Strathprints Home | Open Access | Browse | Search | User area | Copyright | Help | Library Home | SUPrimo

The nitric oxide-donating pravastatin derivative, ncx 6550 [(1s-[1 alpha(beta s*,delta s*), 2 alpha, 6 alpha, 8 beta-(R*),8a alpha]]-1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphtalene-heptanoic acid 4-(nitrooxy) butyl ester)], reduces splenocyte adhesion and reactive oxygen species generation in normal and atherosclerotic mice

Dever, G. and Spickett, C.M. and Kennedy, S. and Rush, C. and Tennant, G.M. and Monopoli, A. and Wainwright, C.L. (2007) The nitric oxide-donating pravastatin derivative, ncx 6550 [(1s-[1 alpha(beta s*,delta s*), 2 alpha, 6 alpha, 8 beta-(R*),8a alpha]]-1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphtalene-heptanoic acid 4-(nitrooxy) butyl ester)], reduces splenocyte adhesion and reactive oxygen species generation in normal and atherosclerotic mice. Journal of Pharmacology and Experimental Therapeutics, 320 (1). pp. 419-426. ISSN 0022-3565

Full text not available in this repository. (Request a copy from the Strathclyde author)

Abstract

Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis, whereas nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550 [(1S-[1α(βS*,δS*),2α,6α,8β-(R*),8aα]]-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid 4-(nitrooxy)butyl ester)], has greater anti-inflammatory properties compared with pravastatin in normal and atherosclerotic apolipoprotein E receptor knockout (ApoE-/-) mice. C57BL/6 and ApoE-/- mice were administered pravastatin (40 mg/kg), NCX 6550 (48.5 mg/kg), or vehicle orally for 5 days. Ex vivo studies assessed splenocyte adhesion to arterial segments and splenocyte reactive oxygen species (ROS) generation. NCX 6550 significantly reduced splenocyte adhesion to artery segments in both C57BL/6 (8.8 ± 1.9% versus 16.6 ± 6.7% adhesion; P < 0.05) and ApoE-/- mice (9.3 ± 2.9% versus 23.4 ± 4.6% adhesion; P < 0.05) concomitant with an inhibition of endothelial intercellular adhesion molecule-1 expression. NCX 6550 also significantly reduced phorbol 12-myristate 13-acetate-induced ROS production that was enhanced in isolated ApoE-/- splenocytes. Conversely, pravastatin had no significant effects on adhesion in normal or ApoE-/- mice but reduced the enhanced ROS production from ApoE-/- splenocytes. In separate groups of ApoE-/- mice, NCX 6550 significantly enhanced endothelium-dependent relaxation to carbachol in aortic segments precon-tracted with phenylephrine (-logEC50, 6.37 ± 0.37) compared with both vehicle-treated (-logEC50, 5.81 ± 0.15; P < 0.001) and pravastatin-treated (-logEC50, 5.57 ± 0.45; P < 0.05) mice. NCX 6550 also significantly reduced plasma monocyte chemoattractant protein-1 levels (648.8 pg/ml) compared with both vehicle (1191.1 pg/ml; P < 0.001) and pravastatin (847 ± 71.0 pg/ml; P < 0.05) treatment. These data show that NCX 6550 exerts superior anti-inflammatory actions compared with pravastatin, possibly through NO-related mechanisms.

Item type: Article
ID code: 4767
Keywords: COA reductase inhibitors, human endothelial cells, coronary heart disease, leukocyte adhesion, inflammation, Pharmacy and materia medica, Therapeutics. Pharmacology
Subjects: Medicine > Pharmacy and materia medica
Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences > Centre for Biophotonics
Unknown Department
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences > Physiology and Pharmacology
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 14 Nov 2007
    Last modified: 16 Jul 2013 20:52
    URI: http://strathprints.strath.ac.uk/id/eprint/4767

    Actions (login required)

    View Item