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Expertise in Molsidomine: Worldwide
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These are the 485 published articles about Molsidomine that originated from Worldwide during 2003-2014.
1 Editorial Inhibition of nitric oxide synthase during sepsis: revival because of isoform selectivity? 2010
ABSTRACT: -- No abstract --
2 Review [The pharmacology of nitric oxide and nitrates]. 2010
Li, Huige / Förstermann, Ulrich. · Institut für Pharmakologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. · Pharm Unserer Zeit · Pubmed #20818683.
ABSTRACT: -- No abstract --
3 Review [Coronary spastic angina refractory to optimal medical therapy treated by angioplasty and stenting. A case report and review of literature]. 2010
Hajlaoui, N / Tarragano, F / Raisky, P / Beaufils, P / Henry, P. · Service de cardiologie, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France. email@example.com
· Ann Cardiol Angeiol (Paris) · Pubmed #19007921.
ABSTRACT: Medical treatment of coronary spastic angina is based classically on the association of calcium channel blockers with nitrate derivatives. Some clinical forms of spastic angina remain refractory to these medications and can thus lead to serious complications (sudden cardiac death secondary to ventricular rhythm disturbance, myocardial infarction...). When the coronary spasm is focal, percutaneous coronary angioplasty with deployment of a stent can offer an interesting therapeutic alternative. We report in this article the case of a patient who had a focal spasm of the right coronary artery, which became refractory to optimal medical treatment. This patient was well improved by percutaneous angioplasty with deployment of a stent in the spastic segment of the right coronary artery. We propose also a review of the literature of the treatment of this pathology, which still remains not well codified.
4 Review [Recent findings on nitrates: their action, bioactivation and development of tolerance]. 2008
ABSTRACT: Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.
5 Review Use of recombinant iron-superoxide dismutase as a marker of nitrative stress. 2008
Larrainzar, Estíbaliz / Urarte, Estíbaliz / Auzmendi, Iñigo / Ariz, Idoia / Arrese-Igor, Cesar / González, Esther M / Moran, Jose F. · Departamento de Ciencias del Medio Natural, Universidad Pública de Navarra, Campus de Arrosadía, E-31006 Pamplona, Navarre, Spain. · Methods Enzymol · Pubmed #18433650.
ABSTRACT: Superoxide dismutases (SODs; EC 18.104.22.168) are a group of metalloenzymes which are essential to protect cells under aerobic conditions. In biological systems, it has been reported that SODs and other proteins are susceptible to be attacked by peroxynitrite (ONOO(-)) which can be originated from the reaction of nitric oxide with superoxide radical. ONOO(-) is a strong oxidant molecule capable of nitrating peptides and proteins at the phenyl side chain of the tyrosine residues. In the present work, bovine serum albumin (BSA) and recombinant iron-superoxide dismutase from the plant cowpea (Vu_FeSOD) are used as target molecules to estimate ONOO(-) production. The method employs the compound SIN-1, which simultaneously generates *NO and O(2)(-) in aerobic aqueous solutions. First, assay conditions were optimized incubating BSA with different concentrations of SIN-1, and at a later stage, the effect on the tyrosine nitration and catalytic activity of Vu_FeSOD was examined by in-gel activity and spectrophotometric assays. Both BSA and Vu_FeSOD are nitrated in a dose-dependent manner, and, at least in BSA nitration, the reaction seems to be metal catalyzed.
6 Review Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease. 2007
Sartori-Valinotti, Julio C / Iliescu, Radu / Fortepiani, Lourdes A / Yanes, Licy L / Reckelhoff, Jane F. · Department of Physiology and Biophysics and The Center of Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216-4504, USA. · Clin Exp Pharmacol Physiol · Pubmed #17645644.
ABSTRACT: 1. In the present review, we addressed studies in humans and rats to determine the role that oxidative stress may play in mediating cardiovascular outcomes. 2. Biochemical evaluation of oxidative stress in both humans and spontaneously hypertensive rats gives equivocal results as to the relative levels in males versus females. Clinical trials with anti-oxidants in humans have not shown consistent results in protecting against detrimental cardiovascular outcomes. In spontaneously hypertensive rats (SHR), blockade studies using tempol or apocynin reduce renal oxidative stress and blood pressure in male SHR, but not in female rats. In addition, increasing oxidative stress with molsidomine increases blood pressure in male, but not female, SHR. Treatment with vitamins E and C reduces blood pressure in young male, but not aged, animals. Furthermore tempol is unable to reduce blood pressure in young male SHR in the absence of a functional nitric oxide system. 3. Neither human nor animal studies are consistent in terms of whether oxidative stress levels are higher in males or females. Furthermore, anti-oxidant therapy in humans often does not ameliorate, or even attenuate, the negative cardiovascular consequences of increased oxidative stress. Our studies in SHR shed light on why these outcomes occur.
7 Review [Acute coronary syndromes with ST-segment elevation]. 2004
ABSTRACT: UNBLOCK THE CORONARY ARTERIES: For the treatment of acute coronary syndromes with ST-segment elevation, emergency repermeabilisation is of the artery is crucial, generally by primary angioplasty than by fibrinolysis. The other treatments have little beneficial effects on mortality. Primary angioplasty is the technique of choice when it can be performed in the intensive care units with staff with sufficient experience and within the 90 minutes following the preliminary medical management, and benefiting from the supply of PG IIb-IIIa. THROMBOLYSIS: Performed before the twelfth hour, thrombolysis reduces mortality. The earlier it is performed the greater the benefits. A significant reduction is mortality is observed even in patients aged over 75. The indications for coronography are determined by the existence of clinical risk factors and by the data of supplementary non-invasive examinations (sonography, scintigraphy, effort testing). When clinical risk factors exist from the start, a coronography must be performed. In the absence of initial risks, and if the non-invasive examination reveals risk factors, then a coronarography should be performed.
8 Guideline ICH guideline for photostability testing: aspects and directions for use. 2003
ABSTRACT: The ICH guideline Q1B for photostability testing gives guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products. The choice of the irradiation method, although complying with the guideline demands, may effect test results. High irradiances may shorten testing times, but can lead to enforcement of photodegradation, which was demonstrated for molsidomine tablets. The exposure to an artificial light source (xenon lamp) was compared and correlated to natural daylight. Suitable testing methods for nifedipine and molsidomine tablets were developed. Deviating from the guideline recommendations, the presentation of powder samples should be done in tiny aluminium pans, facilitating the test procedure, minimising the risk of falsified test results due to improper sampling and improving reproducibility. When using glass dishes for the presentation of tablets to photostability testing, they should be lined by e. g. aluminium foil to avoid influences of light reflected from the sample tray.
9 Clinical Trial Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina. 2006
ABSTRACT: Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.
10 Clinical Trial Long-term treatment with the NO-donor molsidomine reduces circulating ICAM-1 levels in patients with stable angina. 2005
Van Hove, Cor / Carreer-Bruhwyler, Fabienne / Géczy, Joseph / Herman, Arnold G. · University of Antwerp, Division of Pharmacology, Universiteitsplein 1, B-2610 Wilrijk, Belgium. firstname.lastname@example.org · Atherosclerosis · Pubmed #15910868.
ABSTRACT: Recent clinical evidence has indicated that the severity of atherosclerosis is correlated with the level of soluble ICAM-1 (sICAM-1). Nitric oxide (NO) donors are used to treat patients with stable angina pectoris, and the aim of this study was to investigate the short- and long-term effect of molsidomine on the level of this circulating biochemical marker of endothelial function. We included 172 patients and examined the effect of the NO donor treatment on angina related parameters and on sICAM-1 levels after a 4-week- and a 1-year treatment period. After 4 weeks, angina attacks and sublingual (s.l.) isosorbide dinitrate tablet (ISDN) consumption frequency was significantly (p<0.0001) reduced without altering sICAM-1 levels when compared to the baseline values. The anti-anginal effect of molsidomine 16 mg once a day (o.a.d.) was sustained (s.l. ISDN consumption) or improved (angina attacks frequency; p<0.002) during the following year and a significant decrease in sICAM-1 levels (p<0.0001) was observed. When the sICAM-1 changes during the 1-year treatment period were distributed in four categories (quartiles of the distribution), it was demonstrated that the decrease in s.l. ISDN consumption between the start and the end, was most pronounced in the group with the largest sICAM-1 decrease (fourth quartile of distribution; p=0.038). In conclusion, the reduction in the pro-inflammatory marker sICAM-1 after 1-year daily treatment with molsidomine may indicate that this NO donor besides its anti-anginal function, promotes a less activated state of the endothelium in patients with stable angina.
11 Clinical Trial [Transradial approach for diagnostic angiography]. 2004
Michel, C / Laffy, P Y / Leblanc, G / Le Guen, O / Le Blevec, G / Sarfati, L / Riou, J Y / Jue Denis, P. · Service de Radiologie Cardio-Vasculaire, Centre Médico-Chirurgical de l'Europe, Le Port Marly. C.Michel20@wanadoo.fr · J Radiol · Pubmed #15243382.
ABSTRACT: Seventy five arteriographies were performed via the transradial route using 5F 130cm - long catheter. Prior to puncture the radial artery was evaluated with Allen test. Satisfying quality examinations were obtained for the thoracic aorta, selective carotid arteries examinations, infra renal aorta, pelvic and legs arteries. The major advantages obtained for the technique were the very low rate complication and technical failure. Transradial route for arteriography is a reasonable alternative approach to transfemoral or brachial arteriography for out patient management (peripheral angiography) in case in which transfemoral route is not feasible but also with patients with important haemorragic-risks.
12 Clinical Trial [Effect of molsidomine on rheological parameters and the incidence of cardiovascular events]. 2003
Wöhrle, J / Nusser, T / Hoffmeister, A / Kestler, H A / Grebe, O C / Höher, M / Hombach, V / Koenig, W / Kochs, M. · Abteilung Innere Medizin II, Universität Ulm. email@example.com · Dtsch Med Wochenschr · Pubmed #12802741.
ABSTRACT: BACKGROUND AND OBJECTIVE: In-vitro studies revealed that nitric oxide (NO) may affect rheological parameters. We studied the effect of highly-dosed NO-donor molsidomine on blood rheology and the impact of rheological parameters on the incidence of severe cardiovascular events. PATIENTS AND METHODS: In this randomized, placebo-controlled and double-blind trial 166 patients (60 +/- 10 years) with stable angina pectoris and coronary intervention received molsidomine 3 x 8 mg t. i. d. (controlled release tablets) or placebo for 6 months. Patients with inflammatory/neoplastic disorders or elevated values of C-reactive protein were excluded from analysis. A rheological profile (plasma viscosity, blood viscosity, aggregation and flexibility of erythrocytes, filtrability of leukocytes, fibrinogen levels) was done initially and after 6 months. Adverse cardiovascular events (death, myocardial infarction, stroke, coronary/peripheral revascularization) were recorded during 12 months. Furthermore, the impact of rheological parameters regarding the occurrence of severe cardiovascular events (death, myocardial infarction, stroke) was evaluated during a follow-up of median 38 months. RESULTS: The data of 137 patients (n = 71 placebo, n = 66 molsidomine) were analysed. The difference of rheological parameters between the two measurements did not vary between the two groups. Analysis of event-free survival with Kaplan-Meier technique revealed no difference between the two groups. Multivariate Cox regression analysis with adjustment for diabetes mellitus, smoking and therapy with statin showed a significant association of fibrinogen and plasma viscosity with the occurrence of severe cardiovascular events. CONCLUSION: Treatment with molsidomine 3 x 8 mg/day for 6 months does not improve blood rheology or reduce cardiovascular events. But elevated levels of fibrinogen and plasma viscosity were associated with the occurrence of severe cardiovascular events.
13 Clinical Trial A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations. 2003
Messin, Roger / Fenyvesi, Tamas / Carreer-Bruhwyler, Fabienne / Crommen, Jacques / Chiap, Patrice / Hubert, Philippe / Dubois, Claude / Famaey, Jean-Pierre / Géczy, Joseph. · Therabel Pharma S.A., Rue Van Ophem 108, 1180 Brussels, Belgium. firstname.lastname@example.org · Eur J Clin Pharmacol · Pubmed #12734607.
ABSTRACT: OBJECTIVES: A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. METHODS: Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. RESULTS: The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). CONCLUSION: The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.
14 Clinical Trial No effect of highly dosed nitric oxide donor molsidomine on the angiographic restenosis rate after percutaneous coronary angioplasty: a randomized, placebo controlled, double-blind trial. 2003
Wöhrle, Jochen / Höher, Martin / Nusser, Thorsten / Hombach, Vinzenz / Kochs, Matthias. · Department of Cardiology, University of Ulm, Ulm, Germany. email@example.com · Can J Cardiol · Pubmed #12717484.
ABSTRACT: BACKGROUND: Nitric oxide (NO) counteracts several mechanisms involved in the restenotic process after coronary angioplasty. NO mediates an antiproliferative effect on smooth muscle cells, inhibition of leukocyte-vessel wall interactions, and platelet aggregation and adhesion. Because these effects are mainly dose dependent, NO-releasing drugs have to be applied at a high dose to have an effect on restenotic mechanisms. OBJECTIVES: To study the effect of the NO donor molsidomine at a high dose of 8 mg tid on angiographic restenosis rate in a randomized, placebo controlled, double-blind trial. PATIENTS AND METHODS: One hundred and sixty-six patients with de novo stenosis were randomly assigned to molsidomine or placebo treatment for six months (83 patients each). The primary end point was the angiographic restenosis rate at six months. The secondary end points were major adverse cardiac events (MACE) including death, myocardial infarction and revascularization. Analyses were performed by intention to treat. RESULTS: There were no differences in clinical, procedural and angiographic data, including minimum lumen diameter and reference diameter. Provisional stenting was performed in 28% of patients receiving molsidomine and 25% of patients treated with placebo. All other patients were treated with standard balloon angioplasty. Reangiography rate was 89.3% (molsidomine 90 lesions, placebo 97 lesions). Restenosis rate (greater than 50% diameter stenosis) was not significantly different (molsidomine 25.6% and placebo 29.9%). Patients receiving molsidomine improved significantly more in their anginal class than patients receiving placebo (P<0.026). Occurrence of MACE did not significantly differ between both groups (molsidomine 26.8% and placebo 34.9%, P=0.26). CONCLUSION: Treatment with the NO donor molsidomine at a high dose of 8 mg tid for six months after coronary angioplasty has no effect on the angiographic restenosis rate. Due to the vasodilating effect of NO, the anginal status improves slightly more in patients receiving molsidomine.
15 Article Molsidomine prevents cisplatin-induced hepatotoxicity. 2013
Bentli, Recep / Parlakpinar, Hakan / Polat, Alaadin / Samdanci, Emine / Sarihan, Mehmet Ediz / Sagir, Mustafa. · Department of Internal Medicine, Medical Faculty, Inonu University, Malatya, Turkey. Electronic address: firstname.lastname@example.org. · Arch Med Res · Pubmed #24120390.
ABSTRACT: BACKGROUND AND AIMS: Despite its beneficial effects, cisplatin has considerable nephrotoxic, ototoxic, neurotoxic and hepatotoxic side effects. It has been documented that reactive oxygen radical species are involved with the pathophysiology of cisplatin-induced hepatotoxicity. Molsidomine (MOL) can exert antioxidant and anti-inflammatory effects. Therefore, the current study was planned to determine the effects of cisplatin on the liver oxidant/antioxidant system and the possible protective effects of (MOL) on liver toxicity. METHODS: Animals were divided into four groups as follows: (1) control; (2) MOL; (3) cisplatin and (4) MOL plus cisplatin group. Biochemical and histopathological evaluations were performed on the extracted liver tissue. Also, serum levels of serum aspartate transaminase (AST) and serum alanine transaminase (ALT) were determined. RESULTS: Our results clearly indicated that liver antioxidant enzyme activities and ALT levels were significantly decreased, whereas lipid peroxidation and neutrophil accumulation were increased in the cisplatin-treated animals (5 mg/kg single dose, i.p.) compared to the control rats. MOL treatment (4 mg/kg/day, i.p.) for 3 consecutive days provided a significant protection against cisplatin-induced hazardous changes in the liver tissue. Our histopathological findings including caspase-3 activity were also in accordance with the biochemical results. CONCLUSIONS: We propose that MOL acts in the liver as a potent scavenger of free radicals, anti-inflammatory and anti-apoptotic effects to prevent the toxic effects of cisplatin, both at the biochemical and histopathological levels.
16 Article Sauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice. 2013
ABSTRACT: Sauchinone is a phytochemical known as a nitric oxide (NO) inhibitor. NO is a kind of neurotransmitter and involved in psychotic effect of abuse drug. In present, we carried out a study on the effect of sauchinone on methamphetamine-induced alteration of behavior in mice. Locomotory activity and conditioned place preference (CPP) were used to evaluate behavioral changes. As a result, sauchinone inhibited the methamphetamine-induced hyperlocomotion in dose-dependent manner, whereas sauchinone had no effect on normal locomotory activity. The inhibitory effect of sauchinone on methamphetamine-induced hyperlocomotion was reversed by treatment of molsidomine, a NO donor. Sauchinone also significantly blocked the acquisition and expression of CPP induced by methamphetamine in mouse. However, it did not produce place preference or place aversion, when it was treated alone in animals. Taken together, sauchinone blocked drug reward-related behavior as well as acute hyperlocomotion induced by methamphetamine treatment.
17 Article Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells. 2013
ABSTRACT: Reactive oxygen species (ROS)-induced pancreatic β cell death affects insulin secretion and is important in the pathogenesis of diabetes. Lagerstroemia speciosa, a traditional folk medicine, has been used for t he prevention and treatment of diabetes. However, whether Lagerstroemia speciosa has a cytoprotective effect on pancreatic β cells remains to be elucidated. The present study aimed to investigate the cytoprotective effects of hot water extracts from Lagerstroemia speciosa leaves (LWE) on 3-morpholinosydnonimine (SIN-1)-induced oxidative damage in Syrian hamster pancreatic insulinoma HIT-T15 cells. The HIT-T15 cells were first treated with SIN-1 (50 µM) for 24 h and then co-incubated with LWE for 48 h. SIN-1 significantly decreased HIT-T15 cell viability (P<0.05); however, LWE did not exert a significant cytotoxic effect and increased the viability of HIT-T15 cells in a dose‑dependent manner. To further investigate the protective effects of LWE on SIN-1‑induced oxidative stress in HIT-T15 cells, the cellular levels of ROS, lipid peroxidation and endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px), were determined. LWE decreased the intracellular levels of ROS and lipid peroxidation, and increased the activities of antioxidant enzymes. These results suggest that LWE has a cytoprotective effect against SIN-1‑induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, a decrease in ROS levels and an increase in antioxidant enzyme activity. In addition, LWE increased insulin secretion in SIN-1-treated HIT-T15 cells. Our results suggested that LWE were effective in the treatment of diabetes. Further studies are required to study the anti-diabetic molecular mechanism in a cell model.
18 Article Differential effects of the peroxynitrite donor, SIN-1, on atrial and ventricular myocyte electrophysiology. 2013
Bonilla, Ingrid M / Sridhar, Arun / Nishijima, Yoshinori / Györke, Sandor / Cardounel, Arturo J / Carnes, Cynthia A. · College of Pharmacy, Division of Pharmacology, The Ohio State University, Columbus, OH 43210, USA. · J Cardiovasc Pharmacol · Pubmed #23364607.
ABSTRACT: Oxidative stress has been implicated in the pathogenesis of heart failure and atrial fibrillation and can result in increased peroxynitrite production in the myocardium. Atrial and ventricular canine cardiac myocytes were superfused with 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1), a peroxynitrite donor, to evaluate the acute electrophysiologic effects of peroxynitrite. Perforated whole-cell patch clamp techniques were used to record action potentials. SIN-1 (200 µM) increased the action potential duration (APD) in atrial and ventricular myocytes; however, in the atria, APD prolongation was rate independent, whereas in the ventricle APD, prolongation was rate dependent. In addition to prolongation of the action potential, beat-to-beat variability of repolarization was significantly increased in ventricular but not in atrial myocytes. We examined the contribution of intracellular calcium cycling to the effects of SIN-1 by treating myocytes with the SERCA blocker, thapsigargin (5-10 µM). Inhibition of calcium cycling prevented APD prolongation in the atrial and ventricular myocytes, and prevented the SIN-1-induced increase in ventricular beat-to-beat APD variability. Collectively, these data demonstrate that peroxynitrite affects atrial and ventricular electrophysiology differentially. A detailed understanding of oxidative modulation of electrophysiology in specific chambers is critical to optimize therapeutic approaches for cardiac diseases.
19 Article Peroxynitrite alters GABAergic synaptic transmission in immature rat hippocampal slices. 2013
ABSTRACT: Increasing of peroxynitrite (ONOO(-)) production during ischemia in the immature brain was considered to be associated with impaired cognitive function. GABAergic synapses played an important role in memory formation including the induction of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In the present study, we examined the effects of acute exposure of the ONOO(-) donor, SIN-1 on GABAergic synaptic transmission in immature rat hippocampal slices with whole-cell patch-clamp recordings. The results showed that SIN-1 increased the peak amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and decreased paired pulse ratio via the formation of ONOO(-). In addition, it also increased the frequency of spontaneous (but not miniature) IPSCs in a dose-dependent manner without altering amplitudes or rise and decay times of both (sIPSCs and mIPSCs). It further demonstrated that the presynaptic action of SIN-1 was external calcium dependent and was not related to the changes of interneuron excitability. This study provides electrophysiological evidences from developing hippocampal slices to support that SIN-1 enhances action potential-dependent GABA release. It suggests that the potentiation effect of ONOO(-) may contribute to hyperexcitability and seizures and may underlie one of the mechanisms by which ischemia increases seizure susceptibility in the immature brain.
20 Article Angiostatin production increases in response to decreased nitric oxide in aging rat kidney. 2013
Satoh, Minoru / Kidokoro, Kengo / Ozeki, Masahito / Nagasu, Hajime / Nishi, Yuko / Ihoriya, Chieko / Fujimoto, Sohachi / Sasaki, Tamaki / Kashihara, Naoki. · Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan. email@example.com · Lab Invest · Pubmed #23295649.
ABSTRACT: The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin is a kringle-containing fragment of plasminogen and is a potent inhibitor of angiogenesis in vivo. Whether angiostatin generation is increased in the aging kidney has not been investigated. We examined 4, 10, 16, and 24-month-old Sprague-Dawley rats for angiostatin production and found that angiostatin generation was increased in aged rats. The protein expression and the activity of cathepsin D-the enzyme for angiostatin production--were increased in aged rats. In the aging kidney, nitric oxide (NO) availability is decreased. To investigate the role of NO in angiostatin production, human umbilical vein endothelial cells were treated with L-NG-nitroarginine methyl ester (L-NAME). L-NAME-treated cells showed increased cathepsin D activity and angiostatin production. For in vivo experiments, 16- to 18-month-old rats were treated with L-NAME or molsidomine for 3 months. Angiostatin production was increased in L-NAME-treated kidney, accompanied by increased cathepsin D activity. In contrast, angiostatin production was decreased in molsidomine-treated kidney, accompanied by decreased cathepsin D activity. In conclusion, angiostatin generation by cathepsin D was increased in the aging rat kidney. Decreased NO production activated cathepsin D activity. Increased angiostatin production may be related to capillary loss and interstitial damage in the aging rat kidney.
21 Article Neuroprotective effects of Cyperus rotundus on SIN-1 induced nitric oxide generation and protein nitration: ameliorative effect against apoptosis mediated neuronal cell damage. 2013
Hemanth Kumar, Kandikattu / Tamatam, Anand / Pal, Ajay / Khanum, Farhath. · Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore, India. · Neurotoxicology · Pubmed #23174672.
ABSTRACT: Nitrosylation of tyrosine (3-nitro tyrosine, 3-NT) has been implicated in the pathophysiology of various disorders particularly neurodegenerative conditions and aging. Cyperus rotundus rhizome is being used as a traditional folk medicine to alleviate a variety of disorders including neuronal stress. The herb has recently found applications in food and confectionary industries also. In current study, we have explored the protective effects of C. rotundus rhizome extract (CRE) through its oxido-nitrosative and anti apoptotic mechanism to attenuate peroxynitrite (ONOO(-)) induced neurotoxicity using human neuroblastoma SH-SY5Y cells. Our results elucidate that pre-treatment of neurons with CRE ameliorates the mitochondrial and plasma membrane damage induced by 500 μM SIN-1 to 80% and 24% as evidenced by MTT and LDH assays. CRE inhibited NO generation by downregulating i-NOS expression. SIN-1 induced depletion of antioxidant enzyme status was also replenished by CRE which was confirmed by immunoblot analysis of SOD and CAT. The CRE pre-treatment efficiently potentiated the SIN-1 induced apoptotic biomarkers such as bcl-2 and caspase-3 which orchestrate the proteolytic damage of the cell. The ONOO(-) induced damage to cellular, nuclear and mitochondrial integrity was also restored by CRE. Furthermore, CRE pre-treatment also regulated the 3-NT formation which shows the potential of plant extract against tyrosine nitration. Taken together, our findings suggest that CRE might be developed as a preventive agent against ONOO(-) induced apoptosis.
22 Article [Effects of peroxynitrite derived from nitric oxide on cultured bovine ocular explants]. 2013
Lahmar-Belguendouz, K / Belguendouz, H / Hartani, D / Lahlou-Boukoffa, O S / Bédiar-Boulaneb, F / Touil-Boukoffa, C. · Équipe « cytokines et NO synthases : immunité et pathogénie », laboratoire de biologie cellulaire et moléculaire, faculté des sciences biologiques, USTHB Bab Ezzouar, El Alia, BP 32, 16100 Alger, Algérie. · J Fr Ophtalmol · Pubmed #23040446.
ABSTRACT: INTRODUCTION: Several studies have reported a significant production of nitric oxide (NO) with peroxynitrite formation in the setting of intraocular inflammation. In a previous study, we showed the cytotoxic effect of nitrites and nitrates, stable metabolites of NO, on the various tissues forming the layers of the eye, with variable degrees of tissue sensitivity. This study aims to investigate the effect of peroxynitrite on whole ocular bovine explants in culture. METHODS: Healthy ocular bovine eyes, obtained immediately upon enucleation, were dissected and samples were taken from the anterior and posterior segments, and then cultured in DMEM supplemented with 10% fetal bovine serum, 2mM L-glutamine and antibiotics. Cultures were treated with 3-morpholino-sydonimin N-ethyl-carbamide (SIN-1) (molecule which produces NO and superoxide anion O(2)(.-)) at varying concentrations (100 to 500 μM) over 24 hours. After incubation, the explants were fixed in 10% buffered formalin, and histological study was performed. RESULTS: Most of the structures showed changes on tissue and cellular levels after incubation with the peroxynitrite donor and various responses depending on the concentration used. These observations reflect variable concentration-dependent tissue sensitivity. The epithelia (cornea, iris and ciliary process) showed high sensitivity in comparison with sclera, which developed greater resistance. CONCLUSION: In all, our results indicate a deleterious effect of peroxynitrite on bovine ocular structures in vitro. This effect is proportional to the concentration used. These results corroborate those reported by other teams and suggest the role of peroxynitrite derived from NO in the ocular lesions observed in the setting of uveitis.
23 Article Response of mitochondrial antioxidant system and respiratory pathways to reactive nitrogen species in pea leaves. 2013
Martí, María C / Florez-Sarasa, Igor / Camejo, Daymi / Pallol, Beatriz / Ortiz, Ana / Ribas-Carbó, Miquel / Jiménez, Ana / Sevilla, Francisca. · Department of Stress Biology and Plant Pathology, CEBAS-CSIC, Murcia, Spain. · Physiol Plant · Pubmed #22607494.
ABSTRACT: Nitric oxide (NO) has emerged as an important signaling molecule in plants, but little is known about the effects of reactive nitrogen species in plant mitochondria. In this study, the effects of DETA-NONOate, a pure NO slow generator, and of SIN-1 (3-morpholinosydnonimine), a peroxynitrite producer, on the activities of respiratory pathways, enzymatic and non-enzymatic antioxidants have been investigated in isolated mitochondria from pea leaves. No significant changes in lipid peroxidation, protein oxidation or in ascorbate and glutathione redox state were observed after DETA-NONOate treatments whereas cytochrome pathway (CP) respiration was reversibly inhibited and alternative pathway (AP) respiration showed little inhibition. On the other hand, NO did not affect neither activities of Mn superoxide dismutase (Mn-SOD) nor enzymes involved in the ascorbate and glutathione regeneration in mitochondria except for ascorbate peroxidase (APX), which was reversely inhibited depending on ascorbate concentration. Finally, SIN-1 treatment of mitochondria produced a decrease in CP respiration, an increase in protein oxidation and strongly inhibited APX activity (90%), with glutathione reductase and dehydroascorbate reductase (DHAR) being moderately inhibited (30 and 20%, respectively). This treatment did not affect monodehydroascorbate reductase (MDHAR) and Mn-SOD activities. Results showed that mitochondrial nitrosative stress was not necessarily accompanied by oxidative stress. We suggest that NO-resistant AP and mitochondrial APX may be important components of the H(2) O(2) -signaling pathways under nitrosative stress induced by NO in this organelle. Also, MDHAR and DHAR, via ascorbate regeneration, could constitute an essential antioxidant defense together with Mn-SOD, against NO and ONOO(-) stress in plant mitochondria.
24 Article Protection against peroxynitrite by pseudoperoxidase from Leishmania major. 2012
Bose, Moumita / Saha, Rina / Sen Santara, Sumit / Mukherjee, Supratim / Roy, Jayasree / Adak, Subrata. · Division of Structural Biology and Bio-informatics, Indian Institute of Chemical Biology, Kolkata, India. · Free Radic Biol Med · Pubmed #22985938.
ABSTRACT: Heme proteins share the ability to detoxify reactive nitrogen intermediates (NO and peroxynitrite). But, to date, no heme-containing enzymatic defense against toxic reactive nitrogen intermediates has been discovered in Leishmania species. We have cloned, expressed, and characterized a pseudoperoxidase from Leishmania major (LmPP) that is capable of detoxifying peroxynitrite (ONOO(-)). Optical, EPR, and resonance Raman spectral studies demonstrate that ONOO(-) can rapidly convert the six-coordinate ferric low-spin to a ferric high-spin form at neutral pH. Western blotting and immunofluorescence studies with anti-LmPP antibody show that the mature enzyme is located at the plasma membrane of amastigotes and is expressed eightfold higher in amastigotes compared to promastigotes. Moreover, to further investigate its exact physiological role in Leishmania, we have created LmPP-knockout mutants by gene replacement in L. major strains. IC(50) values for exogenously added H(2)O(2) or 3-morpholinosydnonimine (SIN1) show that deletion of LmPP in L. major renders the cell more susceptible to SIN1. The null mutant cells exhibit a marked decrease in virulence on infection with activated macrophages as well as inoculation into BALB/c mice. Collectively, these data provide strong evidence that LmPP plays an important role in the enzymatic defense against ONOO(-) within macrophages.
25 Article Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage. 2012
Kovanecz, Istvan / Rivera, Steve / Nolazco, Gaby / Vernet, Dolores / Segura, Denesse / Gharib, Sahir / Rajfer, Jacob / Gonzalez-Cadavid, Nestor F. · Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute (LABioMed) at Harbor-UCLA Medical Center, Torrance, CA, USA. · J Sex Med · Pubmed #22974131.
ABSTRACT: INTRODUCTION: Long-term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno-occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle-derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage. AIM: To investigate in the BCNR model the effects of sildenafil at lower doses, alone or in combination with MDSC or the NO donor molsidomine, on CVOD and the underlying corporal histopathology. MAIN OUTCOMES MEASURES: CVOD, histological, and biochemical markers in rat corporal tissue. Methods. Rats subjected to BCNR were maintained for 45 days either untreated, or received sildenafil in the water or retrolingually at 10, 2.5, and 1.25 mg/kg/day (medium, low, and very low doses), or intraperitoneal molsidomine, or MDSC implantation into the corpora cavernosa separately or in combination. Cavernosometry evaluated CVOD. Histopathology was assessed on penile sections by Masson trichrome, immunohistochemistry for α-smooth muscle actin (ASMA), or immunofluorescence for neuronal nitric oxide synthase (nNOS)/neurofilament 70, and in fresh tissue by Western blot for various markers and picrosirius red for collagen. RESULTS: All treatments normalized erectile function (drop rate), and most increased the CSMC/collagen ratio and ASMA expression in corporal tissue sections, and reduced collagen content in the penile shaft. MDSC also increased nNOS and brain-derived neurotrophic factor. The combination treatment was not superior to MDSC or sildenafil given alone, and upregulated PDE5. CONCLUSIONS: Lowering the dose of a continuous long-term sildenafil administration still maintained the prevention of CVOD in the BCNR rat previously observed, but it was less effective on the underlying histopathology. As in the aging rat model, MDSC also counteracted CVOD, but supplementation with very low-dose sildenafil did not improve the outcome.