Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism.

OBJECTIVES The aim of the study was to determine if isosorbide-5-mononitrate (IS-5-MN) 120 mg, taken once daily for 7 days, is associated with evidence of endothelial dysfunction and whether this effect is determined by increased free radical production. BACKGROUND Tolerance to nitroglycerin is associated with increased free radical production and abnormal endothelial function. To date, no data is available concerning the effect of IS-5-MN, administered in clinically employed dosages, on endothelial function in humans. METHODS A total of 19 healthy volunteers were randomized in a double-blind fashion to therapy with IS-5-MN (120 mg once daily) or placebo. After 7 days of treatment, forearm blood flow responses to acetylcholine (Ach; 7.5, 15, and 30 microg/min) and N-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 mumol/min) were measured. In a separate study, after 7 days of therapy with IS-5-MN 120 mg once daily, the responses to Ach were assessed during intra-arterial coinfusion of vitamin C (24 mg/min) or saline. RESULTS As compared with placebo, IS-5-MN caused significant blunting of the responses to both Ach (peak responses: placebo 127 +/- 31%; IS-5-MN 52 +/- 24%) and L-NMMA (peak responses: placebo 41 +/- 5%; IS-5-MN 22 +/- 8%). Vitamin C completely restored the forearm blood flow responses to Ach (peak responses: vitamin C 180 +/- 33%; saline 107 +/- 17%). CONCLUSIONS We document for the first time that IS-5-MN impairs endothelial function in humans in vivo. Suggesting a role of oxygen free radicals, nitrate-induced abnormalities in endothelium-dependent vasomotor responses were reversed by the antioxidant vitamin C.