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CLINICAL RESEARCH

Inhibition of vascular oxidative stress in hypercholesterolemia by eccentric isosorbide mononitrate

Senta Müller, DVM^*, Ilona König, PharmD^*, Wilfried Meyer, PhD and Georg Kojda, PharmD, PhD^*,*

^* Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet, Duesseldorf, Germany
Institut fuer Anatomie, Tieraerztliche Hochschule, Hannover, Germany

Manuscript received August 29, 2003; revised manuscript received February 13, 2004, accepted February 17, 2004.

^* Reprint requests and correspondence: Dr. Georg Kojda, Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet, Moorenstr. 5, 40225 Duesseldorf, Germany.
kojda{at}uni-duesseldorf.de

OBJECTIVES: We sought to determine if the nitric oxide (NO) donor isosorbide mononitrate (ISMN) (200 mg/kg body weight/day) decreases vascular bioavailability of superoxide in atherosclerosis.

BACKGROUND: Vascular oxidative stress limits the bioavailability of endothelial NO and promotes atherosclerosis, while NO itself exerts antioxidative effects. It is unknown if therapeutic NO impacts on vascular oxidative stress in atherosclerosis.

METHODS: New Zealand white rabbits (n = 10 each group) were fed either normal chow (control), cholesterol chow (CHOL) (0.75 %), or cholesterol chow enriched with ISMN (CHOL-ISMN). Rabbits were fed twice daily. After 16 weeks we used aortic segments to measure vascular superoxide (5-µM lucigenin), intimal lesion formation, and vasoreactivity to acetylcholine (ACH) and ISMN.

RESULTS: Plasma cholesterol increased by 40-fold in CHOL and CHOL-ISMN. The plasma concentration of ISMN in CHOL-ISMN was 1,529 ± 447 ng/ml. Superoxide formation (control: 228 ± 20 counts/20 min/mg) was strongly enhanced in CHOL (345 ± 46 counts/20 min/mg, p = 0.02) but not in CHOL-ISMN (229 ± 23 counts/20 min/mg) demonstrating antioxidative effects of eccentric ISMN in vivo. In parallel, intima-media thickness of thoracic aorta (159 ± 4 µm in control) was reduced from 645 ± 41 µm (CHOL) to 440 ± 51 µm (CHOL-ISMN, p < 0.05). Likewise, eccentric ISMN partially restored vascular responses to the NO donor S-nitroso-N-acetyl-D,L-penicillamine and improved endothelium-dependent vasorelaxation. The maximal ACH relaxation increased from 26.3 ± 9.6% in CHOL to 49.7 ± 8.1% in CHOL-ISMN; ISMN treatment induced a moderate nitrate tolerance as evidenced by diminished ISMN-induced vasodilation.

CONCLUSIONS: These data suggest that eccentric ISMN can completely inhibit the increase of vascular bioavailability of superoxide and partially prevent intimal lesion formation and endothelial dysfunction in hypercholesterolemia.

Abbreviations and Acronyms   cGMP = cyclic guanosine monophosphate   ecSOD = extracellular superoxide dismutase   GCMS = gas chromatography mass spectrometry   GTN = glyceryl mononitrate   ISMN = isosorbide mononitrate   NO = nitric oxide   sGC = soluble guanylyl cyclase   SNAP = S-nitroso-N-acetyl-D,L-penicillamine   SOD = superoxide dismutase

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