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Joseph F Cotten - One of the best experts on this subject based on the ideXlab platform.

  • halogenated ether alcohol and alkane anesthetics activate task 3 tandem pore Potassium Channels likely through a common mechanism
    Molecular Pharmacology, 2017
    Co-Authors: Anita Luethy, James D Boghosian, Rithu Srikantha, Joseph F Cotten
    Abstract:

    The TWIK-related acid-sensitive Potassium Channel 3 (TASK-3; KCNK9) tandem pore Potassium Channel Function is activated by halogenated anesthetics through binding at a putative anesthetic-binding cavity. To understand the pharmacologic requirements for TASK-3 activation, we studied the concentration–response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α -chloralose, 2,2,2-trichloroethanol [TCE], and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic-binding cavity as observed in a TASK-3 homology model. TASK-3 activation was quantified by Ussing chamber voltage clamp analysis. We mutagenized the residue Val-136, which lines the anesthetic-binding cavity, its flanking residues (132 to 140), and Leu-122, a pore-gating residue. The 2-halogenated ethanols activate wild-type TASK-3 with the following rank order efficacy (normalized current [95% confidence interval]): 2,2,2-tribromo-(267% [240–294]) > 2,2,2-trichloro-(215% [196–234]) > chloral hydrate (165% [161–176]) > 2,2-dichloro- > 2-chloro ≈ 2,2,2-trifluoroethanol > ethanol. Similarly, carbon tetrabromide (296% [245–346]), carbon tetrachloride (180% [163–196]), and 1,1,1,3,3,3-hexafluoropropanol (200% [194–206]) activate TASK-3, whereas the larger carbon tetraiodide and α -chloralose inhibit. Clinical agents activate TASK-3 with the following rank order efficacy: halothane (207% [202–212]) > isoflurane (169% [161–176]) > sevoflurane (164% [150–177]) > desflurane (119% [109–129]). Mutations at and near residue-136 modify TCE activation of TASK-3, and interestingly M159W, V136E, and L122D were resistant to both isoflurane and TCE activation. TASK-3 Function is activated by a multiple agents and requires a halogenated substituent between ∼30 and 232 cm 3 /mol volume with potency increased by halogen polarizeability. Val-136 and adjacent residues may mediate anesthetic binding and stabilize an open state regulated by pore residue Leu-122. Isoflurane and TCE likely share commonalities in their mechanism of TASK-3 activation.

  • breathing stimulant compounds inhibit task 3 Potassium Channel Function likely by binding at a common site in the Channel pore
    Molecular Pharmacology, 2015
    Co-Authors: Rikki H Chokshi, Aaron T Larsen, Brijesh Bhayana, Joseph F Cotten
    Abstract:

    Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ′-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K2P) Potassium Channel Function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118–128 and 228–248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 Potassium Channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; Channel Function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 Function by binding at a common site within the Channel intracellular pore region, although binding outside the Channel pore cannot yet be excluded.

  • the ventilatory stimulant doxapram inhibits task tandem pore k2p Potassium Channel Function but does not affect minimum alveolar anesthetic concentration
    Anesthesia & Analgesia, 2006
    Co-Authors: Joseph F Cotten, Bharat Keshavaprasad, Michael J. Laster, Edmond I. Eger, Susan Connolly Yost
    Abstract:

    TWIK-related acid-sensitive K + -1 (TASK-1 [KCNK3]) and TASK-3 (KCNK9) are tandem pore (K 2P ) Potassium (K) Channel subunits expressed in carotid bodies and the brainstem. Acidic pH values and hypoxia inhibit TASK-1 and TASK-3 Channel Function, and halothane enhances this Function. These Channels have putative roles in ventilatory regulation and volatile anesthetic mechanisms. Doxapram stimulates ventilation through an effect on carotid bodies, and we hypothesized that stimulation might result from inhibition of TASK-1 or TASK-3 K Channel Function. To address this, we expressed TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric, and TASK-1/TASK-3 chimeric K Channels in Xenopus oocytes and studied the effects of doxapram on their Function. Doxapram inhibited TASK-1 (half-maximal effective concentration [EC 50 ], 410 nM), TASK-3 (ECso, 37 μM), and TASK-1/TASK-3 heterodimeric Channel Function (ECso, 9 μM). Chimera studies suggested that the carboxy terminus of TASK-1 is important for doxapram inhibition. Other K 2P Channels required significantly larger concentrations for inhibition. To test the role of TASK-1 and TASK-3 in halothane-induced immobility, the minimum alveolar anesthetic concentration for halothane was determined and found unchanged in rats receiving doxapram by IV infusion. Our data indicate that TASK-1 and TASK-3 do not play a role in mediating the immobility produced by halothane, although they are plausible molecular targets for the ventilatory effects of doxapram.

C J Garland - One of the best experts on this subject based on the ideXlab platform.

  • statins and selective inhibition of rho kinase protect small conductance calcium activated Potassium Channel Function k ca 2 3 in cerebral arteries
    PLOS ONE, 2012
    Co-Authors: Alister J. Mcneish, Graeme S. Cottrell, Francesc Jimenezaltayo, C J Garland
    Abstract:

    Background: In rat middle cerebral and mesenteric arteries the KCa2.3 component of endothelium-dependent hyperpolarization (EDH) is lost following stimulation of thromboxane (TP) receptors, an effect that may contribute to the endothelial dysFunction associated with cardiovascular disease. In cerebral arteries, KCa2.3 loss is associated with NO synthase inhibition, but is restored if TP receptors are blocked. The Rho/Rho kinase pathway is central for TP signalling and statins indirectly inhibit this pathway. The possibility that Rho kinase inhibition and statins sustain KCa2.3 hyperpolarization was investigated in rat middle cerebral arteries (MCA). Methods: MCAs were mounted in a wire myograph. The PAR2 agonist, SLIGRL was used to stimulate EDH responses, assessed by simultaneous measurement of smooth muscle membrane potential and tension. TP expression was assessed with rt-PCR and immunofluorescence. Results: Immunofluorescence detected TP in the endothelial cell layer of MCA. Vasoconstriction to the TP agonist, U46619 was reduced by Rho kinase inhibition. TP receptor stimulation lead to loss of KCa2.3 mediated hyperpolarization, an effect that was reversed by Rho kinase inhibitors or simvastatin. KCa2.3 activity was lost in L-NAME-treated arteries, but was restored by Rho kinase inhibition or statin treatment. The restorative effect of simvastatin was blocked after incubation with geranylgeranyl-pyrophosphate to circumvent loss of isoprenylation. Conclusions: Rho/Rho kinase signalling following TP stimulation and L-NAME regulates endothelial cell KCa2.3 Function. The ability of statins to prevent isoprenylation and perhaps inhibit of Rho restores/protects the input of KCa2.3 to EDH in the MCA, and represents a beneficial pleiotropic effect of statin treatment.

William M. Armstead - One of the best experts on this subject based on the ideXlab platform.

  • Vasopressin-Induced Protein Kinase C–Dependent Superoxide Generation Contributes to ATP-Sensitive Potassium Channel but Not Calcium-Sensitive Potassium Channel Function Impairment After Brain Injury
    2015
    Co-Authors: William M. Armstead
    Abstract:

    Background and Purpose—Pial artery dilation in response to activators of the ATP-sensitive K1 (KATP) and calcium-sensitive K1 (KCa) Channels is impaired after fluid percussion brain injury (FPI). Vasopressin, when coadministered with the KATP and KCa Channel agonists cromakalim and NS1619 in a concentration approximating that observed in cerebrospinal fluid (CSF) after FPI, blunted KATP and KCa Channel–mediated vasodilation. Vasopressin also contributes to impaired KATP and KCa Channel vasodilation after FPI. In addition, protein kinase C (PKC) activation generates superoxide anion (O22), which in turn contributes to KATP Channel impairment after FPI. We tested whether vasopressin generates O22 in a protein kinase C (PKC)-dependent manner, which could link vasopressin release to impaired KATP and KCa Channel–induced pial artery dilation after FPI. Methods—Injury of moderate severity (1.9 to 2.1 atm) was produced with the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase–inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O22 generation. Results—Under sham injury conditions, topical vasopressin (40 pg/mL, the concentration present in CSF after FPI) increased superoxide dismutase–inhibitable NBT reduction from 161 to 2364 pmol/mm2. Chelerythrine (1027 mol/L, a PKC inhibitor) blunted such NBT reduction (161 to 962 pmol/mm2), whereas the vasopressin antagonist l-(b-mercapto-b,b-cyclopentamethylene propionic acid)2-(o-methyl)-Tyr-arginine vasopressin (MEAVP) blocked NB

  • vasopressin induced protein kinase c dependent superoxide generation contributes to atp sensitive Potassium Channel but not calcium sensitive Potassium Channel Function impairment after brain injury
    Stroke, 2001
    Co-Authors: William M. Armstead
    Abstract:

    Background and Purpose—Pial artery dilation in response to activators of the ATP-sensitive K+ (KATP) and calcium-sensitive K+ (KCa) Channels is impaired after fluid percussion brain injury (FPI). Vasopressin, when coadministered with the KATP and KCa Channel agonists cromakalim and NS1619 in a concentration approximating that observed in cerebrospinal fluid (CSF) after FPI, blunted KATP and KCa Channel–mediated vasodilation. Vasopressin also contributes to impaired KATP and KCa Channel vasodilation after FPI. In addition, protein kinase C (PKC) activation generates superoxide anion (O2−), which in turn contributes to KATP Channel impairment after FPI. We tested whether vasopressin generates O2− in a protein kinase C (PKC)-dependent manner, which could link vasopressin release to impaired KATP and KCa Channel–induced pial artery dilation after FPI. Methods—Injury of moderate severity (1.9 to 2.1 atm) was produced with the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial win...

Alister J. Mcneish - One of the best experts on this subject based on the ideXlab platform.

  • Statins and Selective Inhibition of Rho Kinase Protect Small Conductance Calcium-Activated Potassium Channel Function (KCa2.3) in Cerebral Arteries
    2016
    Co-Authors: Alister J. Mcneish, Francesc Jimenez-altayo, Graeme S. Cottrell, Christopher J. Garl
    Abstract:

    Background: In rat middle cerebral and mesenteric arteries the KCa2.3 component of endothelium-dependent hyperpolarization (EDH) is lost following stimulation of thromboxane (TP) receptors, an effect that may contribute to the endothelial dysFunction associated with cardiovascular disease. In cerebral arteries, KCa2.3 loss is associated with NO synthase inhibition, but is restored if TP receptors are blocked. The Rho/Rho kinase pathway is central for TP signalling and statins indirectly inhibit this pathway. The possibility that Rho kinase inhibition and statins sustain KCa2.3 hyperpolarization was investigated in rat middle cerebral arteries (MCA). Methods: MCAs were mounted in a wire myograph. The PAR2 agonist, SLIGRL was used to stimulate EDH responses, assessed by simultaneous measurement of smooth muscle membrane potential and tension. TP expression was assessed with rt-PCR and immunofluorescence. Results: Immunofluorescence detected TP in the endothelial cell layer of MCA. Vasoconstriction to the TP agonist, U46619 was reduced by Rho kinase inhibition. TP receptor stimulation lead to loss of KCa2.3 mediated hyperpolarization, an effect that was reversed by Rho kinase inhibitors or simvastatin. KCa2.3 activity was lost in L-NAME-treated arteries, but was restored by Rho kinase inhibition or statin treatment. The restorative effect of simvastatin was blocked after incubation with geranylgeranyl-pyrophosphate to circumvent loss of isoprenylation

  • statins and selective inhibition of rho kinase protect small conductance calcium activated Potassium Channel Function k ca 2 3 in cerebral arteries
    PLOS ONE, 2012
    Co-Authors: Alister J. Mcneish, Graeme S. Cottrell, Francesc Jimenezaltayo, C J Garland
    Abstract:

    Background: In rat middle cerebral and mesenteric arteries the KCa2.3 component of endothelium-dependent hyperpolarization (EDH) is lost following stimulation of thromboxane (TP) receptors, an effect that may contribute to the endothelial dysFunction associated with cardiovascular disease. In cerebral arteries, KCa2.3 loss is associated with NO synthase inhibition, but is restored if TP receptors are blocked. The Rho/Rho kinase pathway is central for TP signalling and statins indirectly inhibit this pathway. The possibility that Rho kinase inhibition and statins sustain KCa2.3 hyperpolarization was investigated in rat middle cerebral arteries (MCA). Methods: MCAs were mounted in a wire myograph. The PAR2 agonist, SLIGRL was used to stimulate EDH responses, assessed by simultaneous measurement of smooth muscle membrane potential and tension. TP expression was assessed with rt-PCR and immunofluorescence. Results: Immunofluorescence detected TP in the endothelial cell layer of MCA. Vasoconstriction to the TP agonist, U46619 was reduced by Rho kinase inhibition. TP receptor stimulation lead to loss of KCa2.3 mediated hyperpolarization, an effect that was reversed by Rho kinase inhibitors or simvastatin. KCa2.3 activity was lost in L-NAME-treated arteries, but was restored by Rho kinase inhibition or statin treatment. The restorative effect of simvastatin was blocked after incubation with geranylgeranyl-pyrophosphate to circumvent loss of isoprenylation. Conclusions: Rho/Rho kinase signalling following TP stimulation and L-NAME regulates endothelial cell KCa2.3 Function. The ability of statins to prevent isoprenylation and perhaps inhibit of Rho restores/protects the input of KCa2.3 to EDH in the MCA, and represents a beneficial pleiotropic effect of statin treatment.

David D. Gutterman - One of the best experts on this subject based on the ideXlab platform.

  • Redox Modulation of Vascular Tone Focus of Potassium Channel Mechanisms of Dilation
    2016
    Co-Authors: Kathy K. Griendling, David D. Gutterman, Hiroto Miura, Yanping Liu
    Abstract:

    Abstract—Opening of Potassium Channels on vascular smooth muscle cells with resultant hyperpolarization plays a central role in several mechanisms of vasodilation. For example, in the arteriolar circulation where tissue perfusion is regulated, there is an endothelial derived hyperpolarizing factor that opens vascular smooth muscle calcium-activated Potassium Channels, eliciting dilation. Metabolic vasodilation involves the opening of sarcolemmal ATP-sensitive Potassium Channels. Adrenergic dilation as well as basal vasomotor tone in several vascular beds depend upon voltage-dependent Potassium Channels in smooth muscle. Thus hyperpolarization through Potassium Channel opening is a fundamental mechanism for vasodilation. Disease states such as coronary atherosclerosis and its risk factors are associated with elevated levels of reactive oxygen (ROS) and nitrogen species that have well-defined inhibitory effects on nitric oxide–mediated vasodilation. Effects of ROS on hyperpolarization mechanisms of dilation involving opening of Potassium Channels are less well understood but are very important because hyperpolarization-mediated dilation often compensates for loss of other dilator mechanisms. We review the effect of ROS on Potassium Channel Function in the vasculature. Depending on the oxidative species, ROS can activate, inhibit, or leave unaltered Potassium Channel Function in blood vessels. Therefore, discerning the activity of enzymes regulating production or degradation of ROS is important when assessing tissue perfusion in health and disease. (Arterioscler Thromb Vasc Biol. 2005;25:671-678.) Key Words: hyperpolarization factor reactive oxygen species antioxidant vasodilatio

  • ebselen reduces nitration and restores voltage gated Potassium Channel Function in small coronary arteries of diabetic rats
    American Journal of Physiology-heart and Circulatory Physiology, 2007
    Co-Authors: Aaron H Bubolz, David D. Gutterman, Brandon T Larsen, Yanping Liu
    Abstract:

    Small coronary arteries (SCA) from diabetic rats exhibit enhanced peroxynitrite (ONOO−) formation and concurrent impairment of voltage-dependent Potassium (Kv) Channel Function. However, it is uncl...

  • oxidative stress and Potassium Channel Function
    Clinical and Experimental Pharmacology and Physiology, 2002
    Co-Authors: Yanping Liu, David D. Gutterman
    Abstract:

    1. Modulation of K+ Channel activities by cellular oxidative stress has emerged as a significant determinant of vasomotor Function in multiple disease states. 2. Evidence from in vitro and in vivo studies suggest that superoxide (O2-) and hydrogen peroxide (H2O2) enhance BKCa Channel activity in rat and cat cerebral arterioles; however, activity is decreased by peroxynitrite (ONOO-) in rat cerebral arteries. The mechanisms of changes in BKCa Channel properties are not fully understood and may involve oxidation of cysteine residues that are located in the cell membranes. 3. Studies further suggest that O2- increases KATP Channel activity in guinea-pig cardiac myocytes, but decreases opening in cerebral vasculature. Both H2O2 and ONOO- enhance KATP Channel activity in the myocardium and in coronary, renal, mesenteric and cerebral vascular beds. Alteration of KATP Channels by free radicals may be due to oxidation of SH groups or changes in the cytosolic concentration of ATP. 4. It does appear that O2- produced by either reaction of xanthine and xanthine oxidase or elevated levels of glucose reduces Kv Channel activity and the impairments can be partially restored by free radical scavengers, superoxide dismutase and catalase. 5. Thus, redox modulation of Potassium Channel activity is an important mechanism regulating cell vascular smooth muscle membrane potential.