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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans

Evidence of a Free-Radical–Mediated Mechanism

George R. Thomas, PhD^_*, Jonathan M. DiFabio, MSc^_*, Tommaso Gori, MD, PhD and John D. Parker, MD, FACC^_*,_*

^_* Division of Cardiology, Department of Medicine, University Health Network and Mount Sinai Hospitals and the Department of Pharmacology, University of Toronto, Toronto, Canada
Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy. Supported by a research donation from the Henry White Kinnear Foundation. Dr. Parker holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario, Canada. Dr. Gori is the recipient of a grant from the Italian Ministry of Research

Manuscript received May 19, 2006; revised manuscript received September 13, 2006, accepted October 12, 2006.

^_* Reprint requests and correspondence: Dr. John D. Parker, Mount Sinai Hospital, 600 University Avenue, Room 1609, Toronto, Ontario, Canada, M5G 1X5. (Email: jdp{at}ca.inter.net).

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 µg/min) and N-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 µmol/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.

Abbreviations and Acronyms   Ach = acetylcholine   FBF = forearm blood flow   GTN = nitroglycerin   IS-5-MN = isosorbide-5-mononitrate   L-NMMA = N-monomethyl-L-arginine   PETN = pentaerithrityl tetranitrate   ROS = reactive oxygen species

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