title: NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties.
abstract: We compared the lipid-lowering, vasodilating, anti-thrombotic and anti-inflammatory properties of NCX 6560, a novel NO-releasing derivative of atorvastatin, with those of atorvastatin. NCX 6560 and atorvastatin induced similar inhibition of cholesterol biosynthesis in rat smooth muscle cells (IC(50)=1.9+/-0.4 and 3.9+/-1.0 microM, respectively). However, in hyperlipidemic mice, a 5-week oral treatment with NCX 6560 (46.8 mg/kg/day, p.o.) was more effective than equivalent atorvastatin (40 mg/kg/day, p.o.) at lowering serum cholesterol (NCX 6560: -21% vs controls, P<0.05; atorvastatin: -14% vs control, P=NS). In norepinephrine-precontracted rabbit aortic rings, NCX 6560-induced vasodilation (EC(50)=53.5+/-8.3 microM) and in PC12 cells it stimulated cGMP formation (EC(50)=1.8+/-0.7 microM), while atorvastatin was inactive. In lipopolysaccharide from Escherichia coli (LPS)-treated RAW 264.7 macrophages, NCX 6560 reduced iNOS expression and dimer assembly more efficiently than atorvastatin and inhibited nitrite accumulation (IC(50)=6.7+/-1.6 microM) and TNFalpha release. U46619- or collagen plus epinephrine-induced platelet pulmonary thromboembolism in mice was reduced by NCX 6560 at 46.8 mg/kg p.o. (mortality: -44% and -56% vs vehicle, respectively; P<0.05), but not by atorvastatin 40 mg/kg, p.o. In the U46619-induced mortality model, isosorbide mononitrate (ISMN) (20 mg/kg, p.o.), a pure NO-donor, was also active (mortality: -40%, P<0.05). NCX 6560 significantly reduced ex vivo platelet adhesion to collagen at high shear (-31+/-1.3% vs vehicle), and so did ISMN (-33.3+/-1.7% vs vehicle). Atorvastatin was ineffective. NCX 6560, but not atorvastatin, reduced blood pressure in eNOS knockout mice (-16%, P<0.001 vs vehicle), an effect not observed in wild type mice. On the contrary, ISMN provoked a significant drop of blood pressure both in wild type (-20%, P<0.05 vs vehicle) and in eNOS-/- mice (-21%, P<0.05 vs vehicle). In conclusion, NCX 6560 exerts greater lipid-lowering, anti-thrombotic and anti-inflammatory effects than atorvastatin, due to a large extent to NO release.
authors.affiliation: Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Momi
authors.forename: Francesco
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Guzzetta
authors.forename: Roberta
authors.initials: R
authors.lastname: Caracchini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guglielmini
authors.forename: Rossana
authors.initials: R
authors.lastname: Olivieri
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D016716:PC12 Cells; D011655:Pulmonary Embolism / Q000188:drug therapy; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; C524539:NCX 6560; D020030:Nitric Oxide Donors; D009573:Nitrites; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D002784:Cholesterol; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D006152:Cyclic GMP