L-NAME

Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of L-NAME

  • inhibitor l-name
  • synthase inhibitor l-name


  • Selected Abstracts


    Xanthine-analog, KMUP-2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erection

    DRUG DEVELOPMENT RESEARCH, Issue 3 2002
    Rong-Jyh Lin
    Abstract The pharmacological properties of KMUP-2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP-2 caused relaxations that were attenuated by removed endothelium, high K+, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 ,M) and ODQ (1 ,M), a NOS inhibitor, L-NAME (100 ,M), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 ,M), a voltage-dependent K+ channel blocker 4-AP (100 ,M), and the Ca2+ -dependent K+ channel blockers apamin (1 ,M) and charybdotoxin (ChTX, 0.1 ,M). The relaxant responses of KMUP-2 (0.01, 0.05, 0.1 ,M) together with a PDE inhibitor, IBMX (0.5 ,M), had additive effects on rabbit aorta and CCSM. Additionally, KMUP-2 (100 ,M) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP-2 (0.1,100 ,M) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 ,M) and ODQ (10 ,M). Obviously, the relaxant effects of KMUP-2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP-2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K+ channels in rabbit aorta and CCSM. KMUP-2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP-1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. It is concluded that both the increases of cGMP and the opening activity of K+ channels play prominent roles in KMUP-2-induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162,172, 2002. 2002 Wiley-Liss, Inc. [source]


    Thaliporphine protects ischemic and ischemic-reperfused rat hearts via an NO-dependent mechanism

    DRUG DEVELOPMENT RESEARCH, Issue 3 2001
    Li-Man Hung
    Abstract In ischemia or ischemia-reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine, a natural alkaloid with Ca2+ channel-activating and Na+/K+ channel-blocking activities, increased NO levels and exerted cardioprotective action in ischemic or I/R rats. The role of NO in the cardioprotective actions of thaliporphine was assessed. The severity of rhythm disturbances and mortality in anesthetized rats with either coronary artery occlusion for 30 min, or 5 min followed by 30-min reperfusion, were monitored and compared in thaliporphine- vs. placebo-treated groups. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. The mortality of animals was also completely prevented by 1 10,8 moles/kg of thaliporphine. In animals subjected to 4 h of left coronary artery occlusion, 1 10,7 moles/kg of thaliporphine dramatic reduced cardiac infarct zone from 46 6% to 7.1 1.9%. Inhibition of NO synthesis with 3.7 10,6 moles/kg of N, -nitro-L-arginine methyl ester (L-NAME) abolished the beneficial effects of thaliporphine during 30 min or 4 h myocardial ischemia. However, the antiarrhythmic activity and mortality reduction efficacy of thaliporphine during reperfusion after 5 min of ischemia was only partially antagonized by L-NAME. These results showed that thaliporphine efficiently exerted the cardioprotections either in acute or prolonged coronary artery occlusion or occlusion-reperfusion situations. The fact that thaliporphine induced cardioprotective effects were abrogated by L-NAME indicates that NO is an important mediator for the cardioprotective effects of thaliporphine in acute or prolonged ischemia, whereas antioxidant activities may contribute to the protection of I/R injury. Drug Dev. Res. 52:446,453, 2001. 2001 Wiley-Liss, Inc. [source]


    Functional and molecular evidence of adenosine A2A receptor in coronary arteriolar dilation to adenosine

    DRUG DEVELOPMENT RESEARCH, Issue 1-2 2001
    Lih Kuo
    Abstract Adenosine is a potent vasodilator implicated in the regulation of coronary microvascular diameter during metabolic stress. However, the specific adenosine receptors and underlying mechanism responsible for the dilation of coronary microvessels to adenosine remains to be elucidated. Thus, pig subepicardial coronary arterioles (<100 ,m) were isolated, cannulated, and pressurized without flow for in vitro study. All vessels developed basal tone and dilated concentration-dependently to adenosine. Disruption of endothelium and inhibition of nitric oxide (NO) synthase by L-NAME produced identical attenuation of adenosine-induced dilation. KATP channel inhibitor glibenclamide further reduced the dilation of denuded vessels. cAMP antagonist Rp-8-Br-cAMP blocked vasodilation to forskolin, but failed to inhibit vasodilation to adenosine. Coronary dilation to adenosine was blocked by a selective adenosine A2A receptor antagonist ZM241385, but was not altered by an A1 receptor antagonist, DPCPX. Reverse transcription-polymerase chain reaction study revealed that A2A receptor mRNA was expressed in microvessels but not in cardiac myocytes; A1 receptor expression was observed only in cardiac myocytes. These results suggest that adenosine-induced dilation of coronary arterioles is mediated predominantly by A2A receptors. Activation of these receptors elicits vasodilation by endothelial release of NO and by smooth muscle opening of KATP channels in a cAMP-independent manner. Drug Dev. Res. 52:350,356, 2001. 2001 Wiley-Liss, Inc. [source]


    Parathyroid hormone stimulates the endothelial expression of vascular endothelial growth factor

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008
    G. Rashid
    ABSTRACT Background, We showed previously that parathyroid hormone (PTH) may stimulate the endothelial expression of pro-atherosclerotic and pro-inflammatory markers. Considering the impact of PTH on vasculature, we decided to evaluate its effect on mRNA and intra-cellular protein expressions of endothelial vascular endothelial growth factor (VEGF) taking into account that VEGF may play a role in the pathogenesis of endothelial dysfunctions. Materials and methods, Human umbilical vein cords endothelial cells (HUVEC) were stimulated for 24 h with 10,12,10,10 mol L,1 PTH. The VEGF-165 mRNA expression (critical in stimulating endothelial cell proliferation) was evaluated by RT/PCR and the intra-cellular VEGF protein expression by flow cytometry. The pathways by which PTH may have an effect on VEGF expression were also evaluated. Results, PTH (10,10 mol L,1) significantly increased VEGF-165 mRNA expression (P < 005). The addition of 50 nmol L,1 protein kinase C (PKC) and 10 mol L,1 protein kinase A (PKA) inhibitors significantly reduced the VEGF-165 mRNA expression (P = 001). We also examined whether nitric oxide (NO) may be involved in the PTH-induced stimulation of VEGF-165 expression. Pre-treatment of the cells with 200 mol L-nitro arginine methyl ester (L-NAME, NO synthase inhibitor) was found to inhibit VEGF-165 mRNA expression (P = 0006). VEGF protein could not be detected in the medium of HUVEC but it was present in the cell cytoplasm. PTH had no significant effect on cytoplasmatic VEGF protein expression. Conclusion, The stimulatory effect of PTH on endothelial VEGF-165 mRNA expression is partly through PKC and PKA pathways and is also NO dependent. [source]


    D-2-Hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2003
    C. G. Da Silva
    Abstract Background, Tissue accumulation of high amounts of D-2-hydroxyglutaric acid (DGA) is the biochemical hallmark of the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria (DHGA). Patients affected by this disease usually present hypotonia, muscular weakness, hypothrophy and cardiomyopathy, besides severe neurological findings. However, the underlying mechanisms of muscle injury in this disorder are virtually unknown. Materials and methods, In the present study we have evaluated the in vitro role of DGA, at concentrations ranging from 025 to 50 mm, on total, cytosolic and mitochondrial creatine kinase activities from skeletal and cardiac muscle of 30-day-old Wistar rats. We also tested the effects of various antioxidants on the effects elicited by DGA. Results, We first verified that total creatine kinase (CK) activity from homogenates was significantly inhibited by DGA (22,24% inhibition) in skeletal and cardiac muscle, and that this activity was approximately threefold higher in skeletal muscle than in cardiac muscle. We also observed that CK activities from mitochondrial (Mi-CK) and cytosolic (Cy-CK) preparations from skeletal muscle and cardiac muscle were also inhibited (12,35% inhibition) by DGA at concentrations as low as 025 mm, with the effect being more pronounced in cardiac muscle preparations. Finally, we verified that the DGA-inhibitory effect was fully prevented by preincubation of the homogenates with reduced glutathione and cysteine, suggesting that this effect is possibly mediated by modification of essential thiol groups of the enzyme. Furthermore, ,-tocopherol, melatonin and the inhibitor of nitric oxide synthase L-NAME were unable to prevent this effect, indicating that the most common reactive oxygen and nitrogen species were not involved in the inhibition of CK provoked by DGA. Conclusion, Considering the importance of creatine kinase activity for cellular energy homeostasis, our results suggest that inhibition of this enzyme by increased levels of DGA might be an important mechanism involved in the myopathy and cardiomyopathy of patients affected by DHGA. [source]


    Effect of oxytocin on nitric oxide activity controlling gonadotropin secretion in humans

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2003
    P. Chiodera
    Abstract Background Previously described inhibitory effects of the nitric oxide synthase (NOS) inhibitor L-NAME on luteinizing hormone-releasing hormone (LH-RH)-induced LH and follicle stimulating hormone (FSH) secretion in humans suggested modulation by nitric oxide (NO) of the gonadotropin-releasing action of LH-RH. Design In order to establish whether oxytocin (OT) participates in this regulatory mechanism, 10 normal men were treated with LH-RH (100 g as an i.v. bolus) given alone or in the presence of L-NAME (40 g kg,1 injected plus 50 g kg,1 infused i.v. for 60 min), OT (2 IU injected plus 4 IU infused i.v. for 60 min) or a combination of both drugs. Results The administration of OT was unable to change the gonadotropin responses to LH-RH. In contrast, L-NAME significantly reduced both FSH and LH increments induced by LH-RH. When L-NAME was given in the presence of OT, the LH and FSH responses to LH-RH were similar to those observed after the administration of LH-RH alone. Conclusion These data suggest antagonistic actions of OT and L-NAME in the control of NOS activity in regulation of gonadotropin secretion induced by LH-RH. [source]


    In vivo characterization of the angiotensin-(1,7)-induced dopamine and ,-aminobutyric acid release in the striatum of the rat

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005
    Bart Stragier
    Abstract The effect of angiotensin (Ang)-1,7 on dopamine, ,-aminobutyric acid (GABA) and glutamate release in the striatum of the rat was examined using in vivo microdialysis. Ang-(1,7) was administered locally in the striatum through the microdialysis probe. At a concentration of 100 m, Ang-(1,7) caused a significant increase in extracellular dopamine and GABA but had no effect on glutamate release. The Ang-(1,7)-induced dopamine release was blocked by EC33, an inhibitor of aminopeptidase A, an enzyme which converts Ang-(1,7) into Ang-(3,7), suggesting that this effect occurs after metabolism into Ang-(3,7). Indeed, administration of Ang-(3,7) (10,100 m) into the striatum caused a more potent increase in the striatal dopamine release than Ang-(1,7). Because Ang-(3,7) is an inhibitor of insulin-regulated aminopeptidase (IRAP) and because Ang IV, another IRAP inhibitor, also causes a concentration-dependent increase in dopamine in the rat striatum, IRAP may be involved in this effect. In contrast, EC33 had no effect on the Ang-(1,7)-induced GABA increase but the GABA release was blocked by the putative AT1-7 receptor antagonist A779 (0.1 m) and by the nitric oxide synthase inhibitor L-NAME (1 mm). These drugs could not block the effect of Ang-(1,7) on the striatal dopamine release suggesting that only the observed effects on GABA release are mediated by the AT1-7 receptor and/or are associated with a release of nitric oxide. [source]


    Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2005
    Wei-Lin Chien
    Abstract Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold). We have previously shown that YC-1 markedly enhances long-term potentiation in hippocampal and amygdala slices via NO-cGMP-PKG-dependent pathway. We here further investigated whether YC-1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC-1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC-1 30 min after foot-shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC-1 inhibited the scopolamine-induced learning deficit. The enhancement of learning behaviour by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor L-NAME and PKG inhibitors of KT5823 and Rp-8-Br-PET-cGMPS, indicating that NO-cGMP-PKG pathway is also involved in the learning enhancement action of YC-1. YC-1 is thus a good drug candidate for the improvement of learning and memory. [source]


    Pro-VGF-derived peptides induce penile erection in male rats: possible involvement of oxytocin

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2004
    Salvatora Succu
    Abstract The effect of five peptides derived from the C-terminal portion of rat pro-VGF (VGF577-617, VGF588-617, VGF599-617, VGF556-576 and VGF588-597) on penile erection was studied after injection into the hypothalamic paraventricular nucleus of male rats. VGF577-617, VGF588-617, VGF599-617 and, to a lower extent, VGF588-597 (0.1,2 g) induced penile erection episodes in a dose-dependent manner when injected into the paraventricular nucleus, while VGF556-576 was ineffective. VGF588-617 -induced penile erection was reduced by nitro, - l -arginine methylester (L-NAME; 20 g), by morphine (5 g) and by muscimol (1 g), but not by dizocilpine [(+)MK-801; 1 g], nor by cis -flupenthixol (10 g) given into the paraventricular nucleus 10 min before the VGF peptide. d(CH2)5Tyr(Me)-Orn8 -vasotocin (1 g) effectively reduced VGF588-617 -induced penile erection when given into the lateral ventricles but not when injected into the paraventricular nucleus. Immunocytochemistry with antibodies specific for the C-terminal nonapeptide sequence of pro-VGF (VGF609-617) revealed numerous neuronal fibres and terminals within the paraventricular nucleus, including its parvocellular components. Here, many immunostained neuronal terminals impinged on parvocellular oxytocinergic neurons. The present results show for the first time that certain pro-VGF C-terminus-derived peptides promote penile erection when injected into the paraventricular nucleus and suggest that, within this nucleus, these or closely related pro-VGF-derived peptides may be released to influence sexual function by activating paraventricular oxytocinergic neurons mediating penile erection. [source]


    The effects of nitric oxide on magnocellular neurons could involve multiple indirect cyclic GMP-dependent pathways

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003
    C. M. Vacher
    Abstract Nitric oxide (NO) is known to regulate the release of arginine-vasopressin (AVP) and oxytocin (OT) by the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). The aim of the current study was to identify in these nuclei the NO-producing neurons and the NO-receptive cells in mice. The determination of NO-synthesizing neurons was performed by double immunohistochemistry for the neuronal form of NO synthase (NOS), and AVP or OT. Besides, we visualized the NO-receptive cells by detecting cyclic GMP (cGMP), the major second messenger for NO, by immunohistochemistry on hypothalamus slices. Neuronal NOS was exclusively colocalized with OT in the PVN and the SON, suggesting that NO is mainly synthesized by oxytocinergic neurons in mice. By contrast, cGMP was not observed in magnocellular neurons, but in GABA-, tyrosine hydroxylase- and glutamate-positive fibers, as well as in GFAP-stained cells. The cGMP-immunostaining was abolished by incubating brain slices with a NOS inhibitor (L-NAME). Consequently, we provide the first evidence that NO could regulate the release of AVP and OT indirectly by modulating the activity of the main afferents to magnocellular neurons rather than by acting directly on magnocellular neurons. Moreover, both the NADPH-diaphorase activity and the mean intensity of cGMP-immunofluorescence were increased in monoamine oxidase A knock-out mice (Tg8) compared to control mice (C3H) in both nuclei. This suggests that monoamines could enhance the production of NO, contributing by this way to the fine regulation of AVP and OT release and synthesis. [source]


    Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001
    Stefan Klker
    Abstract Neuronal damage in glutaryl-CoA dehydrogenase deficiency (GDD) has previously been addressed to N- methyl- d -aspartate (NMDA) receptor-mediated neurotoxicity of the accumulating neurotoxic metabolite 3-hydroxyglutarate. However, acute encephalopathic crises in GDD patients are typically precipitated by febrile illness or even routine vaccinations, suggesting a potentiating role of inflammatory cytokines. In the present study we investigated the effect of interleukin-1, and interferon-, on 3-hydroxyglutarate toxicity in rat cortical astrocyte cultures and neonatal rat hippocampal cultures. A cotreatment of both culture systems with interleukin-1, and interferon-, induced the protein expression of astrocytic inducible nitric oxide synthase (iNOS), resulting in increased nitric oxide (NO) production. Cytokine pretreatment alone had no effect on cell viability but potentiated 3-hydroxyglutarate neurotoxicity. NOS inhibition by aminoguanidine and L-NAME prevented an iNOS-mediated potentiation of 3-hydroxyglutarate neurotoxicity but failed to protect neurons against 3-hydroxyglutarate alone. In contrast, superoxide dismutase/catalase as well as MK-801 prevented toxicity of 3-hydroxyglutarate alone as well as its potentiation by iNOS, supporting a central role of NMDA receptor stimulation with subsequently increased superoxide anion production. It is concluded that the potentiation of 3-hydroxyglutarate neurotoxicity is most probably due to an induction of astrocytic iNOS and concomitantly increased NO production, enabling enhanced peroxynitrite formation. Thus, we provide evidence for a neuroimmunological approach to the precipitation of acute encephalopathic crises in GDD by inflammatory cytokines. [source]


    Endothelial-Independent Prevention of High Blood Pressure in L-Name-Treated Rats by Angiotensin II type I Receptor Antisense Gene Therapy

    EXPERIMENTAL PHYSIOLOGY, Issue 4 2003
    Phyllis Y. Reaves
    It has previously been established that a single systemic administration of retroviral vector containing angiotensin II type I receptor antisense (AT1R-AS) in the neonatal spontaneously hypertensive rat (SHR) prevents development of hypertension, and in addition cardiac hypertrophy and endothelial dysfunction. However, these studies could not determine whether the effects of AT1R-AS on high blood pressure (BP) and endothelial function were independent. Angiotensin receptor blockers have been shown to reduce BP in the L-NAME (N , -nitro-L-arginine methyl ester hydrochloride)-induced rat model of hypertension. Our objective in the present study was to use the L-NAME model of hypertension to determine whether AT1R-AS treatment would lower high BP and attenuate cardiac hypertrophy under conditions of permanent endothelial damage. A single bolus of LNSV-AT1R-AS viral particles in neonatal Wistar-Kyoto (WKY) rats was without affect on basal BP. Efficacy of the transgene incorporation was assessed by observing a significant reduction in angiotensin-induced dipsogenic response in the AT1R-AS-treated animals. Introduction of L-NAME in the drinking water for 10 weeks resulted in the establishment of hypertension only in the WKY rats treated with vector alone. These hypertensive (BP, 179 4 mmHg) animals showed a 17% increase in heart weight/body weight ratio and a 60% reduction in ACh-induced vasorelaxation in phenylephrine-preconstricted arteries. The L-NAME-induced high BP and cardiac hypertrophy were attenuated in rats expressing AT1R-AS. However, endothelial dysfunction could not be prevented with the antisense therapy. These observations demonstrate that attenuation of endothelial dysfunction is not a prerequisite for the antihypertensive effects of AT1R-AS treatment. [source]


    Salt-Sensitive Hypertension Resulting From Nitric Oxide Synthase Inhibition is Associated with Loss of Regulation of Angiotensin II in the Rat

    EXPERIMENTAL PHYSIOLOGY, Issue 1 2002
    G. Hodge
    In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008%, 2.2% or 4.4% sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg,1 day,1) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist. [source]


    The Effect of Progesterone on Coronary Blood Flow in Anaesthetized Pigs

    EXPERIMENTAL PHYSIOLOGY, Issue 1 2001
    C. Molinari
    The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h,1 of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h,1. The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N, -nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide. [source]


    The Neurogenic Vasodilator Response to Endothelin-1: A Study in Human Skin In Vivo

    EXPERIMENTAL PHYSIOLOGY, Issue 6 2000
    Ruwani Katugampola
    We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 ,M ET-1 (1.43 0.64 ,M, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 0.38 ,M) whilst that in the flare increased to reach a peak value of 2.28 0.61 ,M at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ETA/ETB antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo. [source]


    Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2001
    Subbarao Vemulapalli
    The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 ,M) and yohimbine (30 ,M) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of ,-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of ,-adrenergic receptor blockade. [source]


    Long-term modulation of glucose utilization by IL-1, and TNF-, in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms

    GLIA, Issue 1 2002
    Cline Vga
    Abstract Interleukin-1, (IL-1,) and tumor necrosis factor-, (TNF-,) markedly stimulate glucose utilization in primary cultures of mouse cortical astrocytes. The mechanism that gives rise to this effect, which takes place several hours after application of cytokine, has remained unclear. Experiments were conducted to identify the major signaling cascades involved in the metabolic action of cytokine. First, the selective IL-1 receptor antagonist (IL-1ra) prevents the effect of IL-1, on glucose utilization in a concentration-dependent manner, whereas it has no effect on the action of TNF-,. Then, using inhibitors of three classical signaling cascades known to be activated by cytokines, it appears that the PI3 kinase is essential for the effect of both IL-1, and TNF-,, whereas the action of IL-1, also requires activation of the MAP kinase pathway. Participation of a phospholipase C-dependent pathway does not appear critical for both IL-1, and TNF-,. Inhibition of NO synthase by L-NAME did not prevent the metabolic response to both IL-1, and TNF-,, indicating that nitric oxide is probably not involved. In contrast, the Na+/K+ ATPase inhibitor ouabain prevents the IL-1,- and TNF-,-stimulated 2-deoxyglucose (2DG) uptake. When treatment of astrocytes with a cytokine was followed 24 h later by an acute application of glutamate, a synergistic enhancement in glucose utilization was observed. This effect was greatly reduced by ouabain. These data suggest that Na+ pump activity is a common target for both the long-term metabolic action of cytokines promoted by the activation of distinct signaling pathways and the enhanced metabolic response to glutamate. GLIA 39:10,18, 2002. 2002 Wiley-Liss, Inc. [source]


    Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome

    HEPATOLOGY, Issue 4 2003
    Laurie D. Deleve M.D., Ph.D.
    This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. NG -nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion. (Hepatology 2003;38:900,908). [source]


    The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines

    INTERNATIONAL JOURNAL OF CANCER, Issue 5 2003
    Seok-Woo Park
    Abstract The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2,20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention. 2003 Wiley-Liss, Inc. [source]


    Hydrogen,potassium ATPase inhibitors induce relaxation on rabbit prostatic strips in vitro

    INTERNATIONAL JOURNAL OF UROLOGY, Issue 11 2002
    Ihsan Bagcivan
    Summary Background : To determine the relaxant effect of omeprazole and lansaprazole, hydrogen,potassium (H+,K+) ATPase inhibitors, on rabbit prostatic tissue in vitro. Methods : Male New Zealand white rabbits were sacrificed and their prostatic tissues were removed. The prostatic stromal strips were mounted in organ baths and relaxation responses were obtained in precontracted tissues with phenylephrine, carbachol and potassium chloride (KCl). Relaxation responses were controlled in the presence of various antagonists to explain the mechanism for relaxation exerted by omeprazole and lansaprazole. Results : Omeprazole and lansaprazole caused similar relaxation responses in the prostatic strips precontracted with phenylephrine, carbachol and KCl. The addition of prostaglandin synthase inhibitor indomethacin, nitric oxide synthase inhibitor L-NAME, potassium channel blockers, glibenclamide and tetraethylammonium into the organ baths did not change the relaxations induced by omeprazole and lansaprazole in vitro. Conclusion : Omeprazole and lansaprazole cause a relaxation in prostatic stromal tissue precontracted with phenyephrine, carbachol and KC1 in vitro. This relaxant effect is independent of H+,K+ ATPase inhibition. Additionally, cyclooxygenase and nitric oxide pathways do not contribute to this relaxant effect. Further studies are required to determine whether these drugs may have a beneficial effect in the non-operative treatment of benign prostatic hyperplasia. [source]


    Role of Endothelium/Nitric Oxide and Cyclic AMP in Isoproterenol Potentiation of 17-Estradiol-Mediated Vasorelaxation

    JOURNAL OF CARDIAC SURGERY, Issue 6 2002
    HY Chan
    Estrogen exerts vasorelaxation and cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as -adrenoceptor agonists. However, little is known whether low concentrations of -adrenoceptor agonists would also influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17-estradiol, and to study the role of endothelium and cyclic AMP-dependent pathway in this interaction. Changes in vessel tone of the isolated rat mesenteric artery rings were measured by force-displacement Grass transducer. In 9,11-dideoxy-11,, 9,-epoxy-methanoprostaglandin F2, - preconstricted endothelium-intact rings, 17-estradiol induced concentration-dependent relaxation with pD2 of 5.074 0.043. Pretreatment of endothelium-intact rings with isoproterenol (1-3 10 -9 M, 1-h incubation time) significantly enhanced 17,-estradiol-induced relaxation. Longer incubation (2.5 h) did not produce further amplifying effect. This effect was inhibited by Rp-cGMPS triethylamine (3 10 -6 M), and disappeared in the presence of 3 10 -5 M NG -nitro-L-arginine methyl ester or in the endothelium-denuded rings. The effect of isoproterenol was partially antagonized by propranolol (3 10 -6 M), ICI 118,551 (3 10 -6 M) but not by atenolol (10 -5 M). None of three ,-adrenoceptor antagonists affected 17-estradiol-induced relaxation in the absence of isoproterenol. Rp-cAMPS triethylamine (3 10 -6 M) abolished the effect of isoproterenol. Besides, exposure to 3 10 -9 M forskolin for 1 h also potentiated the relaxant response to 17,-estradiol. In summary, this isoproterenol enhancement was dependent on the presence of endothelium and abolished by L-NAME via a ,2 -adrenoceptor-mediated cyclic AMP-dependent mechanism. These data also indicate the possible existence of cyclic AMP-dependent nitric oxide-producing pathway in the regulation of the vascular response to vasodilators. (supported by UPGC Direct Grant) [source]


    Renal cortex remodeling in nitric oxide deficient rats treated with enalapril

    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2004
    Noemi Barbuto
    Abstract The kidney NO synthase is one of the most important renal controlling systems. This paper aims the quantification of renal cortical components involved in blood pressure regulation under NOs blockade. Spontaneous hypertensive rats (SHRs) are submitted to chronic blockade of NOs by L-nitro-arginine-methyl-ester (L-NAME) and an ACE inhibitor (enalapril) in comparison with the normotensive Wistar rats. Twenty SHRs and 5 Wistar rats were divided in 5 groups and observed for 21 days for blood pressure (BP) and serum creatinine: control Wistar (5) (C-W), control SHR (5) (C-SHR), L-SHR (5) - received L-NAME 30 mg/kg/day, L+E-SHR (5) - received L-NAME and Enalapril maleate 15 mg/kg/day, E-SHR (5) - received Enalapril maleate. A quantitative morphometric study (glomerular density, QA[g1], interstitium volume density, Vv[i], tubular surface and length densities, Sv[t] and Lv[t]) were performed at the end. The BP reached 22615 mmHg in L-SHR group. The BP difference between the L-SHR and the C-SHR groups was significant from the first week while the E-SHR group became significant from the second week. At the end of the experiment the BP of the E-SHR group was similar to the BP in the C-W group. The QA[g1] was similar among C-SHR, L-SHR and L+E-SHR groups and no difference was found between E-SHR and C-W groups. In the L-SHRs serum creatinine was greatly increased, and microscopy showed thickening of arteriolar tunica media with an increase of the wall-to-lumen ratio, perivascular fibrosis, inflammatory infiltrated, tubular atrophy and interstitial fibrosis with focal segmental glomerulosclerosis. The use of enalapril was not completely efficient in reducing BP and morphological injury when the hypertension of SHRs was increased with the NOs blockade suggesting that NO deficiency-induced hypertension is not entirely mediated by the RAAS. [source]


    Beneficial effect of enalapril in spontaneously hypertensive rats cardiac remodeling with nitric oxide synthesis blockade

    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2002
    R. L. de Andrade Zorzi
    Abstract Aims. To study the efficiency of an angiotensin converting enzyme inhibitor on the blood pressure (BP) and the myocardium remodeling when spontaneously hypertensive rats (SHRs) are submitted to nitric oxide synthesis (NOs) blockade (with L-NAME) and simultaneously treated. Methods. Young adult male SHRs were separated in four groups (n = 5) and treated for 20 days: Control, L-NAME, L-NAME+Enalapril, and Enalapril. The alterations of the BP, heart mass/body mass ratio and stereological parameters for myocytes, connective tissue and intramyocardial vessels were studied among the groups. Results. The SHRs with NOs blockade showed a great modification of the myocardium with extensive areas of reparative and interstitial fibrosis and accentuated hypertrophy of the cardiac myocytes (cross sectional area 60% higher in animals taking L-NAME than in Control SHRs). Comparing the SHRs with NO deficiency (L-NAME group), the Control SHRs and the Enalapril treated SHRs significant differences were found in the BP and in all stereological parameters. The NO deficiency caused an important BP increment in SHRs that was partially attenuated by Enalapril. This Enalapril effect was more pronounced in Control SHRs. A significant increment of the intramyocardial vessels was observed in NO deficient SHRs and Control SHRs treated with Enalapril demonstrated by the stereology (greater microvascular densities in treated SHRs). Conclusion. Enalapril administration showed a beneficial effect on vascular remodeling and myocardial hypertrophy in SHRs. In SHRs with NO blockade, however, the beneficial effect of Enalapril occurred only in vascular remodeling. [source]


    iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells,

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2008
    Feng Wu
    Redox regulation of inducible nitric oxide synthase (iNOS) expression was investigated in lipopolysaccharide and interferon-, (LPS,+,IFN,)-stimulated microvascular endothelial cells from mouse skeletal muscle. Unstimulated endothelial cells produced reactive oxygen species (ROS) sensitive to inhibition of NADPH oxidase (apocynin and DPI), mitochondrial respiration (rotenone) and NOS (L-NAME). LPS,+,IFN, caused a marked increase in ROS production; this increase was abolished by inhibition of NADPH oxidase (apocynin, DPI and p47phox deficiency). LPS,+,IFN, induced substantial expression of iNOS protein. iNOS expression was prevented by the antioxidant ascorbate and by NADPH oxidase inhibition (apocynin, DPI and p47phox deficiency), but not by inhibition of mitochondrial respiration (rotenone) and xanthine oxidase (allopurinol). iNOS expression also was prevented by selective antagonists of ERK, JNK, Jak2, and NF,B activation. LPS,+,IFN, stimulated activation/phosphorylation of ERK, JNK, and Jak2 and activation/degradation of I,B, but only the activation of JNK and Jak2 was sensitive to ascorbate, apocynin and p47phox deficiency. Ascorbate, apocynin and p47phox deficiency also inhibited the LPS,+,IFN,-induced DNA binding activity of transcription factors IRF1 and AP1 but not NF,B. In conclusion, LPS,+,IFN,-induced NF,B activation is necessary for iNOS induction but is not dependent on ROS signaling. LPS,+,IFN,-stimulated NADPH oxidase activity produces ROS that activate the JNK-AP1 and Jak2-IRF1 signaling pathways required for iNOS induction. Since blocking either NF,B activation or NADPH oxidase activity is sufficient to prevent iNOS expression, they are separate targets for therapeutic interventions that aim to modulate iNOS expression in sepsis. J. Cell. Physiol. 217: 207,214, 2008. 2008 Wiley-Liss, Inc. [source]


    Insulin restores glucose inhibition of adenosine transport by increasing the expression and activity of the equilibrative nucleoside transporter 2 in human umbilical vein endothelium

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006
    Gonzalo Muoz
    L -Arginine transport and nitric oxide (NO) synthesis (L -arginine/NO pathway) are stimulated by insulin, adenosine or elevated extracellular D -glucose in human umbilical vein endothelial cells (HUVEC). Adenosine uptake via the human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) has been proposed as a mechanism regulating adenosine plasma concentration, and therefore its vascular effects in human umbilical veins. Thus, altered expression and/or activity of hENT1 or hENT2 could lead to abnormal physiological plasma adenosine level. We have characterized insulin effect on adenosine transport in HUVEC cultured in normal (5 mM) or high (25 mM) D -glucose. Insulin (1 nM) increased overall adenosine transport associated with higher hENT2-, but lower hENT1-mediated transport in normal D -glucose. Insulin increased hENT2 protein abundance in normal or high D -glucose, but reduced hENT1 protein abundance in normal D -glucose. Insulin did not alter the reduced hENT1 protein abundance, but blocked the reduced hENT1 and hENT2 mRNA expression induced by high D -glucose. Insulin effect on hENT1 mRNA expression in normal D -glucose was blocked by NG -nitro- L -arginine methyl ester (L-NAME, NO synthase inhibitor) and mimicked by S -nitroso- N -acetyl- L,D -penicillamine (SNAP, NO donor). L-NAME did not block insulin effect on hENT2 expression. In conclusion, insulin stimulation of overall adenosine transport results from increased hENT2 expression and activity via a NO-independent mechanism. These findings could be important in hyperglycemia-associated pathological pregnancies, such as gestational diabetes, where plasma adenosine removal by the endothelium is reduced, a condition that could alter the blood flow from the placenta to the fetus affecting fetus growth and development. J. Cell. Physiol. 209: 826,835, 2006. 2006 Wiley-Liss, Inc. [source]


    Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: Role of nitric oxide synthase isoforms

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2006
    Chi-Jen Chu
    Abstract Background:, Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. Method:, Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N, -nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-, (TNF- ,) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. Results:, Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- , as compared with rats treated with L-canavanine or N/S (P < 0.01). Conclusion:, Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure. [source]


    NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway

    JOURNAL OF NEUROCHEMISTRY, Issue 4 2007
    A. Scorziello
    Abstract To identify the transductional mechanisms responsible for the neuroprotective effect of nitric oxide (NO) during ischemic preconditioning (IPC), we investigated the effects of this gaseous mediator on mitochondrial Mn-superoxide dismutase (Mn-SOD) expression and activity. In addition, the possible involvement of Ras/extracellular-regulated kinase (ERK) ERK1/2 pathway in preserving cortical neurons exposed to oxygen and glucose deprivation (OGD) followed by reoxygenation was also examined. Ischemic preconditioning was obtained by exposing neurons to a 30-min sublethal OGD (95% N2 and 5% CO2). Then, after a 24-h interval, neurons were exposed to 3 h of OGD followed by 24 h of reoxygenation (OGD/Rx). Our results revealed that IPC reduced cytochrome c (cyt c) release into the cytosol, improved mitochondrial function, and decreased free radical production. Moreover, it induced an increase in nNOS expression and NO production and promoted ERK1/2 activation. These effects were paralleled by an increase in Mn-SOD expression and activity that persisted throughout the following OGD phase. When the neurons were treated with L-NAME, a well known NOS inhibitor, the increase in Mn-SOD expression occurring during IPC was reduced and, as a result, IPC-induced neuroprotection was prevented. Similarly, when ERK1/2 was inhibited by its selective inhibitor PD98059, the increase in Mn-SOD expression observed during IPC was almost completely abolished. As a result, its neuroprotective effect on cellular survival was thwarted. The present findings indicate that during IPC the increase in Mn-SOD expression and activity are paralleled by NO production. This suggests that NO neuroprotective role occurs through the stimulation of Mn-SOD expression and activity. In particular, NO via Ras activation stimulates downstream ERK1/2 cascade. This pathway, in turn, post-transcriptionally activates Mn-SOD expression and activity, thus promoting neuroprotection during preconditioning. [source]


    Nitric oxide regulates BDNF release from nodose ganglion neurons in a pattern-dependent and cGMP-independent manner

    JOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2010
    Hui-ya Hsieh
    Abstract Activity of arterial baroreceptors is modulated by neurohumoral factors, including nitric oxide (NO), released from endothelial cells. Baroreceptor reflex responses can also be modulated by NO signaling in the brainstem nucleus tractus solitarius (NTS), the primary central target of cardiovascular afferents. Our recent studies indicate that brain-derived neurotrophic factor (BDNF) is abundantly expressed by developing and adult baroreceptor afferents in vivo, and released from cultured nodose ganglion (NG) neurons by patterns of baroreceptor activity. Using electrical field stimulation and ELISA in situ, we show that exogenous NO nearly abolishes BDNF release from newborn rat NG neurons in vitro stimulated with single pulses delivered at 6 Hz, but not 2-pulse bursts delivered at the same 6-Hz frequency, that corresponds to a rat heart rate. Application of L-NAME, a specific inhibitor of endogenous NO synthases, does not have any significant effect on activity-dependent BDNF release, but leads to upregulation of BDNF expression in an activity-dependent manner. The latter effect suggests a novel mechanism of homeostatic regulation of activity-dependent BDNF expression with endogenous NO as a key player. The exogenous NO-mediated effect does not involve the cGMP-protein kinase G (PKG) pathway, but is largely inhibited by N-ethylmaleimide and TEMPOL that are known to prevent S-nitrosylation. Together, our current data identify previously unknown mechanisms regulating BDNF availability, and point to NO as a likely regulator of BDNF at baroafferent synapses in the NTS. 2009 Wiley-Liss, Inc. [source]


    Gastroprotective activity of ferruginol in mice and rats: effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2008
    Carlos Areche
    The gastroprotective mechanism of the natural diterpene ferruginol was assessed in mice and rats. The involvement of gastric prostaglandins (PGE2), reduced glutathione, nitric oxide or capsaicin receptors was evaluated in mice either treated or untreated with indometacin, N-ethylmaleimide (NEM), N-nitro-L-arginine methyl ester (L-NAME) or ruthenium red, respectively, and then orally treated with ferruginol or vehicle. Gastric lesions were induced by oral administration of ethanol. The effects of ferruginol on the parameters of gastric secretion were assessed in pylorus-ligated rats. Gastric PGE2 content was determined in rats treated with ferruginol and/or indometacin. The reduction of gastric glutathione (GSH) content was determined in rats treated with ethanol after oral administration of ferruginol, lansoprazole or vehicle. Finally, the acute oral toxicity was assessed in mice. Indometacin reversed the gastroprotective effect of ferruginol (25 mg kg,1) but not NEM, ruthenium red or L-NAME. The diterpene (25 mg kg,1) increased the gastric juice volume and its pH value, and reduced the titrable acidity but was devoid of effect on the gastric mucus content. Ferruginol (25, 50 mg kg,1) increased gastric PGE2 content in a dose-dependent manner and prevented the reduction in GSH observed due to ethanol-induced gastric lesions in rats. Single oral doses up to 3 g kg,1 ferruginol did not elicit mortality or acute toxic effects in mice. Our results showed that ferruginol acted as a gastroprotective agent stimulating the gastric PGE2 synthesis, reducing the gastric acid output and improving the antioxidant capacity of the gastric mucosa by maintaining the GSH levels. [source]


    Red wine polyphenolic compounds inhibit tracheal smooth muscle contraction during allergen-induced hyperreactivity of the airways

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2007
    Sona Franova
    The aims of the study were to investigate the short and long-term effects of Provinol (red wine polyphenolic compounds) on tracheal smooth muscle reactivity using an in-vitro model of ovalbumin-induced airway inflammation in guinea-pig trachea, and to evaluate the role of nitric oxide (NO) in the bronchodilatory effect of Provinol. The amplitude of tracheal smooth muscle contraction in response to mediators of bronchoconstriction ,histamine (10 nM-1 mM), acetylcholine (10 nM-1 mM) and to allergen (ovalbumin 10,5 -10,3 g mL,1) was used as a parameter of tracheal smooth muscle reactivity. To test the short-term effects of Provinol, isolated tracheal strips were pre-treated for 30 min with Provinol (10,4mg mL,1) alone or in combination with N, -nitro-L-arginine methyl ester (L-NAME; 10,6mol L,1). To test the long-term effects of Provinol, isolated tracheal strips were prepared from guinea pigs that had been treated for 14 days with Provinol (20mg kg,1 per day) alone or in combination with L-NAME (40 mg kg,1 per day). Incubation of tracheal smooth muscle with Provinol decreased the amplitude of contraction in response to ovalbumin, histamine and acetylcholine. The non-selective NO synthase inhibitor L-NAME partially abolished the effect of Provinol on acetylcholine and ovalbumin-induced but not histamine-induced bronchoconstriction. A similar profile was observed after 14 days' oral administration of Provinol. In conclusion, Provinol inhibited the allergen- and spasmogen-induced contraction of tracheal smooth muscle in ovalbumin-sensitized guinea pigs via a mechanism that was mediated at least partially through the metabolism of NO. [source]