QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.109298v1 320/1/419    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dever, G. Articles by Wainwright, C. L. Search for Related Content PubMed PubMed Citation Articles by Dever, G. Articles by Wainwright, C. L.

CARDIOVASCULAR

The Nitric Oxide-Donating Pravastatin Derivative, NCX 6550 [(1S-[1(S*, S*), 2, 6, 8-(R*), 8a]]-1,2,6,7,8,8a-Hexahydro-, , 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

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom (G.D., C.M.S., S.K., C.R., G.T.); Nicox Research Institute, Milan, Italy (A.M.); and School of Pharmacy, Robert Gordon University, Aberdeen, Scotland, United Kingdom (C.L.W.)

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-[1(S*,S*),2,6,8-(R*),8a]]-1,2,6,7,8,8a-hexahydro-,,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.

Address correspondence to: Cherry L. Wainwright, School of Pharmacy, The Robert Gordon University, Schoolhill, Aberdeen AB10 1FR, UK. E-mail: c.wainwright{at}rgu.ac.uk