Published Online
on January 30, 2006

A more recent version of this article appeared on March 1, 2006

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Submitted on October 27, 2005
Revised on November 14, 2005

Chronic Antioxidant Supplementation Impairs Coronary Endothelial Function and Myocardial Perfusion in Normal Pigs

Daniele Versari; Elena Daghini; Martin Rodriguez-Porcel; Katherine Sattler; Offer Galili; Kevin Pilarczyk; Claudio Napoli; Lilach O. Lerman; and Amir Lerman^*

From the Divisions of Cardiovascular Diseases (D.V., M.R.-P., K.S., O.G., K.P., L.O.L., A.L.) and Nephrology and Hypertension (E.D., L.O.L.), Mayo Clinic College of Medicine, Rochester, Minn; Departments of Clinical Pathology and Medicine and Excellence Research Center on Cardiovascular Diseases (C.N.), University of Naples, Naples, Italy; and Evans Department of Medicine and Whitaker Cardiovascular Institute (C.N.), Boston University, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: lerman.amir{at}mayo.edu.

Abstract--Experimental studies have shown the beneficial effects of antioxidant supplementation on endothelial function in the presence of increased endogenous oxidative stress, whereas limited data are available under normal conditions. The present study tested the hypothesis that in normal pigs long-term antioxidants would have deleterious effects on the cardiovascular system. Normal domestic pigs (V, n=6) were studied 12 weeks after dietary supplementation with vitamin E (100 IU/kg per day) and vitamin C (1 g/day) and compared with normal controls (C, n=7). Myocardial perfusion and permeability index were evaluated by electron beam computed tomography after intravenous adenosine and dobutamine. Coronary endothelial function was evaluated in vitro by organ chamber and coronary tissue studied by immunoblotting and staining. Myocardial perfusion response was lower in V than in C after adenosine (10.1±4.5 versus 53.4±5.2%; P<0.01) and dobutamine (V, 78.4±8.1; C, 193.0±39.0%; P<0.05). The permeability index increased in V after adenosine (48.8±5.1%) and dobutamine (59.9±13.6%) and did not change in C. Coronary vasodilation to bradykinin and substance P was lower in V than in C. Moreover, in V, coronary nitrotyrosine and superoxide content was significantly higher than in C. The groups had similar total monomer expression of endothelial nitric oxide synthase, whereas the dimerized form, reflecting coupled enzyme, was lower in V. These findings suggest that long-term experimental antioxidant vitamin supplementation in normal pigs impairs myocardial perfusion and coronary endothelial function via an increased level of oxidative stress in the arterial wall, which may be partly related to the uncoupling of endothelial nitric oxide synthase and/or the direct prooxidant effect of vitamin radicals.

Key words: antioxidants • endothelium • myocardial • oxidative stress • vasodilation • nitric oxide synthase

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