Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis

被引:72
作者
Napoli, C
Aldini, G
Wallace, JL
de Nigris, F
Maffei, R
Abete, P
Bonaduce, D
Condorelli, G
Rengo, F
Sica, V
D'Armiento, FP
Mignogna, C
de Rosa, G
Condorelli, M
Lerman, LO
Ignarro, LJ [1 ]
机构
[1] Mayo Clin, Dept Internal Med, Div Hypertens, Rochester, MN 55905 USA
[2] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA
[3] Univ Naples 2, I-80100 Naples, Italy
[4] Salvatore Maugeri Fdn, Inst Care & Sci Res, I-83050 Telese, Italy
[5] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[6] Univ Calgary, Dept Pharmacol & Therapeut, Calgary, AB T2N 4N1, Canada
[7] Univ Milan, Inst Pharmaceut Chem, I-20131 Milan, Italy
[8] Univ Calif San Diego, Dept Med 0682, La Jolla, CA 92093 USA
[9] Univ Naples Federico II, Dept Med, I-80131 Naples, Italy
[10] Univ Naples Federico II, Dept Geriatr, I-80131 Naples, Italy
[11] Univ Naples Federico II, Dept Human Pathol, I-80131 Naples, Italy
关键词
D O I
10.1073/pnas.022639399
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague-Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S-nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA, NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.
引用
收藏
页码:1689 / 1694
页数:6
相关论文
共 61 条
[1]   Aspirin [J].
Awtry, EH ;
Loscalzo, J .
CIRCULATION, 2000, 101 (10) :1206-1218
[2]   Oxidative stress as a signaling mechanism of the vascular response to injury: The redox hypothesis of restenosis [J].
Azevedo, LCP ;
Pedro, MD ;
Souza, LC ;
de Souza, HP ;
Janiszewski, M ;
da Luz, PL ;
Laurindo, FRM .
CARDIOVASCULAR RESEARCH, 2000, 47 (03) :436-445
[3]  
Bilato C, 1996, AGING CLIN EXP RES, V8, P221
[4]   LC coupled to ion-trap MS for the rapid screening and detection of polyphenol antioxidants from Helichrysum stoechas [J].
Carini, M ;
Aldini, G ;
Furlanetto, S ;
Stefani, R ;
Facino, RM .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2001, 24 (03) :517-526
[5]   TELOMERE LENGTH AND REPLICATIVE AGING IN HUMAN VASCULAR TISSUES [J].
CHANG, E ;
HARLEY, CB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (24) :11190-11194
[6]   Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice [J].
Condorelli, G ;
Aycock, JK ;
Frati, G ;
Napoli, C .
FASEB JOURNAL, 2001, 15 (12) :2162-2170
[7]   NO-aspirins: a class of new antiinflammatory and antithrombotic agents [J].
del Soldato, P ;
Sorrentino, R ;
Pinto, A .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1999, 20 (08) :319-323
[8]   Reductive assays for S-nitrosothiols:: Implications for measurements in biological systems [J].
Fang, KZ ;
Ragsdale, NV ;
Carey, RM ;
MacDonald, T ;
Gaston, B .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 252 (03) :535-540
[9]   Comparative effects of several nitric oxide donors on intracellular cyclic GMP levels in bovine chromaffin cells:: correlation with nitric oxide production [J].
Ferrero, R ;
Rodríguez-Pascual, F ;
Miras-Portugal, MT ;
Torres, M .
BRITISH JOURNAL OF PHARMACOLOGY, 1999, 127 (03) :779-787
[10]   Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats [J].
Fiorucci, S ;
Antonelli, E ;
Santucci, L ;
Morelli, O ;
Miglietti, M ;
Federici, B ;
Mannucci, R ;
Del Soldato, P ;
Morelli, A .
GASTROENTEROLOGY, 1999, 116 (05) :1089-1106