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Hydrogen Sulfide as an allosteric modulator of ATP sensitive potassium channels in colonic inflammation.Gade, Aravind 18 April 2012 (has links)
The ATP sensitive potassium channel (KATP) in mouse colonic smooth muscle cell is a complex containing a pore forming subunit (Kir6.1) and a sulfonyl urea receptor subunit (SUR2B). These channels are responsible for maintaining the cellular excitability of the smooth muscle cell which in turn regulates the motility patterns in the colon. We used whole-cell voltage-clamp techniques to study the alterations in these channels in smooth muscle cells in experimental model of colitis (colonic inflammation). Colitis was induced in BALB/C mice following an intracolonic administration of trinitrobenzene sulfonic acid (TNBS). KATP currents were measured at Vh -60 mV in high K+ external solution. The dose-response to levcromakalim (LEVC), a KATP channel opener, was significantly shifted to the left in the inflamed smooth muscle cells. Both the affinity and maximal currents induced by LEV were enhanced in inflammation. The EC50 in control was 6259 nM (n=10) and 422 nM (n=8) in inflamed colon while the maximal currents were 9.9 ± 0.71 pA/pF (60 μM) in control and 39.7 ± 8.8 pA/pF (3 μM) following inflammation. Similar to LEVC, KATP currents activated by sodium hydrogen sulfide (NaHS) (10-1000 μM) were significantly greater in inflamed compared to controls. In control cells, pretreatment with 100 µM NaHS shifted the EC50 for LEV-induced currents from 2838 nM (n=6) to 154 nM (n=8). These data suggest that NaHS can act as an allosteric modulator for LEV-induced KATP currents. Decreased colonic motility may result from enhanced KATP activation by increased release of H2S in colitis.
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Mechanisms by Which Arachidonic acid Metabolite, Epoxyeicosatrienoic acid Elicit Cardioprotection Against Ischemic Reperfusion InjuryBATCHU, SRI NAGARJUN Unknown Date
No description available.
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Efeitos gastroprotetores do timol em úlceras agudas e crônicas em ratos : evidências do envolvimento das prostaglandinas, canais para potássio sensíveis a ATP e secreção do muco gástrico / Gastroprotective effects of thymol on acute and chronic ulcers in rats: evidence involment of prostaglandins, ATP-sensitive K+ channels, and gastric mucus secretionDiniz, Polyana Borges França 16 December 2016 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Thymol, a monoterpene phenol derivative of cymene, is found in abundance in the essential oils produced by numerous herbs and spices such as thyme (Thymus vulgaris L.), oregano (Origanum vulgaris L.) and Lippia alba (mill.). Several biological effects have been described for thymol such as antioxidant, anti-inflammatory, local anesthetics, antinoceptive, healing and antibacterial properties. It was described the application of thymol in food Science, as herbicidad and inseticides. Moreover, essential oils containing thymol have been used in folk medicine to treat various physiological disorders such as gastrites, indigestion and stomach pains. The present study investigated the gastroprotective actions of thymol (10, 30 and 100 mg/kg, p.o.) in the acute indomethacin and ethanol and chronic acetic acid-induced ulcer models in rats. Some of the mechanisms underlying to the gastroprotective effect of thymol were investigated in the ethanol-induced ulcer model. Gastric secretion parameters (volume, pH, and total acidity) were also evaluted by the pylorus ligature model, and the mucus in the gastric content was determined. The antimicrobial activity against Helicobacter pylori of thymol was performed using the agar-well diffusion method. Thymol produced a dose dependent reduction (p < 0.01) on the total lesion area in the ethanol-induced ulcer model. This gastroprotection was also evaluated microscopically showing that the thymol at all doses decreased the loss of epithelial cells. The gastroprotective response caused by thymol (30 mg/kg) was signigicantly attenuated (P < 0.001) by intraperitoneal treatment of rats with indomethacin (a non-selective inhibitior of cyclo-oxygenase, 10 mg/kg) and glibenclamide (ATP-sensitive K channel blocker), but not by DL-Propargylglycine (PAG, a cystathionine-γ-lyase inhibitor) and Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME, a non-selective inhibitor of nitric oxide synthase). Thymol (30 and 100 mg/kg) also reduced the ulcer index (p < 0.05) and the total lesion area (p < 0.001) in the indomethacin and acetic-induced ulcer models, respectively. In the model of pylorus ligature, the treatment with thymol failed to significantly change the gastric secretion parameters. However, after treatment with thymol (30 and 100 mg/kg) there was a significant increase (p < 0.01) in mucus production. Thymol showed no antimicrobial activity against H. pilory in vitro. Collectively, the present results provide evidence that thymol displays gastroprotective actions on the acute and chronic ulcer models involving mechanisms as increased amount of mucus, prostaglandins, and ATP-sensitive K+ channels. / O timol, um monoterpeno fenólico derivado do cimeno encontrado abundantemente em óleos essenciais, é produzido por numerosas plantas aromáticas e especiarias tais como tomilho (Timus vulgaris L.), orégano (Origanum vulgaris L.) e Lippia alba (mill.). Diversos efeitos biológicos têm sido descritos para o timol tais como antioxidante, anti-inflamatório, anestésico local, antinoceptivo, cicatrizante e antibactericida. É descrita a aplicação do timol em ciências dos alimentos, herbicida e inseticidas. Além disso, óleos essenciais contendo timol tem sido usados pela medicina popular para tratar diversas desordens fisiológicas como gastrite, indigestão e dores estomacais. O presente estudo investigou ações gastroprotetoras do timol (10, 30 e 100 mg/kg, v.o.) em modelos de úlcera aguda induzida por indometacina e etanol, e crônica induzida por ácido acético em ratos. Alguns dos mecanismos subjacentes ao efeito gastroprotetor do timol foram investigados em modelo de úlcera induzida por etanol. Parâmetros da secreção gástrica (volume, pH; e acidez total) também foram avaliados pelo modelo de ligadura de piloro, e o conteúdo do muco gástrico foi determinado. A atividade contra Helicobacter pylori do timol foi realizada pelo método de difusão em ágar. O timol produziu efeito dose-dependente reduzindo (p < 0,01) a área total de lesão em modelo de úlcera induzida por etanol. Esta gastroproteção também foi avaliada microscopicamente mostrando que o timol, em todas as doses, diminuiu a perda das células epiteliais. A resposta gastroprotetora causada pelo timol (30 mg/kg) foi significativamente atenuada (p < 0,001) pelo tratamento intraperitoneal dos ratos com indometacina (um inibidor não-seletivo da ciclo-oxigenase, 10 mg/kg) e glibenclamida (bloqueador de canais para potássio sensíveis a ATP), mas não pela DL-Propargilglicina (PAG, inibidor da cistationina-γ-liase) ou Nw-nitro-L-arginina metil éster cloridrato (L-NAME, um inibidor não-seletivo da sintase do óxido nítrico). O timol (30 e 100 mg/kg) também reduziu o índice de úlcera (p < 0,05) e área total de lesão (p < 0,001) por indometacina e por ácido acético, respectivamente. Em modelo de ligadura de piloro, o tratamento com timol não alterou os parâmetros de secreção gástrica. No entanto, após o tratamento com o timol houve um aumento significativo (p < 0,01) na produção do muco. O timol não apresentou atividade contra H. pylori in vitro. Coletivamente, os resultados apresentados fornecem evidências de que o timol exibe ações gastroprotetoras sobre os modelos de úlceras agudas e crônicas envolvendo mecanismos como o aumento da quantidade de muco, prostaglandinas e canais para potássio sensíveis a ATP.
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Comparison of in Vitro Preconditioning Responses of Isolated Pig and Rabbit Cardiomyocytes: Effects of a Protein Phosphatase Inhibitor, FostriecinArmstrong, S. C., Kao, R., Gao, W., Shivell, L. C., Downey, J. M., Honkanen, R. E., Ganote, C. E. 01 January 1997 (has links)
Calcium tolerant pig and rabbit cardiomyocytes were isolated using retrograde aortic perfusion of nominally calcium-free collagenase. Preconditioning protocols used 1 or 3 x l0-min episodes of ischemic pelleting or pre-incubation with 100 μM adenosine, followed by a 15-min post-incubation and 180-240-min ischemic pelleting. Control cells were incubated and washed in parallel with the experimental groups. Injury was assessed by determination of cell morphology, trypan blue permeability following osmotic swelling, lactate and HPLC analysis of adenine nucleotides. Preconditioned pig cardiomyocytes had a reduced rate of ischemic contracture, but protection occurred without conservation of ATP. Preconditioned rabbit cardiomyocytes were protected without significant changes in rates of ischemic contracture or ATP depletion. Incubation of ischemic cells with the protein phosphatase inhibitor, fostriecin, at PP2A-selective concentrations (0.1-10 μM), mimicked preconditioning in both rabbit and pig cardiomyocytes. In rabbits, the K(ATP) channel blocker, 5-hydroxydecanoate (5-HD), did not block preconditioning or fostriecin protection. In the pig, 5-HD blocked both preconditioning and fostriecin protection, with return of the rates of ischemic contracture to control. However, 5-HD was an effective blocker of protection only in early ischemia. Fostriecin mimicked preconditioning in the rabbit and the early responses of the preconditioned pig. Preconditioning appears associated with protein phosphorylation in both the rabbit and the pig, but major pathways leading to protection may differ in the two species.
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The Impact of ROS Scavenging on NMDA and AMPA Receptor Whole Cell Currents in Pyramidal Neurons of the Anoxia Tolerant Western Painted TurtleDukoff, David 22 November 2013 (has links)
Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.
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The Impact of ROS Scavenging on NMDA and AMPA Receptor Whole Cell Currents in Pyramidal Neurons of the Anoxia Tolerant Western Painted TurtleDukoff, David 22 November 2013 (has links)
Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.
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Modification of ion channel auxiliary subunits in cardiac diseaseAl Katat, Aya 10 1900 (has links)
L’infarctus du myocarde (IM) survenant après l’obstruction de l’artère coronaire est la cause
principale des décès cardiovasculaires. Après l’IM, le coeur endommagé répond à l’augmentation
du stress hémodynamique avec une cicatrice et une hypertrophie dans la région non-infarcie du
myocarde. Dans la région infarcie, la cicatrice se forme grâce au dépôt du collagène. Pendant
formation de la cicatrice, les cardiomyocytes ventriculaires résidant dans la région non-infarcie
subissent une réponse hypertrophique après l’activation chronique due au système sympathique et
à l’angiotensine II. La cicatrisation préserve l’intégrité structurale du coeur et l'hypertrophie des
cardiomyocytes apporte un support ionotropique.
Le canal CaV1.2 joue un rôle dans la réponse hypertrophique après l’IM. L’activation du
CaV1.2 déclenche la signalisation dépendante de Ca2+ induisant l’hypertrophie. Cependant, il est
rapporté que l’ouverture des canaux potassiques (KATP) ATP sensitifs joue un rôle sélectif dans
l’expansion de la cicatrice après IM. Malgré leur expression dans les coeurs mâles, les KATP
fournissent une cardioprotection sexe dépendante limitant l’expansion de la cicatrice chez les
femelles.
L’administration de rapamycine aux rates ayant subi un infarctus produit l’expansion de la
cicatrice, soutenant la relation possible entre la cible de rapamycine, mTORC1 et les KATP dans la
cardioprotection sexe spécifique.
Effectivement, dans les cellules pancréatiques α, la signalisation mTORC1 était couplée à
l'activation du KATP. Cependant, le lien entre mTORC1 et les canaux KATP dans le coeur reste
inconnu. L'objectif de la thèse est d’examiner le rôle des canaux ioniques dans le remodelage
cardiaque post-IM, surtout des canaux calciques dans l'hypertrophie et d'élucider la relation entre
les KATP et mTORC1.
L’hypothèse première teste que l’hypertrophie médiée par le système sympathique des
cardiomyocytes ventriculaires des rats néonataux (NRCM) produit une augmentation de l’influx
calcique après une augmentation des sous-unités du CaV1.2. Le traitement de norépinéphrine (NE)
quadruple l’amplitude du courant calcique type L et double l’expression protéique des sous unités
de CaVα2δ1 et CaVβ3. L’hypertrophie des NRCM au NE s’associe à une augmentation de la
phosphorylation de la Kinase ERK 1/2. Le β1-bloqueur metoprolol et l’inhibiteur
ii
de ERK1/2 diminuent l’effet de NE sur CaVα2δ1. Cependant, l’augmentation de CaVβ3 et de la
réponse hypertrophique persiste. Ainsi, le signal β1-adrenergique à travers ERK augmente les
sous-unités CaVα2δ1 outre l’hypertrophie.
L’autre hypothèse examine la spécificité du sexe sur l’expansion cicatricielle médiée par
rapamycine et l’influence de mTOR sur l’expression de KATP. Rapamycin augmente la surface de
la cicatrice et inhibe la phosphorylation de mTOR chez les coeurs de femelles. Dans les coeurs des
deux sexes, la phosphorylation de mTOR et l’expression de KATP, Kir6.2 et SUR2A sont
similaires. Cependant, une grande inactivation de la tubérine et une faible expression de raptor
sont détectées chez les femelles. Le traitement à l’ester de phorbol des NRCM induit
l’hypertrophie, augmente la phosphorylation de p70S6K et l’expression SUR2A. Le prétraitement
par Rapamycine atténue chacune des réponses. Rapamycin démontre un patron d’expansion
cicatriciel sexe spécifique et une régulation de phosphorylation de mTOR dans IM. Aussi,
l’augmentation de SUR2A dans les NRCM traités par PDBu révèle une interaction entre mTOR
et KATP. / Myocardial infarction (MI) secondary to the obstruction of the coronary artery is the main cause
of cardiovascular death. Following MI, the damaged heart adapts to the increased hemodynamic
stress via formation of a scar and a hypertrophic response of ventricular cardiomyocytes in the
non-infarcted myocardium. In the infarcted region, a scar is formed via the rapid deposition of
collagen. With ongoing scar formation, ventricular cardiomyocytes in the non-infarcted
myocardium undergo a hypertrophic response secondary to the chronic activation by the
sympathetic system and angiotensin II. Collectively, scar formation and cardiomyocyte
hypertrophy preserve the structural integrity of the heart and provide inotropic support,
respectively.
CaV1.2 channels play a significant role in the hypertrophic response post-MI. Notably, the
activation of CaV1.2 channel triggers Ca2+-dependent signaling that induces hypertrophy. By
contrast, the opening of ATP-sensitive potassium (KATP) channels was shown to partake in
selective scar expansion following MI. Notwithstanding its expression in male hearts, KATP
channels endow a sex-dependent cardioprotection limiting scar expansion selectively in females.
Moreover, administration of the macrolide rapamycin to the infarcted female rat heart led to scar
expansion, supporting the possible relationship between the target of rapamycin, mTORC1 and
KATP channels in providing sex-specific cardioprotection. Indeed, in pancreatic-α cells, mTORC1
signaling was coupled to KATP channel activation. However, whether mTORC1 targets KATP
channels in the heart remains unknown. Thus, the AIM of the thesis was to explore the role of ion
channels in cardiac remodeling post-MI by specifically addressing the role of Ca channels in
cardiomyocyte hypertrophy and elucidate the potential relationship between KATP channels and
mTORC1 signaling.
The first study tested the hypothesis that hypertrophied neonatal rat ventricular
cardiomyocytes (NRVMs) following sympathetic stimulation translated to an increase in calcium
influx secondary to the augmentation of CaV1.2 channel subunits. NE treatment led to a 4-fold
increase of L-type Ca2+ peak current associated with a 2-fold upregulation of CaVα2δ1 and CaVβ3
protein subunits in hypertrophied NRVMs. The hypertrophic response of NNVMs to NE was
associated with the increased phosphorylation of extracellular regulated kinase (ERK1/2). The β1-blocker metoprolol and the ERK1/2 inhibitor suppressed NE-mediated protein upregulation of
CaVα2δ1 whereas CaVβ3 upregulation and the hypertrophic response persisted. Therefore,
sympathetic mediated β1-adrenergic signaling via ERK selectively upregulated the CaVα2δ1
subunit independent of NRVM hypertrophy.
The second study tested the hypothesis that rapamycin-mediated scar expansion was sexspecific and mTOR influenced KATP channel subunit expression. Rapamycin administration
translated to scar expansion and inhibited mTOR phosphorylation exclusively in females. In
normal adult male and female rat hearts, mTOR phosphorylation and protein levels of KATP
channel subunits Kir6.2 and SUR2A were similar. However, greater tuberin inactivation and
reduced raptor protein levels were detected in females. NRVMs treated with a phorbol ester
induced hypertrophy, increased p70S6K phosphorylation and SUR2A protein levels and
rapamycin pretreatment attenuated each response. Thus, rapamycin administration to MI rats
unmasked a sex-specific pattern of scar expansion and highlighted the disparate regulation of
mTOR phosphorylation. Moreover, rapamycin-dependent upregulation of SUR2A in PDButreated NRVMs revealed a novel interaction between mTOR and KATP channel subunit expression
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Über die differentielle Regulation von Ionenkanälen in spezifischen Nanodomänen atrialer und ventrikulärer Kardiomyozyten / Differential Regulation of Ion Channels in Specific Nanodomains of Atrial and Ventricular CardiomyocytesBrandenburg, Sören 29 June 2017 (has links)
No description available.
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