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Molsidomine HELP
Based on 399 articles since 2004

These are the 399 published articles about Molsidomine that originated from Worldwide during 2004-2014.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14 · 15 · 16
1 Editorial Inhibition of nitric oxide synthase during sepsis: revival because of isoform selectivity? 2010

Stahl, Wolfgang / Matejovic, Martin / Radermacher, Peter. · · Shock · Pubmed #20601934.

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. nadhem_2001@yahoo.fr · 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

Münzel, T. · Medizinische Klinik für Kardiologie, Angiologie und internistische Intensivmedizin, Johannes Gutenberg Universität Mainz. tmuenzel@uni-mainz.de · Dtsch Med Wochenschr · Pubmed #18946854.

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 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

Genest, Marc / Pochmalicki, Gilbert. · Service de cardiologie CH Provins, Provins. marc.genest@wanadoo.fr · Presse Med · Pubmed #15226697.

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 Clinical Trial Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina. 2006

Messin, Roger / Bruhwyler, Jacques / Dubois, Claude / Famaey, Jean-Pierre / Géczy, Joseph. · Therabel Pharma SA/NV, Brussels, Belgium. · Adv Ther · Pubmed #17050502.

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.

9 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. cor.vanhove@ua.ac.be · 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.

10 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.

11 Article Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect. 2014

Durmus, N / Bagcivan, I / Ozdemir, E / Altun, A / Gursoy, S. · · Bratisl Lek Listy · Pubmed #25023422.

ABSTRACT: OBJECTIVES: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS: Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS: PPIX, SIN-1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION: These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29).

12 Article Topical combinations to treat microvascular dysfunction of chronic postischemia pain. 2014

Laferrière, André / Abaji, Rachid / Tsai, Cheng-Yu Mark / Ragavendran, J Vaigunda / Coderre, Terence J. · From the *Alan Edwards Centre for Research on Pain, Department of Anesthesia, †Department of Psychology, ‡Alan Edwards Centre for Research on Pain, Department of Anesthesia, Neurology and Neurosurgery, and Psychology, and §Anesthesia Research Unit, McGill University Health Centre Research Institute, Montreal, QC, Canada. · Anesth Analg · Pubmed #24651238.

ABSTRACT: BACKGROUND: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. METHODS: Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. RESULTS: Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). CONCLUSIONS: The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.

13 Article Effects of molsidomine against doxorubicin-induced cardiotoxicity in rats. 2013

Disli, O M / Sarihan, E / Colak, M C / Vardi, N / Polat, A / Yagmur, J / Tamtekin, B / Parlakpinar, H. · Department of Cardiovascular Surgery, Inonu University Faculty of Medicine, Malatya, Turkey. · Eur Surg Res · Pubmed #24157421.

ABSTRACT: PURPOSE: To explore the protective and curative effects of molsidomine (MOL) on doxorubicin (DOX)-induced cardiac damage in the in vivo rat heart. METHODS: Forty rats were randomized into five groups (n = 8): (1) the control group; (2) the MOL group (10 mg/kg for 21 days); (3) the DOX group (a single dose of 20 mg/kg); (4) the DOX + MOL group (3 days after the single dose of DOX, 10 mg/kg MOL continued for 21 days), and (5) the MOL + DOX group (24 h after a 21-day regimen of 10 mg/kg MOL, a single dose of DOX). The rats were monitored for mean arterial blood pressure, heart rate, O2 saturation, and electrocardiography. Heart tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and nitric oxide (NO) were determined. RESULTS: Blood pressure and O2 saturation values indicated a significant decrease in the DOX group compared with the control group. T negativity was observed in 4 of 8 rats in the DOX group, in 1 of 8 rats in the DOX + MOL group, and in 4 of 8 rats in the MOL + DOX group. MDA levels were significantly higher in the DOX group. SOD, GSH, and NO levels were significantly lower in the DOX group compared with the other groups. There was no statistically significant difference in the CAT levels in any of the study groups compared with controls. DOX treatment induced morphological alterations, such as disorganization of cardiomyocytes, loss of myofibrils, and cytoplasmic vacuolization in the heart. On the other hand, histological damage was significantly reduced in the DOX + MOL and MOL + DOX groups. CONCLUSION: This study implies that there are cardioprotective effects of MOL on DOX-induced cardiotoxicity.

14 Article Alterations in the expression of nNOS in the substantia nigra and subthalamic nucleus of 6-OHDA-lesioned rats: the effects of chronic treatment with l-DOPA and the nitric oxide donor, molsidomine. 2013

Czarnecka, Anna / Lenda, Tomasz / Domin, Helena / Konieczny, Jolanta / Smiałowska, Maria / Lorenc-Koci, Elżbieta. · Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., PL 31-343 Kraków, Poland. Electronic address: czarnec@if-pan.krakow.pl. · Brain Res · Pubmed #24129225.

ABSTRACT: Recently, it has been strongly suggested that reciprocal interactions between nitrergic and dopaminergic systems play a crucial role in the control of the nigrostriatal pathway. Degeneration of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease leads to disturbances in the nitrergic transmission in the basal ganglia. In the present study, we aimed to compare regional distribution of nNOS immunoreactivity and NADPH-diaphorase activity in the SN and subthalamic nucleus (STN) of unilaterally 6-OHDA-lesioned rats treated chronically with l-DOPA (25mg/kg) and the nitric oxide donor, molsidomine (2 or 4mg/kg). Our results showed that degeneration of dopaminergic neurons in the ipsilateral SN resulted in a 25% decrease in the number of nNOS-immunoreactive neurons in that structure and in nNOS protein level determined by Western blot. We also found that nNOS was present in about 70% of all SN neurons. NADPH-d histochemistry did not reveal nNOS activity in the SN of any studied groups. Furthermore, the stereological analysis of the SN volume showed that chronic administration of l-DOPA evoked a hypertrophy of the ipsilateral SN when compared to the contralateral side. Such difference between sides was abolished in the group receiving l-DOPA in combination with molsidomine. Degeneration of the nigrostriatal pathway had no influence on the number of nNOS-ir neurons in the STN. NADPH-histochemistry revealed nNOS activity only in a part of neurons of that structure. Our results make an essential contribution to the research on the role of nitric oxide in the regulation of basal ganglia function.

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: dr_bentli@hotmail.com. · 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 Molsidomine, a nitric oxide donor, modulates rotational behavior and monoamine metabolism in 6-OHDA lesioned rats treated chronically with L-DOPA. 2013

Lorenc-Koci, Elżbieta / Czarnecka, Anna / Lenda, Tomasz / Kamińska, Kinga / Konieczny, Jolanta. · Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna St., PL-31-343 Kraków, Poland. Electronic address: lorenc@if-pan.krakow.pl. · Neurochem Int · Pubmed #24090640.

ABSTRACT: Some biochemical and histological studies of Parkinson's disease patients' brains and 6-OHDA-lesioned rats suggest that dopaminergic dennervation of the striatum leads to the nitrergic system hypofunction in this structure. Hence, recently the modulation of nitric oxide (NO)- soluble guanylyl cyclase-cyclic GMP signaling is considered to be a new target for the treatment of Parkinson's disease. The aim of our study was to examine the impact of chronic combined treatment with low doses of the NO donor molsidomine (2 and 4mg/kg) and L-DOPA (12.5 and 25mg/kg) on rotational behavior and monoamine metabolism in the striatum (STR) and substantia nigra (SN) of unilaterally 6-OHDA-lesioned rats. Chronic administration of molsidomine at a dose of 2mg/kg jointly with 25mg/kg of L-DOPA significantly decreased the number of contralateral rotations when compared to L-DOPA alone. Other combinations of the examined drug doses were less effective. The tissue DA levels in the ipsilateral STR and SN after the last chronic doses of molsidomine (2mg/kg) and L-DOPA (12.5 or 25mg/kg), were significantly higher than after L-DOPA alone. Chronic L-DOPA treatment alone or jointly with a lower dose of molsidomine decreased 5-HT levels and accelerated its catabolism in the examined structures. However, combination of a higher dose of molsidomine with L-DOPA (25mg/kg) did not reduce 5-HT content while its catabolism was less intensive. The obtained results show that low doses of molsidomine can modulate rotational behavior and tissue DA and 5-HT concentrations in the STR and SN of 6-OHDA-lesioned rats treated chronically with L-DOPA.

17 Article Sauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice. 2013

Kim, Dahn Hyo / Yang, Chae Ha / Hwang, Meeyul. · Department of Oriental Medicine, College of Oriental Medicine, Daegu Haany University, Daegu 706-060, South Korea. · Phytomedicine · Pubmed #23809251.

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.

18 Article The nitric oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy. 2013

Zordan, Paola / Sciorati, Clara / Campana, Lara / Cottone, Lucia / Clementi, Emilio / Querini, Patrizia-Rovere / Brunelli, Silvia. · Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy. · Eur J Pharmacol · Pubmed #23707352.

ABSTRACT: Inflammation plays a crucial role in muscle remodeling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice, a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most of the remaining macrophages displayed characteristics of the transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing during chronic muscle damage. This, alongside its already approved use in human, makes molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

19 Article Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells. 2013

Song, Jia-Le / Zhao, Xin / Wang, Qiang / Zhang, Ting. · Department of Food Science and Nutrition, Pusan National University, Busan 609-735, Republic of Korea. · Mol Med Rep · Pubmed #23545843.

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.

20 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.

21 Article Peroxynitrite alters GABAergic synaptic transmission in immature rat hippocampal slices. 2013

Yang, Jiajia / Liu, Zhaowei / Xie, Yongling / Yang, Zhuo / Zhang, Tao. · College of Life Sciences, Nankai University, Tianjin 300071, PR China. · Neurosci Res · Pubmed #23357207.

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.

22 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. msatoh@med.kawasaki-m.ac.jp · 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.

23 Article Tyrosine nitration provokes inhibition of sunflower carbonic anhydrase (β-CA) activity under high temperature stress. 2013

Chaki, Mounira / Carreras, Alfonso / López-Jaramillo, Javier / Begara-Morales, Juan C / Sánchez-Calvo, Beatriz / Valderrama, Raquel / Corpas, Francisco J / Barroso, Juan B. · Grupo de Señalización Molecular y Sistemas Antioxidantes en Plantas, Unidad Asociada al CSIC (EEZ), Departamento de Bioquímica y Biología Molecular, Universidad de Jaén, Spain. · Nitric Oxide · Pubmed #23266784.

ABSTRACT: Protein tyrosine nitration is a post-translational modification (PTM) mediated by reactive nitrogen species (RNS) and it is a new area of research in higher plants. Previously, it was demonstrated that the exposition of sunflower (Helianthus annuus L.) seedlings to high temperature (HT) caused both oxidative and nitrosative stress. The nitroproteome analysis under this stress condition showed the induction of 13 tyrosine-nitrated proteins being the carbonic anhydrase (CA) one of these proteins. The analysis of CA activity under high temperature showed that this stress inhibited the CA activity by a 43%. To evaluate the effect of nitration on the CA activity in sunflower it was used 3-morpholinosydnonimine (SIN-1) (peroxynitrite donor) as the nitrating agent. Thus the CA activity was inhibited by 41%. In silico analysis of the pea CA protein sequence suggests that Tyr(205) is the most likely potential target for nitration.

24 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.

25 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.