TY - JOUR T1 - MECHANISM OF TOLERANCE DEVELOPMENT TO ORGANIC NITRATES JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 709 LP - 715 VL - 184 IS - 3 AU - PHILIP NEEDLEMAN AU - EUGENE M. JOHNSON, JR. Y1 - 1973/03/01 UR - http://jpet.aspetjournals.org/content/184/3/709.abstract N2 - 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. © 1973 by The Williams & Wilkins Co. ER -