Preservation of endothelium-dependent and Nomega-nitro-L-arginine methyl ester- and indomethacin-resistant arterial relaxation in high-cholesterol-diet fed rabbits by treatment with fluvastatin, an HMG-CoA reductase inhibitor.
This study was designed to test the hypothesis that fluvastatin preserves endothelium-dependent and nitric oxide (NO)-independent relaxations in arterial preparations from rabbits fed a high-cholesterol diet in the absence of any cholesterol-lowering action. Rabbits were fed a 0.5% high-cholesterol diet for 12 weeks and then fed the high-cholesterol diet with/without fluvastatin 2 mg/kg/d for an additional 8 weeks. Plasma total and LDL-cholesterol concentrations were not affected by fluvastatin treatment. Endothelium-dependent and NO-mediated relaxation elicited by acetylcholine and A23187 in both the thoracic aorta and femoral artery was impaired in the high-cholesterol group but not in the fluvastatin-treated group. Endothelium-independent relaxation elicited by sodium nitroprusside was similar among the 3 groups. Preincubation of thoracic aortas from each of the 3 groups with Nomega-nitro-L-arginine methyl ester (L-NAME) and indomethacin completely abolished the relaxant response to acetylcholine. In contrast, the maximal response to acetylcholine (1 microM) in femoral artery was only partially reversed in the presence of L-NAME and indomethacin. Fluvastatin treatment preserved the acetylcholine-induced L-NAME and indomethacin-resistant relaxation impaired in the femoral artery from the high-cholesterol diet group. These results suggest that fluvastatin treatment preserves endothelium-dependent, NO-independent function as well as NO-dependent function in absence of its lipid lowering-action.
Mitani
Hironobu
H
Research Divsion, Novartis Pharma, Tsukuba Research Institute, Tsukuba, Ibaraki, Japan. hironobu.mitani@pharma.novartis.com
Kimura
Masaaki
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D004032:Diet; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D011817:Rabbits; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D002791:Cholesterol, Dietary; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D009569:Nitric Oxide; D000001:Calcimycin; D000077340:Fluvastatin; D002784:Cholesterol; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin