Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation.
We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.
Naruse
K
K
Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
Shimizu
K
K
Muramatsu
M
M
Toki
Y
Y
Miyazaki
Y
Y
Okumura
K
K
Hashimoto
H
H
Ito
T
T
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006937:Hypercholesterolemia / Q000150:complications*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000502:physiology*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects
D011463:Prostaglandins H; D009569:Nitric Oxide; D044262:Prostaglandin H2; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester