The effect of nitrites and nitrates on arterial adenosine triphosphatase. J. Pharmacol. exp. Ther. 102, 16–21 (1951).PubMedGoogle Scholar
  37. Kukovitz, W.R., Poch, G., Juan, H.: The role of phosphodiesterase inhibition and the mechanism of coronary dilation by drugs. Fourth Int. Congr. Pharmacol., pp. 170. Basel: Schwabea and Co. 1969.Google Scholar
  38. Kypson, J., Hait, G.: Metabolic effects of nitroglycerin and tranylcypromine in unanesthetized rabbits. Proc. Soc. exp. Biol. (N. Y.) 136, 285–289 (1971).Google Scholar
  39. Lang, S., Johnson, E.M., Jr., Needleman, P.: Metabolism and vascular response of glyceryl trinitrate in the eviscerated rat. Biochem. Pharmacol. 21, 422–424 (1972).PubMedCrossRefGoogle Scholar
  40. Levy, J. V.: Effect of organic nitrates on myocardial oxygen consumption in vitro. Brit. J. Pharmacol. 38, 743–748 (1970).Google Scholar
  41. Levy, B., Wilkenfeld, B.E.: The potentiation of rat uterine inhibitory response to noradrenaline by theophylline and nitroglycerine. Brit. J. Pharmacol. 34, 604–612 (1968).Google Scholar
  42. Marshall, C.R.: The mode of action of nitric esters. J. Pharmacol. exp. Ther. 83, 106–119 (1945).Google Scholar
  43. McGuinness, B.W., Harris, L.: “Monday head”: An interesting occupational disorder. Brit. med. J. 1961 II, 2, 245–247.Google Scholar
  44. Myers, H.B., Austin, V.T.: Nitrite toleration. J. Pharmacol. exp. Ther. 36, 227–230 (1929).Google Scholar
  45. Namm, D.H.: The activation of glycogen Phosphorylase in arterial smooth muscle. J. Pharmacol. exp. Ther. 178, 299–310 (1971).PubMedGoogle Scholar
  46. Needleman, P.: Tolerance to the vascular effects of glyceryl trinitrate. J. Pharmacol. exp. Ther. 171, 93–102(1970).Google Scholar
  47. Needleman, P., Blehm, D.J., Harkey, A.B., Johnson, E.M., Jr., Lang, S.: The metabolic pathway in the degradation of glyceryl trinitrate. J. Pharmacol. exp. Ther. 179, 347–353 (1971).PubMedGoogle Scholar
  48. Needleman, P., Blehm, D. J., Rotskoff, K.S.: Relationship between glutathione-dependent denization and the vasodilator effectiveness of organic nitrates. J. Pharmacol. exp. Ther. 165, 286–288 (1969).PubMedGoogle Scholar
  49. Needleman, P., Harkey, A.B.: Role of endogenous glutathione in the metabolism of glyceryl trinitrate by isolated perfused rat liver. Biochem. Pharmacol. 20, 1867–1876 (1971).PubMedCrossRefGoogle Scholar
  50. Needleman, P., Hunter, F.E., Jr.: The transformation of glyceryl trinitrate and other nitrates by glutathione organic nitrate reductease. Molec. Pharmacol. 1, 77–86 (1965).Google Scholar
  51. Needleman, P., Hunter, F. E., Jr.: Effects of organic nitrates on mitochondrial respiration and swelling: Possible correlations with the mechanism of pharmacologic action. Molec. Pharmacol. 2, 134–143 (1966).Google Scholar
  52. Needleman, P., Jakschik, B. A., Johnson, E. M., Jr.: Sulfhydryl requirement for relaxation of vascular smooth muscle. J. Pharmacol. exp. Ther. 187, 324–331 (1973).PubMedGoogle Scholar
  53. Needleman, P., Johnson, E.M., Jr.: Mechanism of tolerance development to organic nitrates. J. Pharmacol. exp. Ther. 184, 709–715 (1973).PubMedGoogle Scholar
  54. Needleman, P., Krantz, J.C., Jr.: The biotransformation of nitroglycerin. Biochem. Pharmacol. 14, 1225–1230(1965).PubMedCrossRefGoogle Scholar
  55. Ogawa, K., Gudbjarnason, S.: A correlation between the inhibition of monoamine oxidase activity and the relief of angina pain by organic nitrates. Arch. Int. pharmacodyn. 172, 172–182(1968).PubMedGoogle Scholar
  56. Ogawa, K., Gudbjarnason, S., Bing, R.J.: Nitroglycerin (glyceryl trinitrate) as a monoamine oxidase inhibitor. J. Pharmacol. exp. Ther. 155, 449–455 (1967).PubMedGoogle Scholar
  57. Posadas del Rio, F., Hunter, F.E., Jr.: GSH-organic nitrate ester reductase-purification and properties. Fed. Proc. 32, 733 (1973).Google Scholar
  58. Rush, M.L., Lang, W. J., Rand, M. J.: Studies on compensatory reflexes and tolerance to glyceryl trinitrate (GTN). Europ. J. Pharmacol. 16, 148–155 (1971).CrossRefGoogle Scholar
  59. Smith, R. P., Layne, W.R.: A. comparison of the lethal effects of nitrite and hydroxylamine in the mouse. J. Pharmacol. exp. Ther. 165, 30–35 (1969).PubMedGoogle Scholar
  60. Stewart, D.D.: Tolerance to nitroglycerine. J. Amer. med. Ass. 44, 1678–1681 (1905).Google Scholar
  61. Triner, L., Nahas, G.G., Vulliemoz, Y., Overweg, N.I.A., Verosky, M., Habif, D.V., Ngal, S.H.: Cyclic AMP and smooth muscle function. Ann. N. Y. Acad. Sci. 185, 458–476 (1971).PubMedCrossRefGoogle Scholar
  62. Triner, L., Vulliemoz, Y., Verosky, M., Habif, D.V., Nahas, G.G.: Adenyl cyclase-phosphodiesterase system in arterial smooth muscle. Life Sci. 11, 817–824 (1972).CrossRefGoogle Scholar
  63. Vella, F.: Observations on spontaneous hemolysis in shed blood. Experientia (Basel) 15, 433–435 (1959).CrossRefGoogle Scholar
  64. Vigliani, E.C., Cavagna, G., Locati, G., Foa, V.: Biological effects of nitroglycol on the metabolism of catecholamines. Arch. Environ. Hlth 16, 477–483 (1968).Google Scholar
  65. Waldeck, B.: Failure to demonstrate monoamine oxidase inhibition by glyceryl trinitrate in vivo. Acta Pharmacol. Toxicol. 28, 406–412 (1970).CrossRefGoogle Scholar
  66. Wilhelmi, H.: Studien über Methaemoglobinbildring. XXIII. Mitteilung, Blutwirkung aliphatischer Salpetersäureester. Arch. exp. Pathol. Pharmakol. 200, 305–323 (1942).CrossRefGoogle Scholar
  67. Zelis, R., Mason, D.T.: Demonstration of nitrite tolerance: attenuation of the venodilator response to nitroglycerin by the chronic administration of isosorbide dinitrate. Circulation 40, Suppl. III, 221 (1969).Google Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1975

Authors and Affiliations

  • Philip Needleman
  • Eugene M. JohnsonJr.

There are no affiliations available

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