Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism.
OBJECTIVE
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.
Thomas
George R
GR
Division of Cardiology, Department of Medicine, University Health Network and Mount Sinai Hospitals and the Department of Pharmacology, University of Toronto, Toronto, Canada.
DiFabio
Jonathan M
JM
Gori
Tommaso
T
Parker
John D
JD
D000293:Adolescent; D000328:Adult; D001205:Ascorbic Acid / Q000008:administration & dosage; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D005609:Free Radicals; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; D001205:Ascorbic Acid