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NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties.
Eur J Pharmacol. 2007 Sep 10; 570(1-3):115-24.EJ

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+Show Affiliations

Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17632098

Citation

Momi, Stefania, et al. "NCX 6560, a Nitric Oxide-releasing Derivative of Atorvastatin, Inhibits Cholesterol Biosynthesis and Shows Anti-inflammatory and Anti-thrombotic Properties." European Journal of Pharmacology, vol. 570, no. 1-3, 2007, pp. 115-24.
Momi S, Impagnatiello F, Guzzetta M, et al. NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. Eur J Pharmacol. 2007;570(1-3):115-24.
Momi, S., Impagnatiello, F., Guzzetta, M., Caracchini, R., Guglielmini, G., Olivieri, R., Monopoli, A., & Gresele, P. (2007). NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. European Journal of Pharmacology, 570(1-3), 115-24.
Momi S, et al. NCX 6560, a Nitric Oxide-releasing Derivative of Atorvastatin, Inhibits Cholesterol Biosynthesis and Shows Anti-inflammatory and Anti-thrombotic Properties. Eur J Pharmacol. 2007 Sep 10;570(1-3):115-24. PubMed PMID: 17632098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. AU - Momi,Stefania, AU - Impagnatiello,Francesco, AU - Guzzetta,Massimiliano, AU - Caracchini,Roberta, AU - Guglielmini,Giuseppe, AU - Olivieri,Rossana, AU - Monopoli,Angela, AU - Gresele,Paolo, Y1 - 2007/06/05/ PY - 2006/08/30/received PY - 2007/05/03/revised PY - 2007/05/16/accepted PY - 2007/7/17/pubmed PY - 2007/12/6/medline PY - 2007/7/17/entrez SP - 115 EP - 24 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 570 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17632098/NCX_6560_a_nitric_oxide_releasing_derivative_of_atorvastatin_inhibits_cholesterol_biosynthesis_and_shows_anti_inflammatory_and_anti_thrombotic_properties_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00609-7 DB - PRIME DP - Unbound Medicine ER -