Tolerance to Intravenous Nitrates

There is increasing evidence that attenuation of the beneficial effects of intravenous (i.v.) nitrate treatment may occur in various clinical settings, as is the case with other formulations such as transdermal nitroglycerin or sustained-release oral preparations, designed to produce steady-state plasma nitrate concentrations. Not all patients exhibit this phenomenon, but its incidence and predictive factor(s) are still unknown. The mechanisms of nitrate tolerance are controversial, but they involve changes at the smooth muscle cell level as well as neurohormonal activation. Intermittent treatment regimens that would be suitable for patients with chronic and stable conditions are often inappropriate when intravenous therapy is required. At the present time, the routine use of N-acetylcysteine in preventing or reversing nitrate tolerance is not warranted. The place for substances analogous to nitrates as an alternative therapy such as sydnonimines, which are reputed to induce less attenuation during prolonged administration, is still not settled and requires further well-designed studies.