Abstract
NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated withNG-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by l-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.
Footnotes
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Send reprint requests to: Dr. Giuseppe Rossoni, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail:giuseppe.rossoni{at}unimi.it
- Abbreviations:
- NO
- nitric oxide
- ASA
- aspirin
- NCX 4016
- 2-acetoxy-benzoate 2-[1-nitroxy-methyl]-phenyl ester
- BP
- blood pressure
- LVP
- left ventricular pressure
- LCA
- left main coronary artery
- MAP
- mean arterial pressure
- LVDevP
- left ventricular developed pressure
- PRI
- pressure rate index
- VPB
- ventricular premature beat
- VT
- ventricular tachycardia
- VF
- ventricular fibrillation
- MPO
- myeloperoxidase
- CPK
- creatine phosphokinase
- MI/R
- myocardial ischemia-reperfusion
- PEG 400
- polyethylene glycol 400
- l-NAME
- NG-nitro-l-arginine methyl ester
- Received October 11, 2000.
- Accepted January 2, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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