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

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 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-naphthaleneheptanoic 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 (-logEC(50), 6.37 +/- 0.37) compared with both vehicle-treated (-logEC(50), 5.81 +/- 0.15; P < 0.001) and pravastatin-treated (-logEC(50), 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.