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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:183.)
© 2003 American Heart Association, Inc.

Vascular Biology

Fluvastatin Prevents Renal Dysfunction and Vascular NO Deficit in Apolipoprotein E-Deficient Mice

Marianne Gervais; Sandrine Pons; Antonino Nicoletti; Claudine Cosson; Jean-François Giudicelli; Christine Richer

From the Département de Pharmacologie, Faculté de Médecine Paris-Sud and INSERM E00.01 (M.G., S.P., J.-F.G., C.R.), Le Kremlin-Bicêtre; INSERM U430, Hôpital Broussais (A.N.), Paris; and Département de Biochimie, Hôpital du Kremlin-Bicêtre (C.C.), Le Kremlin-Bicêtre, France.

Correspondence to Dr C. Richer, Département de Pharmacologie, Inserm E00.01, Faculté de Médecine Paris-Sud, 63 rue Gabriel Péri, 94276 Le Kremlin Bicêtre, Cedex, France. E-mail christine.giudicelli{at}kb.u-psud.fr

Objective— The objective of this study was to investigate the effects of fluvastatin on atherosclerosis, systemic and regional hemodynamics, and vascular reactivity in apolipoprotein E-deficient (ApoE^-/-) mice.

Methods and Results— Hemodynamics (fluospheres) and vasomotor responses of thoracic aorta and carotid artery were evaluated in male wild-type (WT) and untreated (ApoE^-/- Control) or fluvastatin-treated (50 mg/kg per day for 20 weeks) ApoE^-/- mice, all fed a Western-type diet. Plasma cholesterol and aortic root atherosclerotic lesions (ALs) were greater in ApoE^-/- Control mice (19±1 mmol/L and 63 0176±38 785 µm², respectively) than in WT mice (2±1 mmol/L and 1±1 µm², respectively, P<0.01). Fluvastatin significantly decreased plasma cholesterol (-53%) but failed to limit ALs. Renal blood flow was significantly reduced in ApoE^-/- Control versus WT (-25%, P<0.05) mice. This reduction was prevented by fluvastatin. Aortic and carotid endothelium-dependent relaxations to acetylcholine were not altered in ApoE^-/- Control versus WT mice. In carotid arteries from WT mice, these responses were abolished after nitro-L-arginine (L-NA), whereas those from ApoE^-/- Control were only partially inhibited after L-NA but fully abolished after L-NA+diclofenac. Thus, in carotid arteries from ApoE^-/- mice, vasodilating prostanoids compensate the deficit in NO availability. Fluvastatin prevented this carotid NO deficit.

Conclusions— In ApoE^-/- mice, chronic fluvastatin treatment preserved renal perfusion and vascular NO availability independently from atherosclerotic lesion prevention.

Key Words: apolipoprotein E-deficient mice • hypercholesterolemia • endothelial function • renal perfusion • statin

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