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Fernando Q. Cunha - One of the best experts on this subject based on the ideXlab platform.

  • ATP-sensitive Potassium Channel Blockage Attenuates Cisplatin-Induced Renal Damage
    Kidney & blood pressure research, 2007
    Co-Authors: Andréa G.c. Flávio, Fernando Q. Cunha, Heloísa D. Colletta Francescato, Telma De Jesus Soares, Roberto Silva Costa, Fernando Barbosa Júnior, Terezila Machado Coimbra
    Abstract:

    Background: Cisplatin-induced renal damage was associated with an inflammatory process. ATP-sensitive Potassium Channels can be involved in neutrophil migration. This study evaluate

  • the atp sensitive Potassium Channel blocker glibenclamide prevents renal ischemia reperfusion injury in rats
    Kidney International, 2005
    Co-Authors: Kenia Pompermayer, Jamil Assreuy, Danielle G. Souza, Giovanna G. Lara, Kátia D. Silveira, Geovanni Dantas Cassali, Anderson A. Andrade, Cláudio A. Bonjardim, Kátia Tomagnini Passaglio, Fernando Q. Cunha
    Abstract:

    The ATP-sensitive Potassium Channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats. Background Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. Adenosine-triphosphate (ATP)-sensitive Potassium (K ATP ) Channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a K ATP Channel blocker, in renal I/R injury in rats. Methods The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-10] 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na + , and K + levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia. Results Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-α levels and nuclear factor-κB (NF-κB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours. Conclusion Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.

  • The Role of ATP-sensitive Potassium Channels in Neutrophil Migration and Plasma Exudation
    The Journal of pharmacology and experimental therapeutics, 2002
    Co-Authors: José Eduardo Da Silva-santos, Fernando Q. Cunha, Maria Cláudia Santos-silva, Jamil Assreuy
    Abstract:

    Neutrophil activation and migration during an inflammatory response is preceded or accompanied by plasma membrane electrical changes. Besides changes in calcium currents, neutrophils have a high permeability to Potassium, mainly through Potassium Channels. However, the significance of Potassium Channels in neutrophil physiology is still unclear. Here, we show that the treatment of rats with the ATP-sensitive Potassium Channel blocker glibenclamide (4, 20, or 40 micromol/kg) dose dependently decreased carrageenan-, N-formyl-methionyl-leucyl-phenylalanine (fMLP)-, and lipopolysaccharide-induced neutrophil influx and fluid leakage into the interpleural space. On the other hand, minoxidil (an ATP-sensitive Potassium Channel opener; 25, 50, and 100 micromol/kg) increased both neutrophil influx and fluid leakage induced by a submaximal dose of carrageenan. In addition, in vitro human neutrophil chemotaxis induced by leukotriene B4 or fMLP (both 1 microM) was fully blocked by glibenclamide (10, 30, and 100 microM) or tetraethylammonium (a nonselective Potassium Channel blocker; 1, 3, and 10 mM). Thus, our results disclose the possibility that ATP-sensitive Potassium Channels may have a role in neutrophil migration and chemotaxis and plasma exudation in the inflammatory response.

Brian Orourke - One of the best experts on this subject based on the ideXlab platform.

  • single Channel properties of the romk pore forming subunit of the mitochondrial atp sensitive Potassium Channel
    International Journal of Molecular Sciences, 2019
    Co-Authors: Michal Laskowski, Monika żochowska, Justyna Kalisz, Bartlomiej Augustynek, Brian Orourke, Adam Szewczyk, Piotr Bednarczyk, Bogusz Kulawiak
    Abstract:

    An increased flux of Potassium ions into the mitochondrial matrix through the ATP-sensitive Potassium Channel (mitoKATP) has been shown to provide protection against ischemia-reperfusion injury. Recently, it was proposed that the mitochondrial-targeted isoform of the renal outer medullary Potassium Channel (ROMK) protein creates a pore-forming subunit of mitoKATP in heart mitochondria. Our research focuses on the properties of mitoKATP from heart-derived H9c2 cells. For the first time, we detected single-Channel activity and describe the pharmacology of mitoKATP in the H9c2 heart-derived cells. The patch-clamping of mitoplasts from wild type (WT) and cells overexpressing ROMK2 revealed the existence of a Potassium Channel that exhibits the same basic properties previously attributed to mitoKATP. ROMK2 overexpression resulted in a significant increase of mitoKATP activity. The conductance of both Channels in symmetric 150/150 mM KCl was around 97 ± 2 pS in WT cells and 94 ± 3 pS in cells overexpressing ROMK2. The Channels were inhibited by 5-hydroxydecanoic acid (a mitoKATP inhibitor) and by Tertiapin Q (an inhibitor of both the ROMK-type Channels and mitoKATP). Additionally, mitoKATP from cells overexpressing ROMK2 were inhibited by ATP/Mg2+ and activated by diazoxide. We used an assay based on proteinase K to examine the topology of the Channel in the inner mitochondrial membrane and found that both termini of the protein localized to the mitochondrial matrix. We conclude that the observed activity of the Channel formed by the ROMK protein corresponds to the electrophysiological and pharmacological properties of mitoKATP.

  • mitochondrial romk Channel is a molecular component of mitokatp
    Circulation Research, 2012
    Co-Authors: Brian D Foster, Alice S Ho, Agnieszka Sidor, Anders O Garlid, Keith D. Garlid, Jasma Rucker, Ling Chen, Brian Orourke
    Abstract:

    Rationale:Activation of the mitochondrial ATP-sensitive Potassium Channel (mitoKATP) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown. Objective:To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K+ Channel underlying mitoKATP. Methods and Results:Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the Channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoKATP activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA—mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mito...

  • a mitochondrial atp sensitive Potassium Channel from the romk family
    Biophysical Journal, 2011
    Co-Authors: Brian D Foster, Alice Ho, Anders O Garlid, Keith D. Garlid, Jasma Rucker, Marjan Gucek, Robert Cole, Brian Orourke
    Abstract:

    Mitochondrial Potassium modulates mitochondrial bioenergetics, and the existence of resident Potassium Channels in the mitochondrial inner membrane has been amply validated, yet the pore-forming subunits of these Channels remain unidentified. We therefore undertook an in-depth proteomic analysis of the mitochondria employing repeated fractionation at the organellar, protein, and peptide levels. Briefly, density-purified inner membranes were extracted with 1% lauryl maltoside, and fractionated by sucrose gradient centrifugation. Each fraction was digested with trypsin and subjected to strong-cation exchange HPLC prior to reversed-phase LC-coupled tandem mass spectrometry. 964 proteins were identified, of which 684 were classified as mitochondrial in UniProtKB and/or MitoCarta databases. From the inner membrane fraction, the ROMK (renal outer-medullary Potassium) Channel, was identified by 6 spectra matching two overlapping peptides. Matches were statistically validated at >95%. Subsequent bioinformatic analysis using TargetP and PSORT detected a mitochondrial localization sequence near the N-terminus of ROMK. Mitochondrial localization was confirmed in neonatal rat ventricular myocytes (NRVM) transiently transfected with truncation mutants of human ROMK isoforms fused with green fluorescence protein (GFP) or V5-tag at the C-terminus of the Channel. Imaging by 2-photon microscopy showed that predicted targeting presequences confer colocalization of GFP with tetramethylrhodamine methyl ester (TMRM) staining of the mitochondria. Furthermore, to determine whether a ROMK isoform might mediate mitochondrial Potassium uptake, we measured K+-dependent swelling in rat heart mitochondria. In preliminary studies, cromakalim-induced mitochondrial swelling of liver mitochondria was abrogated by Tertiapin-Q, a high-affinity ROMK Channel toxin, with half-maximal inhibition in the picomolar range. Reverse-Transcription/Polymerase Chain Reaction (RT-PCR) identified 3 isoforms (ROMK1, ROMK2 &ROMK6) in the adult rat hearts and NRVMs. The findings support an isoform of ROMK as a candidate for the pore-forming subunit of mitoKATP.

S.a. Greenfield - One of the best experts on this subject based on the ideXlab platform.

  • Psychopharmacological evidence for a role of the ATP-sensitive Potassium Channel in the substantia nigra of the rat
    Neuropharmacology, 1991
    Co-Authors: D. Lévesque, S.a. Greenfield
    Abstract:

    Abstract Recent evidence suggests that an ATP-sensitive Potassium Channel is present in the brain. From ligand binding studies it has been inferred that this relatively unfamiliar Channel is particularly densely distributed in areas associated with motor control. The aim of this study was thus to examine whether pharmacological agents, specific for the ATP-sensitive Channel in other tissues, had effects on a particular motor behaviour associated with the substantia nigra: the effects of microinfusion into the substantia nigra of diverse Potassium Channel blocking agents were examined on the initiation of circling behaviour in the normal rat. Application of tolbutamide and quinine, but not tetraethylammonium, caused circling behaviour in the presence of a systemically administered challenge of amphethamine. However, in the case of application of tolbutamide, the direction of circling was dependent on whether the site of infusion was in the pars compacta or pars reticula. On the other hand, the effects of quinine were the same, irrespective of site of application within the substantia nigra, i.e. in the same direction, as seen after injection of tolbutamide into the pars compacta. Quinine and tolbutamide are different chemical species which both, unlike tetraethylammonium, principally block the ATP-sensitive Potassium Channel. It therefore seems that an ATP-sensitive Potassium Channel in the pars compacta cells of the substantia nigra could play a selective role in modifying the net activity of the nigrostriatal pathway and hence the control of movement.

Hai Wang - One of the best experts on this subject based on the ideXlab platform.

  • Activation of mitochondrial ATP-sensitive Potassium Channels improves rotenone-related motor and neurochemical alterations in rats.
    The international journal of neuropsychopharmacology, 2005
    Co-Authors: Yong Yang, Xing Liu, Yan Long, Fang Wang, Jian-hua Ding, Su-yi Liu, Ye-hong Sun, Hong-hong Yao, Hai Wang
    Abstract:

    Our previous studies revealed that activation of mitochondrial ATP-sensitive Potassium Channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive Potassium-Channel opener, and diazoxide, a selective mitochondrial ATP-sensitive Potassium-Channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxy-decanoate, a selective mitochondrial ATP-sensitive Potassium-Channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive Potassium Channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive Potassium Channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.

  • Systematic administration of iptakalim, an ATP-sensitive Potassium Channel opener, prevents rotenone-induced motor and neurochemical alterations in rats.
    Journal of neuroscience research, 2005
    Co-Authors: Yong Yang, Xing Liu, Yan Long, Fang Wang, Jian-hua Ding, Su-yi Liu, Ye-hong Sun, Hong-hong Yao, Hai Wang
    Abstract:

    Our previous studies revealed that iptakalim, a novel ATP-sensitive Potassium Channel opener, has a significant neuroprotective function against ischemia in vivo or rotenone-induced neurotoxicity in vitro. To investigate the potential pharmaceutical benefit of ATP-sensitive Potassium Channel openers on neurodegenerative diseases, we studied the effects of iptakalim and diazoxide, a selective mitochondrial ATP-sensitive Potassium Channel opener, on the rotenone-induced nigrostriatal degeneration in rats. Iptakalim (1.5 mg/kg/day, orally) or diazoxide (1.5 mg/kg/day, orally) alone was administered to rats for 3 days, and then for 4 weeks was used daily with an injection of rotenone (2.5 mg/kg/day, subcutaneously) 1 hr later each time. The results showed that rotenone-infused rats exhibited parkinsonian symptoms and had dopamine depletion in the striatum and substantia nigra. Pretreatment with iptakalim or diazoxide prevented rotenone-induced catalepsy and the reduction of striatum dopamine contents. Moreover, iptakalim and diazoxide reduced the enzymatic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. These neuroprotective effects of iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive Potassium Channel blocker. In conclusion, our data suggested that mitochondrial ATP-sensitive Potassium Channels might play a key role in preventing both parkinsonian symptoms and neurochemistry alterations induced by rotenone in rats. The selective activation of mitochondrial ATP-sensitive Potassium Channels may provide a new therapeutic strategy for prevention and treatment of neurodegenerative disorders such as Parkinson's disease.

Y Kasuya - One of the best experts on this subject based on the ideXlab platform.

  • Reduction in ATP-sensitive Potassium Channel-mediated antinociception in diabetic mice.
    Psychopharmacology, 1994
    Co-Authors: J Kamei, N Kawashima, M Narita, T Suzuki, M Misawa, Y Kasuya
    Abstract:

    To test our hypothesis that the abnormally low efficacy of mu-opioid agonists in diabetic mice may be due to functional changes in ATP-sensitive Potassium Channels, we evaluated the effects of cromakalim on the tail-flick latencies in diabetic and non-diabetic mice. Anti nociceptive effects of morphine (10 micrograms, ICV) in diabetic mice were significantly less than that in non-diabetic mice. Morphine-induced antinociception in non-diabetic mice was antagonized by pretreatment with glibenclamide (30 micrograms, ICV), an ATP-sensitive Potassium Channel blocker. Cromakalim (0.3 and 1 micrograms, ICV) produced significant, dose-dependent antinociception in non-diabetic mice, which was significantly reduced by pretreatment with glibenclamide. However, cromakalim did not markedly affect the tail-flick latencies in diabetic mice, even at higher doses (3 micrograms, ICV). On the other hand, [D-Pen2,5]enkephaline (DPDPE, 5 micrograms, ICV), a selective delta-opioid receptor agonist, produced significant antinociception in both diabetic and non-diabetic mice. Since pretreatment with glibenclamide significantly reduced the antinociceptive effect of DPDPE in non-diabetic mice but not in diabetic mice, delta-opioid receptor-mediated antinociception in diabetic mice may be independent of Potassium Channels. These results suggest that dysfunction of ATP-sensitive Potassium Channels may contribute to the demonstrated poor antinociceptive response of diabetic mice to mu-opioid agonists.

  • Reduction in ATP-sensitive Potassium Channel-mediated antinociception in diabetic mice
    Psychopharmacology, 1994
    Co-Authors: Junzo Kamei, N Kawashima, M Narita, T Suzuki, M Misawa, Y Kasuya
    Abstract:

    To test our hypothesis that the abnormally low efficacy of μ-opioid agonists in diabetic mice may be due to functional changes in ATP-sensitive Potassium Channels, we evaluated the effects of cromakalim on the tail-flick latencies in diabetic and non-diabetic mice. Anti nociceptive effects of morphine (10 µg, ICV) in diabetic mice were significantly less than that in non-diabetic mice. Morphine-induced antinociception in non-diabetic mice was antagonized by pretreatment with glibenclamide (30 µg, ICV), an ATP-sensitive Potassium Channel blocker. Cromakalim (0.3 and 1 µg, ICV) produced significant, dose-dependent antinociception in non-diabetic mice, which was significantly reduced by pretreatment with glibenclamide. However, cromakalim did not markedly affect the tail-flick latencies in diabetic mice, even at higher doses (3 µg, ICV). On the other hand, [D-Pen2,5]enkephaline (DPDPE, 5 µg, ICV), a selective δ-opioid receptor agonist, produced significant antinociception in both diabetic and non-diabetic mice. Since pretreatment with glibenclamide significantly reduced the antinociceptive effect of DPDPE in non-diabetic mice but not in diabetic mice, δ-opioid receptor-mediated antinociception in diabetic mice may be independent of Potassium Channels. These results suggest that dysfunction of ATP-sensitive Potassium Channels may contribute to the demonstrated poor antinociceptive response of diabetic mice to μ-opioid agonists.