Involvement of the nitric oxide system in the anti-atherosclerotic potential of lacidipine in the ApoE-deficient mouse: a morphological, functional, and electrochemical study.
The present study investigated the anti-atherosclerotic activity of lacidipine, a calcium antagonist with antioxidant properties in apoE-deficient mice. These mice show widespread vascular lesions which closely resemble the inflammatory-fibrous plaques seen in humans in atherosclerosis. Mice were fed a Western-type diet (WTD), and treated for 8 weeks with either vehicle or lacidipine at 3 or 10 mg/kg/day. In parallel with histological studies of atherosclerotic lesions in the aorta, functional studies on vascular acetylcholine (ACh) reactivity and analysis of voltammetric levels of nitric oxide (NO) were performed. Recent work has suggested that dihydropyridines (DHPs) modulate vascular relaxation via an increase in the release of NO. Lacidipine treatment had no effect on the plasma lipid profile. However, a significant (p < 0.01) dose-related reduction of 36.4% and 43.3% of the aortic lesion area in respect to methocel-treated mice was observed. Moreover, the aortic ring from control apoE-deficient mice fed a WTD for 8 weeks showed a lower relaxation in response to ACh in comparison to wild-type C57BL/6J mice; on the contrary, lacidipine-treated apoE-deficient mice lacidipine-treated displayed a response similar to that of wildtype C57BL/6J mice. Voltammetric analyses demonstrated a significant decrease of NO release in apoE-deficient mice, while lacidipine-treated mice showed enhanced activity of the NO system. We conclude that lacidipine reduced the extent of atherosclerotic area in hypercholesterolemic apoE-deficient mice, and this reduction may be associated with the capacity of the drug to maintain endothelial NO levels at concentrations useful to protect against vascular damage.
Cristofori
Patrizia G
PG
Safety Assessment Department, Pathology, Glaxo Smith Kline Research Centre, Verona, Italy. Patrizia.G.Cristofori@gsk.com
Crivellente
Federica A
FA
Faustinelli
Ivo
I
Lanzoni
Anna R
AR
Lazzarini
Chiara
C
Vecchiato
Elena
E
Andreoli
Michela
M
Turton
John A
JA
Zancanaro
Carlo
C
Crespi
Francesco M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004095:Dihydropyridines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D005260:Female; D006720:Homozygote; D008747:Methylcellulose / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D001057:Apolipoproteins E; D004095:Dihydropyridines; D014665:Vasodilator Agents; C060285:lacidipine; D009569:Nitric Oxide; D008747:Methylcellulose; D002784:Cholesterol; D000109:Acetylcholine