DigitalUM :: Browsing by Subject "Nitric oxide"

Browsing by Subject "Nitric oxide"

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Open Access
Chronic inhibition of NO synthesis produces myocardial fibrosis and arterial media hyperplasia
(Murcia : F. Hernández, 1997) Babál, P.; Pecháñová, O.; Bernátwá, I.; Stvrtina, S.
Pathophysiological effects of nitric oxide (NO)-deficient hypertension are much better known than are the potential morphological changes. Hearts and main arteries were studied in 15 week old male Wistar rats administered N~-nitro-L-arginine methyl ester (L NAME) for 4 weeks. A dose of 40 mgkgíday increased systolic arterial pressure by 30%, while heart rate decreased by 20%. Heartlbody weight ratios were not significantly changed. Total cardiac RNA and DNA content and [14c]leucine incorporation into myocardial protein were, however, increased by 15%, 228% and 97%, respectively. Light microscopy of hearts showed subendocardial areas of necrosis along with different stages of healing. Morphometric evaluation demonstrated significant increase in myocardial fibrosis. Serum lactate dehydrogenase increased by 91%. Proliferation cell nuclear antigen (PCNA) immunohistochemistry indicated positive cells in areas of postischemic repair. Chronic inhibition of NO synthase (NOS) resulted in periarterial fibrosis and hyperplasia of the media in coronary arteries and aorta. RNA and DNA content, and [14c]leucine incorporation into protein of aorta increased by 255%, 95% and 49%, respectively. PCNA staining showed numerous positive nuclei in the media of coronary arteries and the aorta. It is concluded that inhibition of NOS leads to systemic hypertension with foca1 myocardial fibrosis reflecting reparative responses associated to ischemic injury. This sequence of alterations involves impaired arterial relaxation, and uncontrolled vascular media1 proliferation attributed to the absence of smooth muscle cell proliferation inhibition by NO.
Open Access
Effects of chronic L-NAME on nitrotyrosine expression and renal vascular reactivity in rats with chronic bile-duct ligation
(Porland Press LTD, 2008-01-09) Alcaraz, Antonia; Hernández, David; Iyú, David; Mota, Rubén; Atucha, Noemí M.; Ortiz Ruiz, Antonio José; García Estañ, Joaquín; Ortiz, María C.; Dermatología, Estomatología, Radiología y Medicina Física
In liver cirrhosis, elevated levels of NO and ROS (reactive oxygen species) might greatly favour the generation of peroxynitrite. Peroxynitrite is a highly reactive oxidant and it can potentially alter the vascular reactivity and the function of different organs. In the present study, we evaluated whether peroxynitrite levels are related to the progression of renal vascular and excretory dysfunction during experimental cirrhosis induced by chronic BDL (bile-duct ligation) in rats. Experiments were performed at 7, 15 and 21 days after BDL in rats and in rats 21 days post-BDL chronically treated with L-NAME (NG-nitro-L-arginine methyl ester). Sodium balance, BP (blood pressure), basal RPP (renal perfusion pressure) and the renal vascular response to PHE (phenylephrine) and ACh (acetylcholine) in isolated perfused kidneys were measured. NO levels were calculated as 24-h urinary excretion of nitrites, ROS as TBARS (thiobarbituric acid-reacting substances), and peroxynitrite formation as the renal expression of nitrotyrosine. BDL rats had progressive sodium retention, and decreased BP, RPP and renal vascular responses to PHE and ACh in the time following BDL. They also had increasing levels of NO and ROS, and renal nitrotyrosine accumulation, especially in the medulla. All of these changes were either prevented or significantly decreased by chronic L-NAME administration. In conclusion, these results suggest that the increasing levels of peroxynitrite might contribute to the altered renal vascular response and sodium retention in the development of the experimental biliary cirrhosis. Moreover, the beneficial effects of decreasing NO synthesis are, at least in part, mediated by anti-peroxinitrite-related effects.
Open Access
Evaluación de los efectos de extractos de hojas de morera Morus alba L. sobre la función cardiovascular, renal y plaquetaria en la hipertensión arterial experimental
(Universidad de Murcia, 2024-11-12) Akbariaghdam, Masoud; Marín Atucha, Noemí; Pagán Bernabéu, Ana; García-Estañ López, Joaquín; Escuela Internacional de Doctorado
Según la Organización Mundial de la Salud (OMS 2023), las enfermedades del sistema cardiovascular son una de las principales causas de muerte en los países occidentales. De ellas, la hipertensión arterial (HTA) es un factor de riesgo muy importante para la enfermedad cardiovascular y una preocupación para la salud pública. Desde hace décadas se han logrado importantes descubrimientos tanto en la fisiopatología como en el tratamiento de la hipertensión mediante una panoplia de fármacos entre los que se encuentran los que afectan al sistema renina-angiotensina (SRAA), los diuréticos, antagonistas alfa-adrenérgicos y bloqueantes de los canales de calcio, entre otros (Hall 2024). desde hace años, muchos estudios epidemiológicos han observado que el uso de alimentos ricos en polifenoles y flavonoides en la dieta tiene efectos beneficiosos en algunas enfermedades crónicas como la HTA (García-Estañ 2019). En general, a más ingestión de flavonoides menos propensión de padecer daños cardiovasculares (Atucha 2022; Vargas 2018). Estudios recientes de nuestro laboratorio (Paredes 2018a y 2018b) han demostrado que algunos flavonoides tienen un efecto beneficioso como agentes antihipertensivos en varios modelos animales de HTA. En esta tesis nos propusimos evaluar el efecto de los extractos de morera Morus alba L. en un modelo de HTA experimental por déficit de óxido nítrico. Métodos: Se han utilizado ratas macho Sprague-Dawley, divididas en grupos control, hipertensas a las que se les trató con un tratamiento de seis semanas de duración de un inhibidor de la síntesis de NO (L-NAME) en el agua de bebida, hipertensas tratadas con un extracto de Morus alba L e hipertensas tratadas simultáneamente con captopril. Después de seis semanas de tratamiento, se midió presión arterial y función renal, además de la función vascular endotelial en aorta y la función de agregación plaquetaria. Resultados: Los experimentos han mostrado que el extracto de Morus alba L es seguro para su uso en animales. Previene el desarrollo de la hipertensión arterial por déficit de óxido nítrico, aunque sin normalizarla completamente. Igualmente reduce la excesiva respuesta vasoconstrictora a fenilefrina en anillos aórticos y mejora la vasodilatación a acetilcolina, ambos efectos dependientes del aumento de la producción de óxido nítrico. Además, el extracto de Morus alba L redujo la mayor agregación plaquetaria a ADP y colágeno de los animales hipertensos, aunque sin llegar a normalizarla. Igualmente, el extracto mejoró las alteraciones morfológicas renales de los animales hipertensos. Conclusiones: El extracto de Morus alba L tiene efecto antihipertensor, mejora la reactividad vascular, la agregación plaquetaria y las alteraciones morfológicas renales en un modelo de hipertensión arterial por déficit de óxido nítrico. Estos efectos están relacionados con un aumento de los efectos del óxido nítrico.
Open Access
Hepatic response to chronic hypoxia in experimental rat model through HIF-1 alpha, activator protein-1 and NF-kappa B
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Lau, Thomas Y.H.; Xiao, Jia; Liong, Emily C.; Liao, Linchuan; Leung, Tung-Ming; Nanji, Amin A.; Fung, Man Lung; Tipoe, George L.
Chronic liver diseases are commonly associated with tissue hypoxia that may cause inflammation, oxidative stress, liver cell injury and increased nuclear transcriptional regulation. The hepatic response to chronic hypoxia at the molecular level has not yet been clearly understood until now. The aim of this study is to investigate whether nuclear transcription factors [hypoxia-inducible factor-1 (HIF-1α), activator protein-1 (AP-1), nuclear factor-kappa B (NF-κB)] exhibit activity changes during hepatic response to chronic hypoxia. Blood and liver samples were collected from adult Sprague-Dawley rats living in atmospheric air or 10% oxygen for four weeks. Levels of serum alanine aminotransferase (ALT), 8-isoprostane and nitrotyrosine were measured. The activities of nuclear transcription factors and the expression of downstream genes (iNOS, eNOS, ET-1 and VEGF) were measured using RT-PCR, Western blotting and Gel shift analysis. Results showed that serum ALT level, 8-isoprostane level and formation of nitrotyrosine were within normal range at all time-points. In the hypoxic liver, DNAbinding activities of HIF-1α, NF-κB and AP-1 increased significantly. Expression levels of iNOS, VEGF and ET1 progressively increased from day 7 to day 28. eNOS was also elevated in the hypoxic liver. In conclusion, our study suggests that increased activity of HIF-1α, AP-1 and NF-κB may partly play a significant role in the hepatic response to oxidative stress and liver injury under chronic hypoxia. The increased expression of VEGF, ET-1, iNOS and eNOS may be partly due to the compensatory mechanism in the vascular beds of the liver in response to chronic hypoxia.
Embargo
Immediate effects of spinal manipulation on nitric oxide, substance Pand pain perception
(Elsevier, 2014-02-23) Molina Ortega, Francisco; Lomas Vega, Rafael; Hita Contreras, Fidel; Plaza Manzano, Gustavo; Achalandabaso, Alexander; Ramos Morcillo, Antonio Jesús; Martínez Amat, Antonio; Enfermería
Previous studies have analyzed the effects of spinal manipulation on pain sensitivity by using severalsensory modalities, but to our knowledge, no studies have focused on serum biomarkers involved in thenociceptive pathway after spinal manipulation. Our objectives were to determine the immediate effect ofcervical and dorsal manipulation over the production of nitric oxide and substance P, and establishingtheir relationship with changes in pressure pain thresholds in asymptomatic subjects. In this single-blindrandomized controlled trial, 30 asymptomatic subjects (16 men) were randomly distributed into 3groups (n¼10 per group): control, cervical and dorsal manipulation groups. Blood samples wereextracted to obtain serum. ELISA assay for substance P and chemiluminescence analysis for nitric oxidedetermination were performed. Pressure pain thresholds were measured with a pressure algometer atthe C5eC6 joint, the lateral epicondyle and the tibialis anterior muscle. Outcome measures were ob-tained before intervention, just after intervention and 2 h after intervention. Our results indicated anincrease in substance P plasma level in the cervical manipulation group (70.55%) when compared withother groups (p<0.05). This group also showed an elevation in the pressure pain threshold at C5eC6(26.75%) and lateral epicondyle level (21.63%) immediately after the intervention (p<0.05). No changesin nitric oxide production were observed. In conclusion, mechanical stimulus provided by cervicalmanipulation increases substance P levels and pressure pain threshold but does not change nitric oxideconcentrations. Part of the hypoalgesic effect of spinal manipulation may be due to the action of sub-stance P.
Open Access
Induction of NADPH diaphoraselnitric oxide synthase in the spinal cord motor neurons of rats following a single and multiple non-penetrative blasts
(Murcia : F. Hernández, 1999) Kaur, C.; Singh, J.; Moochhala, S.; Lim, M.K.; Lu, J.; Ling, E. A.
The present study has demonstrated the induction of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) reactivity and nitric oxide synthase-like immunoreactivity (NOS-LI) in the ventral horn motoneurons of the spinal cord in rats subjected to a single or multiple underground, or a single surface blast. Both enzyme activities were first detected in some motoneurons in laminae V111 and IX of Rexed, 3 hours after the blast. Some NADPH-d and NOS-L1 positive neurons were also distributed in laminae V1 and V11. The number and intensity of the labelled cells appeared to increase progressively, peaking at 2-3 days after the blast but were drastically reduced thereafter, so that at 7 days after the blast only a few positive neurons were observed. In rats killed at 2 weeks and in longer surviving intervals, i.e. up to 1 month, NADPH-d/NOS reactivity in the ventral horn motor neurons had diminished. The functional significance of the transient expression of neuronal NADPH-d/NOS after the blasts remains uncertain, although from a speculative point of view, the induction of these enzymes probably would reflect an increased production of nitric oxide (NO). In view of the lack of atrophic changes in most, if not all, of motor neurons, it is suggested that the increased levels of NO production after the blast injury may be involved in a neuroprotective function.
Open Access
Moderate Effect of Flavonoids on Vascular and Renal Function in Spontaneously Hypertensive Rats
(MDPI, 2018-08-16) Paredes, María Dolores; Romecín, Paola; Atucha, Noemí M.; O'Valle, Francisco; Castillo, Julián; Ortiz, M. Clara; García-Estañ, Joaquín; Fisiología
Many studies have shown that flavonoids are effective as antihypertensive drugs in arterial hypertension. In the present work, we have analyzed the effects of some flavonoid extracts in the spontaneous hypertensive rat model (SHR). An important feature of this study is that we have used a low dose, far from those that are usually applied in human therapy or experimental animals, a dose that responded to the criterion of a potential future commercial use in human subjects. Treatments were carried out for 6 and 12 weeks in two groups of SHR rats, which received apigenin, lemon extract, grapefruit + bitter orange (GBO) extracts, and cocoa extract. Captopril was used as a positive control in the SHR group treated for 6 weeks (SHR6) and Diosmin was used as the industry reference in the SHR group treated for 12 weeks (SHR12). Captopril and GBO extracts lowered the high arterial pressure of the SHR6 animals, but none of the extracts were effective in the SHR12 group. Apigenin, lemon extract (LE), GBO, and captopril also improved aortic vascular relaxation and increased plasma and urinary excretion of nitrites, but only in the SHR6 group. Kidney and urinary thiobarbituric acid reactive substances (TBARS) were also significantly reduced by GBO in the SHR6 rats. Apigenin also improved vascular relaxation in the SHR12 group and all the flavonoids studied reduced urinary thiobarbituric acid reactive substances (TBARS) excretion and proteinuria. Vascular abnormalities, such as lumen/wall ratio in heart arteries and thoracic aorta, were moderately improved by these treatments in the SHR6 group. In conclusion, the flavonoid-rich extracts included in this study, especially apigenin, LE and GBO improved vascular vasodilatory function of young adult SHRs but only the GBO-treated rats benefited from a reduction in blood pressure. These extracts may be used as functional food ingredients with a moderate therapeutic benefit, especially in the early phases of arterial hypertension
Open Access
Nitric oxide and nitric oxide synthase: biology, pathology, localization
(Murcia : F. Hernández, 1997) Wolf, G.
Nitric oxide (NO) has opened a new and vigorous field of biological and clinical experimentation as evidenced presently by about one hundred original publications every week. Being a biological signal under physiological conditions, NO may be «foe or friendn to pathologically affected tissues. Major insights into the biology and pathology of this unorthodox biomolecule have come from the histochemical analysis of NO synthase (NOS) and its molecular isoforms that are responsible for the formation of NO. Immunocytochemistry as well as NADPH-diaphorase histochemistry are most widely used to visualize NOS in various tissues. There are several constraints regarding specificity and sensitivity of the techniques used and, therefore, apparent discrepancies in the literature concerning the cellular and subcellular distribution of NOS and its isoforms. Despite such inconsistencies there is a wealth of data that has an important impact on further investigation of NO-mediated processes underlying a vast number of NO-mediated physiological and pathological mechanisms.
Open Access
Nitric oxide synthase in skeletal muscle fibers, a signaling component of the dystrophin-glycoprotein complex
(Murcia : F. Hernández, 1999) Grozdanovic, Z.; Baumgarten, H.G.
The present review deals with the anatomical distribution, physiological importance, and pathological implications of the neuronal-type nitric oxide synthase (nNOS) in skeletal muscle. Throughout the body, nNOS is located beneath the sarcolemma of skeletal muscle fibers. In rodents, nNOS is enriched in type IIb muscle fibers, but is more homogenously distributed among type I1 and type I fibers in humans and subhuman primates. It is accumulated on the postsynaptic membrane at the neuromuscular junction. An increased concentration of nNOS is noted at the sarcolemma of muscle spindle fibers, in particular nuclear bag fibers, which belong to type I fibers. The association of nNOS with the sarcolemma is mediated by the dystrophin-g1 ycoprotein complex. Specifically, nNOS is linked to al-syntrophin through PDZ domain interactions. Possibly, it also directly binds to dystrophin. The activity and expression of nNOS are regulated by both myogenic and neurogenic factors. Besides acetylcholine, glutamate has also been shown to stimulate nNOS, probably acting through Nmethyl- D-aspartate receptors, which are colocalized with nNOS at the junctional sarcolemma. Functional studies have implicated nitric oxide as a modulator of skeletal muscle contractility, mitochondrial respiration, carbohydrate metabolism, and neuromuscular transmission. A clinically relevant aspect of nNOS is its absence from the skeletal muscle sarcolemma of patients with Duchenne muscular dystrophy (DMD). A concept is presented which suggests that, as a consequence of the disruption of the dystrophin-glyoprotein complex in DMD, nNOS fails to become attached to the sarcolemma and is subject to downregulation in the cytosol.
Open Access
Nitric oxide, a biological double-faced janus- Is this good or bad?
(Murcia : F. Hernández, 2006) Thippeswamy, T.; McKay, J.S.; Quinn, J.P.; Morris, R.
Nitric oxide (NO) is a biological messenger molecule produced by one of the essential amino acids L-arginine by the catalytic action of the enzyme NO synthase (NOS). The dual role of NO as a protective or toxic molecule is due to several factors, such as; the isoform of NOS involved, concentration of NO and the type of cells in which it is synthesised, the availability of the substrate L-arginine, generation of guanosine 3,5’- cyclic monophosphate (cGMP) from soluble guanylate cyclase and the overall extra and intracellular environment in which NO is produced. NOS activation as a result of trauma (calcium influx) or infection leads to NO production, which activates its downstream receptor sGC to synthesise cGMP and/or leads to protein nitrosylation. This may lead to one or more systemic effects including altered neurotransmission which can be protective or toxic, vaso/bronchodilatation in the cardiovascular and respiratory systems and enhanced immune activity against invading pathogens. In addition to these major functions, NO plays important role in thermoregulation, renal function, gastrointestinal motility, endocrine function, and various functions of the urogenital system ranging from renin secretion to micturation; spermatogenesis to penile erection; and ovulation to implantation and parturition. A schematic summary of the functions of NO and the various isoforms of NOS expressed in body systems is shown in figure 1. In this review, the historical background, biochemistry and biosynthesis of NO and its enzymes together with the mechanism of NO actions in physiology and pathophysiology are discussed.
Embargo
Production and localization of hydrogen peroxide and nitric oxide in grapevine cells elicited with cyclodextrins and methyl jasmonate
(Elsevier, 2019-06) Belchi Navarro, Sarai; Abellán Rubio, Marina; Pedreño, María Ángeles; Almagro Romero, Lorena; Biología Vegetal
The use of methyl jasmonate, alone or in combination with cyclic oligosaccharides such as cyclodextrins, has proved to be a successful strategy for increasing the production of trans-resveratrol in Vitis vinifera cell cultures. However, understanding the intracellular signalling pathways involved in its production would improve the management of grapevine cells as biofactories of this high-value natural product. The results obtained herein conﬁrm the involvement of hydrogen peroxide and nitric oxide in cyclodextrins and methyl jasmonate-induced trans-resveratrol production in grapevine cell cultures. In fact, methyl jasmonate led to maximal intracellular levels of hydrogen peroxide and nitric oxide after 24 h of treatment, but extracellular hydrogen peroxide was only detected in the culture medium when grapevine cells were treated with cyclodextrins. The results derived from the cytochemical detection of H2O2 in elicited grapevine cell cultures also suggested that the combined treatment with cyclodextrins and methyl jasmonate not only increased the production of H2O2 but also released cell wall fragments with electron-dense deposits. Moreover, nitric oxide was localized in all the cellular compartments, particularly in the nucleus and cyto-plasmic organelles, whereas hydrogen peroxide was mainly found in cytoplasmic areas close to the cell wall, and in the nucleoplasm.
Embargo
Renal effects of cyclooxygenase inhibition when nitric oxide synthesis is reduced and angiotensin II levels are enhanced
(Lippincott, Williams & Wilkins, 2015-05) López, Ruth; Llinás Más, María Teresa; Salazar, Elena; Salazar, Francisco Javier; Fisiología
The involvement of both cyclooxygenase (COX) isoforms in regulating renal function is well known but their interactions with other regulatory mechanisms, such as angiotensin II (Ang II) and nitric oxide (NO), are not well defined. This study has evaluated the relative contribution of both COX isoforms in regulating renal function when NO synthesis is reduced with and without a simultaneous increment in Ang II levels. The renal responses to a nonselective (meclofenamate) or a selective COX2 (nimesulide) inhibitor were examined in dogs pretreated with L-NAME with or without an intrarenal Ang II infusion. Meclofenamate induced a greater (P < 0.05) renal vasoconstriction than nimesulide in dogs pretreated with L-NAME. This vasoconstriction seems to be Ang II-dependent because it was reduced (P < 0.05) by captopril administration. Meclofenamate also induced a greater (P < 0.05) renal vasoconstriction than that elicited by nimesulide in dogs with reduced NO synthesis and elevated Ang II levels. The renal vasoconstriction induced by nimesulide but not that elicited by meclofenamate in dogs pretreated with L-NAME and Ang II, decreased (P < 0.05) during an extracellular volume expansion. These results demonstrate that the nonselective COX inhibition induces a greater renal vasoconstriction than that elicited by the selective COX2 inhibition when NO synthesis is reduced, and when NO synthesis is reduced and Ang II levels are elevated.
Open Access
Role of nitric oxide in murine cytomegalovirus (MCMV) infection
(Murcia : F. Hernández, 2001) Tanaka, K.; Noda, S.
Cytomegalovirus (CMV) is a typical pathogen of an opportunistic infection. In this review article, various roles of nitric oxide (NO) in murine CMV (MCMV) infections, including acute, persistent and latent infections, are discussed. In the acute phase of MCMV infection, NO plays a protective role against MCMV infection. In contrast, NO has been proven to act as a pathogenic factor in a model of MCMV pneumonitis. In MCMV persistent infection, when MCMV was detected only in the salivary gland, T cells of mice were modified to produce a massive amount of such cytokines as TNF-a and IFN-y upon in vivo stimulation with anti-CD3. These cytokines then induced mRNA for inducible NO synthase (iNOS), thus resulting in the production of a large amount of NO. A histochemical study demonstrated that NO damaged bronchial epithelial cells, and thereby apparently inducing pneumonitis. In the case of a latent infection, when viral DNA was detected in the host in spite of the absence of any infectious particle, NO increased the amount of persistently-infected MCMV-DNA. As a result, NO was found to act as "a double edged sword" in the CMV-host relationship.
Open Access
Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis
(MDPI, 2023-06-30) Romecín, Paola; García Estañ López, Joaquín María; Marin Atucha, Noemí; Akbari Aghdam, Masoud; Fisiología
: Introduction: Previously, we found that intracellular calcium (Ca2+) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. Objective: In the present study, we analyzed the role of nitric oxide in the abnormal calcium signaling responses of an experimental cirrhosis model, the bile duct-ligated rat. Methods: Chronic treatment with LNAME was used to inhibit NO production in a group of control and BDL animals, and the responses compared to those obtained in a control and BDL untreated group (n = 6 each). The experiments were conducted on isolated platelets loaded with fura-2, using fluorescence spectrometry. Results: Chronic treatment with L-NAME increased thrombin-induced Ca2+ release from internal stores in both control and BDL rats. However, the effect was significantly greater in the BDL rats (p < 0.05). Thrombin-induced calcium entry from the extracellular space was also elevated but at lower doses and, similarly in both control and BDL platelets, treated with the NO synthesis inhibitor. Capacitative calcium entry was also enhanced in the control platelets but not in platelets from BDL rats treated with L-NAME. Total calcium in intracellular stores was elevated in untreated platelets from BDL rats, and L-NAME pretreatment significantly (p < 0.05) elevated these values both in controls and in BDL but significantly more in the BDL rats (p < 0.05). Conclusions: Our results suggest that nitric oxide plays a role in the abnormal calcium signaling responses observed in platelets from BDL rats by interfering with the mechanism that releases calcium from the internal stores.
Open Access
Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis.
(2023-06-30) Romecín, P.; Garcia-estañ Lopez, J. M.; Marin Atucha, N. T.; Akbari Aghdam, Masoud; Fisiología
Open Access
Role of nitric oxide in the regulation of fibrogenic factors in experimental liver fibrosis in mice
(Murcia: F. Hernández, 2011) Leung, Tung-Ming; Fung, Man-Lung; Liong, Emily C.; Lau, Thomas Y.H.; Nanji, Amin A.; Tipoe, George L.
Previously, we have shown that an increased expression level of iNOS but a reduction in the expression of eNOS is associated with increased oxidative stress markers in CCl4-induced experimental liver fibrosis. The present study aimed to investigate the effect of L-arginine and 5-methylisothiourea hemisulfate (SMT) in the expression of profibrogenic factors in chronic liver injury. ICR mice were treated with CCl4 with or without treatment of L-arginine, an NO donor, or SMT, an iNOS inhibitor. The expression of matrix metalloptroteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), α-smooth muscle actin (α- SMA), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) were investigated by RTPCR. The activity of the MMP-2 and MMP-9 were measured by zymography. Our results showed that CCl4- treated mice showed significant up-regulation of expression of pro-fibrogenic factors, TNF-α and COX-2. Treatment with L-arginine or SMT showed a significant reduction in CCl4-induced expression of these profibrogenic factors, TNF-α and COX-2. In conclusion, both SMT and L-arginine effectively attenuated the progression of CCl4-induced liver fibrosis. SMT suppresses iNOS mediated NO production. However, Larginine augments NO production. The similar effect of the two drugs on liver fibrosis indicates that there may be two distinct pathways of NOS mediated fibrogenesis in chronic liver injury by iNOS and eNOS. Our results suggest that eNOS-mediated liver fibrogenesis may play a more important role than that of iNOS in chronic liver injury. Taken together, these results support the contention that NO plays an active role in the progression of liver fibrosis and hepatocellular damage.
Open Access
The role of nitric oxide in remodeling of capillary network in rat interscapular brown adipose tissue after long-term cold acclimation
(Murcia : F. Hernández, 2008) Korac, A.; Buzadzic, B.; Petrovic, V.; Vasilijevic, A.; Jankovic, A.; Micunovic, K.; Korac, B.
Cold exposure has been shown to increase blood flow in interscapular brown adipose tissue (IBAT). The aim of the present study was to evaluate the role of the L-arginine-nitric oxide (•NO) pathway on IBAT capillary network remodeling and its possible correlation with superoxide anion radical (O2 •–). In the rats that received L-arginine (2.25%) or NG-nitro-L-arginine methyl ester (L-NAME, 0.01%) as a drinking liquid and maintained at room (22±1°C) or low (4±1°C) temperature for 45 days, IBAT capillaries were analyzed by stereology and observed by light and electron microscopy. Additionally, endothelial •NO synthase (eNOS) expression, nitrotyrosine immunoreactivity and both copper zinc superoxide dismutase (CuZnSOD) enzyme activity and immunohistochemical localization were examined. Stereological analyses of IBAT show that the capillary volume density, as well as capillary-tobrown adipocytes ratio, are increased in cold. L-arginine treatment increases, while L-NAME decreases both parameters, compared to respective controls. Those changes were accompanied by capillary dilatation observed by light and electron microscopy. The activity of CuZnSOD is lower in control cold-acclimated rats, as well as in both L-arginine-treated groups, when compared to control animals acclimated to room temperature. L-NAME treatment attenuates the effects both of cold and L-arginine on CuZnSOD and increases immunopositivity for CuZnSOD in room temperatureacclimated rats. Our results show that •NO induces remodeling of the IBAT capillary network by angiogenesis, and presumably that interaction with O2 •– has a role in that modulation. The increased eNOS expression accompanied by an increased nitrotyrosine immunoreaction observed in both L-arginine-treated groups compared to corresponding controls strengthens this hypothesis.
Open Access
To NO or not to NO, where, is the question
(Murcia : F. Hernández, 2004) Govers, R.; Oess, S.
Nitric oxide (NO) is a gaseous radical with unique biological functions essential for the cardiovascular system, host defense and neurotransmission. For two decades it was thought that NO was able to diffuse freely across relatively long distances and to traverse major parts of the cell, if not multiple cell layers. However, NO has been proven to be extremely reactive: it reacts with other reactive oxygen species, heavy metals, as well as with cysteine and tyrosine residues in proteins. In accordance, it is now widely accepted that once NO is generated, it is very short-lived and diffuses only over a short distance. This urges for the local production of NO and the localization of NO synthases in the proximity of their downstream targets. This review discusses the highly organized localization of NO synthases, with the endothelial isoform (eNOS) as its main focus, since from this synthase most is known about its subcellular localization and regulation.

Browsing by Subject "Nitric oxide"

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