The nitric oxide-donating pravastatin derivative, NCX 6550 [(1S-[1α(βS*,δS*), 2α ,6α,8 β-(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. and Wainwright, C.L. (2007) The nitric oxide-donating pravastatin derivative, NCX 6550 [(1S-[1α(βS*,δS*), 2α ,6α,8 β-(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, 320(1), pp. 419-426. (doi: 10.1124/jpet.106.109298)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kennedy, Professor Simon
Authors: Dever, G., Spickett, C.M., Kennedy, S., Rush, C., Tennant, G., Monopoli, A., and Wainwright, C.L.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Nursing and Health Care
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Pharmacology and Experimental Therapeutics
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
ISSN (Online):1521-0103

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