Marcelo N. Muscará
University of São Paulo
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Featured researches published by Marcelo N. Muscará.
Hypertension | 2003
Glaucia E. Callera; Rhian M. Touyz; Simone A. Teixeira; Marcelo N. Muscará; Maria Helena C. Carvalho; Zuleica B. Fortes; Dorothy Nigro; Ernesto L. Schiffrin; Rita C. Tostes
Abstract—Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ETA receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210±9 mm Hg; P <0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9±10.3% of ethidium bromide–positive nuclei; P <0.05) versus control uninephrectomized (UniNx) rats (118±3 mm Hg; 18.5±3%, respectively). In DOCA-salt rats, the ETA antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170±4 versus UniNx, 120±3 mm Hg) and normalized superoxide production (21.7±6 versus UniNx, 11.9±7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8±7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8±4.2% versus UniNx, 95.4±1.9%, P <0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5±4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ETA receptors in DOCA-salt hypertension, in apparently blood pressure–independent fashion.
European Journal of Pharmacology | 1997
Moacir Serralvo Faria; Marcelo N. Muscará; Heitor Moreno; Simone A. Teixeira; Heidi Bernadetta Dias; Benedito Oliveira; Frederico G. Graeff; Gilberto De Nucci
The involvement of nitric oxide (NO) in anxiety was investigated in rats, using the elevated plus maze test. Acute, but not chronic, systemic treatment with N omega-nitro-L-arginine methyl ester (L-NAME, 10 and 60 mg.kg-1), an inhibitor of NO synthase, increased the time spent by the rats in the open arms. Both the acute and chronic treatments with L-NAME inhibited NO synthase in endothelial cells and in the central nervous system, as shown by the increase in mean arterial pressure and decreased NO synthase activity in brain tissue. Chronic treatment with L-NAME also decreased the serum nitrate levels. The anxiolysis induced by acute L-NAME treatment is unlikely to be due to hypertension, since two-kidney one-clip hypertension in non-L-NAME-treated rats failed to significantly change exploratory behaviour in the elevated plus maze. These results indicate that acute inhibition of NO synthesis decreases anxiety in rats.
British Journal of Pharmacology | 2008
B S Herrera; Taisuke Ohira; Li Gao; Kazuhiro Omori; Rong Yang; Min Zhu; Marcelo N. Muscará; Charles N. Serhan; T. E. Van Dyke; Robert Gyurko
The inflammation‐resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammation‐induced bone loss in vivo in experimental periodontitis. It was of interest to determine whether RvE1 has direct actions on osteoclast (OC) development and bone resorption.
British Journal of Haematology | 1996
Péricles M. Dias‐Da‐Motta; Valder R. Arruda; Marcelo N. Muscará; Sara Teresinha Olalla Saad; Gilberto De Nucci; Fernando Ferreira Costa; Antonio Condino-Neto
The aim of this work was to investigate the release of nitric oxide and superoxide by neutrophils and mononuclear cells from patients with sickle cell anaemia. Nitric oxide release was assayed by the ability of leucocytes to inhibit thrombin‐induced washed platelet aggregation. Superoxide release was assessed by a cytochrome c reduction assay. Neutrophils from sickle cell anaemia patients released nitric oxide in a similar manner to those from healthy controls, because inhibition of platelet aggregation by neutrophils from sickle cell anaemia or from healthy controls was blocked by the inhibitor of nitric oxide synthesis N ω‐nitro‐l‐arginine methyl ester (300 μm), but not by N ω‐nitro‐d‐arginine methyl ester (300 μm) and was reversed by l‐arginine (1 mm). Additionally, a similar number of neutrophils from sickle cell anaemia patients and from healthy controls was required to inhibit platelet aggregation. Mononuclear cells from sickle cell anaemia patients inhibited platelet aggregation only in the presence of superoxide dismutase (60 U ml−1). Phorbol 12‐myristate 13‐acetate (PMA, 30 nm)‐ or zymosan (100 particles/cell)‐induced release of superoxide by mononuclear cells from sickle cell anaemia patients was significantly higher than that observed in mononuclear cells from healthy controls (P < 0.001 and P < 0.01 respectively, Mann‐Whitney test). The levels of superoxide released by neutrophils from sickle cell anaemia patients were similar to those from healthy controls. We conclude that mononuclear cells from sickle cell anaemia patients release more superoxide than those from healthy controls, when stimulated with PMA or zymosan in vitro. Considering that superoxide inactivates nitric oxide, that nitric oxide is an important endogenous vasodilator, and that superoxide produces oxidant damage, this greater production of superoxide by mononuclear cells from sickle cell anaemia patients may represent an additional risk factor for the obstruction of the microcirculation and tissue damage in these patients.
Pain | 2009
Julie Keeble; Jennifer V. Bodkin; Lihuan Liang; Rachel Wodarski; Meirion Davies; Elizabeth S. Fernandes; Carly de Faria Coelho; Fiona A. Russell; Rabea Graepel; Marcelo N. Muscará; Marzia Malcangio; Susan D. Brain
Abstract Inflammatory diseases associated with pain are often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Recently, there has been considerable interest in the role of reactive oxygen species (ROS) in inflammatory disease, but little is known of the role of hydrogen peroxide (H2O2) in hyperalgesia. In the present study, intraplantar injection of H2O2‐induced a significant dose‐ and time‐dependent mechanical and thermal hyperalgesia in the mouse hind paw, with increased c‐fos activity observed in the dorsal horn of the spinal cord. H2O2 also induced significant nociceptive behavior such as increased paw licking and decreased body liftings. H2O2 levels were significantly raised in the carrageenan‐induced hind paw inflammation model, showing that this ROS is produced endogenously in a model of inflammation. Moreover, superoxide dismutase and catalase significantly reduced carrageenan‐induced mechanical and thermal hyperalgesia, providing evidence of a functionally significant endogenous role. Thermal, but not mechanical, hyperalgesia in response to H2O2 (i.pl.) was longer lasting in TRPV1 wild type mice compared to TRPV1 knockouts. It is unlikely that downstream lipid peroxidation was increased by H2O2. In conclusion, we demonstrate a notable effect of H2O2 in mediating inflammatory hyperalgesia, thus highlighting H2O2 removal as a novel therapeutic target for anti‐hyperalgesic drugs in the clinic.
Life Sciences | 1998
Marcelo N. Muscará; Webb McKnight; Piero Del Soldato; John L. Wallace
NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.
Journal of Chromatography B: Biomedical Sciences and Applications | 1996
Marcelo N. Muscará; Gilberto De Nucci
A high-performance liquid chromatographic method for the determination of nitrite and nitrate anions derived from nitric oxide in biological fluids is presented. After separation on a strong anion-exchange column (Spherisorb SAX, 250 x 4.6 mm I.D., 5 microns), two on-line post-column reactions occur. The first involves nitrate reduction to nitrite on a copper-plated cadmium-filled column. In the second, the diazotization-coupling reaction between nitrite and the Griess reagent (0.05% naphtylethylendiamine dihydrochloride plus 0.5% sulphanilamide in 5% phosphoric acid) takes place, and the absorbance of the chromophore is read at 540 nm. This methodology was applied to biological fluids. Before injection into the chromatographic system, the samples were diluted and submitted to suitable clean-up procedures (urine and cell culture supernatant samples are passed through C18 cartridges, and serum samples were deproteinized by ultrafiltration through membranes with a molecular mass cut-off of 3000). The method has a sensitivity of 30 pmol for both anions, as little as 0.05-0.1 ml sample volume is required and linearity is observed up to 60 nmol for each anion.
British Journal of Pharmacology | 2010
E. Ekundi-Valentim; Karen T. dos Santos; Enilton A. Camargo; Alexandre Denadai-Souza; Simone A. Teixeira; C. I. Zanoni; Andrew D. Grant; John L. Wallace; Marcelo N. Muscará; Soraia K.P. Costa
Background and purpose: Recent findings suggest that the noxious gas H2S is produced endogenously, and that physiological concentrations of H2S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H2S to modulate carrageenan‐induced synovitis in the rat knee.
British Journal of Pharmacology | 2001
Marcelo N. Muscará; Fina Lovren; Webb McKnight; Michael Dicay; Piero Del Soldato; Chris R. Triggle; John L. Wallace
Nonsteroidal anti‐inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti‐hypertensive therapies. In this study, we tested the effects of a gastric‐sparing, nitric oxide‐releasing derivative of aspirin (NCX‐4016) on hypertension in rats. Hypertension was induced by administering L‐NAME in the drinking water (400 mg l−1). Groups of rats were treated daily with aspirin, NCX‐4016 or vehicle. NCX‐4016 significantly reduced blood pressure relative to the aspirin‐treated group over the 2‐week period of treatment. Aspirin and, to a lesser extent, NCX‐4016 suppressed whole blood thromboxane synthesis. In anaesthetized rats, acute intravenous administration of NCX‐4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls. In vitro, NCX‐4016 relaxed phenylephrine‐pre‐contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine. These results suggest that NCX‐4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti‐thrombotic effects, suggest that NCX‐4016 may be a safer alternative to aspirin for use by hypertensive patients.
Molecular Medicine | 2012
Tarcio Teodoro Braga; Matheus Correa-Costa; Yuri Felipe Souza Guise; Angela Castoldi; Cassiano D. Oliveira; Meire Ioshie Hyane; Marcos Antonio Cenedeze; Simone A. Teixeira; Marcelo N. Muscará; Katia R. Perez; Iolanda M. Cuccovia; Alvaro Pacheco-Silva; Giselle Martins Gonçalves; Niels Olsen Saraiva Camara
Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4+ T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (TH2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished TH2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10+ and CD206+ CDllbhigh cells, at 7 d after surgery. We evaluated the role of a TH2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and TH1:TH2 balance, as TH2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.