The nitric oxide-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-naphtalene-heptanoic acid 4-(nitrooxy)butyl ester), reduces splenocyte adhesion and reactive oxygen species generation in normal and atherosclerotic mice.

Dever, G.; Spickett, C.M.; Kennedy, S.; Rush, C.; Tennant, G.; Monopoli, A.; Wainwright, C.L.

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 antiinflammatory 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 precontracted 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.

Citation

DEVER, G., SPICKETT, C.M., KENNEDY, S., RUSH, C., TENNANT, G., MONOPOLI, A. and WAINWRIGHT, C.L. 2007. The nitric oxide-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-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 [online], 320(1), pages 419-426. Available from: https://doi.org/10.1124/jpet.106.109298

• Journal Article Type: Article
• Acceptance Date: Sep 26, 2006
• Online Publication Date: Jan 3, 2025
• Publication Date: Jan 8, 2007
• Deposit Date: Jan 31, 2021
• Publicly Available Date: Jan 7, 2025
• Journal: Journal of pharmacology and experimental therapeutics
• Print ISSN: 0022-3565
• Electronic ISSN: 1521-0103
• Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
• Peer Reviewed: Peer Reviewed
• Volume: 320
• Issue: 1
• Pages: 419-426
• DOI: https://doi.org/10.1124/jpet.106.109298
• Keywords: Molecular Medicine; Pharmacology
• Public URL: https://rgu-repository.worktribe.com/output/1167706
• Other Repo URL: https://publications.aston.ac.uk/id/eprint/23074/