Inhibition of vascular oxidative stress in hypercholesterolemia by eccentric isosorbide mononitrate.
OBJECTIVE
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-microM 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 microm in control) was reduced from 645 +/- 41 microm (CHOL) to 440 +/- 51 microm (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.
Müller
Senta
S
Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet, Duesseldorf, Germany.
König
Ilona
I
Meyer
Wilfried
W
Kojda
Georg
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000473:pathology; D001682:Biological Availability; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011817:Rabbits; D013481:Superoxides / Q000097:blood*; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D000975:Antioxidants; D020030:Nitric Oxide Donors; D013481:Superoxides; D002784:Cholesterol; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate