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1 The Edward Mallinckrodt Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri
Tolerance to the vasodilator activity of organic nitrates appears to involve an alteration in a receptor in vascular smooth muscle. An in vitro model of nitrate tolerance was developed by incubation of rabbit thoracic aorta with organic nitrate at alkaline pH, producing a time- and concentration-dependent decrease in sensitivity to glyceryl trinitrate. Cross-tolerance is observed to all organic nitrates studied but not to nonnitrate vasodilators. When aortic strips are incubated at alkaline pH, nitrite formation is enhanced and tissue SH levels decrease. It s proposed that organic nitrate tolerance involves the oxidation of a critical sulfhydryl in the glyceryl trinitrate "receptor." This hypothesis is supported by the reversal of both in vitro- and in vivo-induced glyceryl trinitrate tolerance by the disulfide reducing agent, dithiothreitol.
Submitted on July 20, 1972
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