Ital Heart J. 2000 Feb;1(2):146-55.
Myocardial protection by the nitroderivative of aspirin, NCX 4016: in vitro and in vivo experiments in the rabbit.
Rossoni G, Berti M, Colonna VD, Bernareggi M, Del Soldato P, Berti F. Department of Pharmacology, Chemotherapy and Medical Toxicology, Institute of Pharmacological Sciences, University of Milan, Italy.
BACKGROUND: A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency. METHODS: In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species. RESULTS: The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity. CONCLUSIONS: In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.
Gastroenterology. 2000 Feb;118(2):404-21.
NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase-dependent processing of Th1-like cytokines.
Fiorucci S, Santucci L, Antonelli E, Distrutti E, Del Sero G, Morelli O, Romani L, Federici B, Del Soldato P, Morelli A. Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Universita degli Studi di Perugia, Perugia, Italy.
BACKGROUND & AIMS: Concanavalin A (con A)-induced hepatitis is an immunomediated disease in which assembly of CD4(+) T cells and T helper (Th)1-like cytokines causes Fas-mediated liver cell death. Nitric oxide (NO) modulates Th1 response in vitro. NCX-4016 is an NO-aspirin derivative that spares the gastrointestinal tract and shares molecular targets with NO. The aim of this study was to investigate whether this NO-aspirin modulates Th1-like response induced by con A. METHODS: BALB/c mice were injected with 0.3 mg con A per mouse alone or in combination with NO-aspirin (18-100 mg/kg) or aspirin (10-55 mg/kg). RESULTS: NO-aspirin, but not aspirin, caused a dose-dependent protection against liver damage induced by con A. At a dose of 100 mg/kg, NO-aspirin caused a 40%-80% reduction of interleukin (IL)-1beta, IL-12, IL-18, interferon (IFN)-gamma, and tumor necrosis factor alpha production without affecting cytokine messenger RNA expression. NO-aspirin prevented Fas, Fas ligand, and IL-2 receptor up-regulation on spleen lymphocytes and Fas ligand on hepatocytes and caused the S-nitrosylation/inhibition of IL-1beta-converting enzyme-like cysteine proteases (caspases) involved in the processing and maturation of IL-1beta and IL-18. IL-18 immunoneutralization prevented IFN-gamma release and protected from liver injury induced by con A. In contrast to a selective caspase 1 inhibitor, zVAD.FMK, a pancaspase inhibitor, prevented IFN-gamma release and protected the liver from injury. CONCLUSIONS: Th1-like response induced by con A is mediated by IL-18 and requires activation of multiple caspases. NCX-4016 causes the S-nitrosylation/inhibition of caspases involved in cytokine production. Inhibition of Th1-like response is a new anti-inflammatory mechanism of action of NO-aspirin.
