RELATIONSHIP BETWEEN GLUTATHIONE-DEPENDENT DENITRATION AND THE VASODILATOR EFFECTIVENESS OF ORGANIC NITRATES

¹ The Edward Maltinckrodt Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri

Organic nitrate esters which were previously found to be denitrated by glutathione (GSH)-organic nitrate reductase were tested for vasodepressor activity in dogs. Long-chain derivatives of glyceryl dinitrate were also tested in an attempt to determine whether vasodilator activity could be separated from GSH-dependent denitration. The lipid soluble organic nitrate derivatives did not affect dog blood pressure, and they were ineffective as smooth muscle relaxants in rabbit aorta strips. They did not appear to compete with glyceryl trinitrate for its receptor site. These compounds are not metabolized by GSH-organic nitrate reductase and apparently do not undergo denitration. The long side chain of these nitrate derivatives appears to block the interaction between nitrate esters and GSH. The organic nitrates that were potent vasodilator compounds (i.e., glyceryl trinitrate, mannitol hexanitrate, butanetriol trinitrate, erythrityl tetranitrate) are the nitrates which are readily denitrated in the presence of GSH.

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