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.
Part of the Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology book series (HEP, volume 40)


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).


Sodium Nitrite Ethacrynic Acid Isosorbide Dinitrate Organic Nitrate Biochemical Interaction 
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© Springer-Verlag Berlin · Heidelberg 1975

Authors and Affiliations

  • Philip Needleman
  • Eugene M. JohnsonJr.

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