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Nitrate tolerance--problems both new and old.

Nitrate tolerance has been recognized for many years but only recently has it been shown to be an important clinical problem. Tolerance develops very rapidly during oral, transdermal or intravenous nitrate administration and treatment strategies designed to provide therapeutic effects throughout 24 h each day are associated with marked attenuation of nitrate effects. The mechanisms responsible for tolerance are not clearly understood. The hypotheses put forward to explain this phenomenon include reduction of sulfhydryl groups in vascular smooth muscle with resultant diminished nitric oxide production, neurohormonal activation, plasma volume expansion, and superoxide anion production. Attempts to prevent or reverse tolerance with sulfhydryl group donors, angiotensin-converting enzyme inhibitors, and hydralazine have not been uniformly successful and such approaches are impractical. The beneficial nitrate effect can be preserved by appropriate dosing which provides a period of many hours of nitrate washout during each 24 h period.