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bk channel inhibitor

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https://www.readbyqxmd.com/read/28732502/chronic-glucocorticoid-exposure-activates-bk-nlrp1-signal-involving-in-hippocampal-neuron-damage
#1
Biqiong Zhang, Yaodong Zhang, Wenning Wu, Tanzhen Xu, Yanyan Yin, Junyan Zhang, Dake Huang, Weizu Li
BACKGROUND: Neuroinflammation mediated by NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome plays an important role in many neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our previous studies showed that chronic glucocorticoid (GC) exposure increased brain inflammation via NLRP1 inflammasome and induce neurodegeneration. However, little is known about the mechanism of chronic GC exposure on NLRP1 inflammasome activation in hippocampal neurons...
July 21, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28686356/relaxing-responses-to-hydrogen-peroxide-and-nitric-oxide-in-human-pericardial-resistance-arteries-stimulated-with-endothelin-1
#2
Thomas M Leurgans, Maria Bloksgaard, Akhmadjon Irmukhamedov, Lars P Riber, Jo G R De Mey
In human pericardial resistance arteries, effects of the endothelium-dependent vasodilator bradykinin are mediated by NO during contraction induced by K(+) or the TxA2 analogue U46619 and by H2 O2 during contraction by endothelin-1 (ET-1), respectively. We tested the hypotheses that ET-1 reduces relaxing effects of NO and increases those of H2 O2 in resistance artery smooth muscle of patients with cardiovascular disease. Arterial segments, dissected from the parietal pericardium of 39 cardiothoracic surgery patients, were studied by myography during amplitude-matched contractions induced by K(+) , the TXA2 analogue U46619 or ET-1...
July 7, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28641545/role-of-bradykinin-in-the-regulation-of-endothelial-nitric-oxide-synthase-expression-by-cardiovascular-drugs
#3
Jin Bo Su
NO produced by eNOS plays important roles in the cardiovascular system. Alterations in eNOS activity and expression occur in various cardiovascular disorders and eNOS constitutes a therapeutic target. In addition to posttranslational modifications of eNOS that affect eNOS activity, transcriptional and post-transcriptional regulation of eNOS expression also controlls eNOS-derived NO production. Bradykinin is an important determinant of vascular function and participates in the regulation of eNOS activity and expression...
June 22, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28550175/chronic-hypoxia-attenuates-the-vasodilator-efficacy-of-protein-kinase-g-in-fetal-and-adult-ovine-cerebral-arteries
#4
Richard B Thorpe, Margaret C Hubbell, Jinjutha Silpanisong, James M Williams, William J Pearce
Long-term hypoxia (LTH) attenuates nitric oxide (NO) induced vasorelaxation in ovine middle cerebral arteries. Because cGMP-dependent protein kinase (PKG) is an important mediator of NO signaling in vascular smooth muscle, we tested the hypothesis that LTH diminishes the ability of PKG to interact with target proteins and cause vasorelaxation. Prominent among proteins that regulate vascular tone is the large conductance calcium-sensitive potassium (BK) channel, which is a substrate for PKG and is responsive to phosphorylation on multiple serine/threonine residues...
May 26, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28481415/large-conductance-ca-2-activated-k-channel-activation-by-apical-p2y-receptor-agonists-requires-hydrocortisone-in-differentiated-airway-epithelium
#5
Nathan A Zaidman, Angela Panoskaltsis-Mortari, Scott M O'Grady
KEY POINTS: Hydrocortisone (HC) is required for activation of large-conductance Ca(2+) -activated K(+) current (BK) by purinergic receptor agonists. HC reduces insertion of the stress-regulated exon (STREX) in the KCNMA1 gene, permitting protein kinase C (PKC)-dependent channel activation. Overlapping and unique purinergic signalling regions exist at the apical border of differentiated surface cells. BK channels localize in the cilia of surface cells. ABSTRACT: In the present study we investigated the role of hydrocortisone (HC) on uridine-5'-triphosphate (UTP)-stimulated ion transport in differentiated, pseudostratified epithelia derived from normal human bronchial basal cells...
July 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28294531/tyrphostin-ag556-increases-the-activity-of-large-conductance-ca-2-activated-k-channels-by-inhibiting-epidermal-growth-factor-receptor-tyrosine-kinase
#6
Yan Wang, Hai-Ying Sun, Ying-Guang Liu, Zheng Song, Gang She, Guo-Sheng Xiao, Yan Wang, Gui-Rong Li, Xiu-Ling Deng
The present study was designed to investigate whether large conductance Ca(2+) -activated K(+) (BK) channels were regulated by epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase. BK current and channel tyrosine phosphorylation level were measured in BK-HEK 293 cells expressing both functional α-subunits and the auxiliary β1-subunits using electrophysiology, immunoprecipitation and Western blotting approaches, respectively, and the function of rat cerebral basilar arteries was determined with a wire myography system...
March 14, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28289184/renal-tubular-ubiquitin-protein-ligase-nedd4-2-is-required-for-renal-adaptation-during-long-term-potassium-depletion
#7
Lama Al-Qusairi, Denis Basquin, Ankita Roy, Renuga Devi Rajaram, Marc P Maillard, Arohan R Subramanya, Olivier Staub
Adaptation of the organism to potassium (K(+)) deficiency requires precise coordination among organs involved in K(+) homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K(+) retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na(+)/Cl(-) cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K(+) restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout (Nedd4L(Pax8/LC1) ) mice exhibited severe hypokalemia and urinary K(+) wasting...
March 13, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28283888/kinin-receptors-sensitize-trpv4-channel-and-induce-mechanical-hyperalgesia-relevance-to-paclitaxel-induced-peripheral-neuropathy-in-mice
#8
Robson Costa, Maíra A Bicca, Marianne N Manjavachi, Gabriela C Segat, Fabiana Chaves Dias, Elizabeth S Fernandes, João B Calixto
Kinin B1 (B1R) and B2 receptors (B2R) and the transient receptor potential vanilloid 4 (TRPV4) channel are known to play a critical role in the peripheral neuropathy induced by paclitaxel (PTX) in rodents. However, the downstream pathways activated by kinin receptors as well as the sensitizers of the TRPV4 channel involved in this process remain unknown. Herein, we investigated whether kinins sensitize TRPV4 channels in order to maintain PTX-induced peripheral neuropathy in mice. The mechanical hyperalgesia induced by bradykinin (BK, a B2R agonist) or des-Arg(9)-BK (DABK, a B1R agonist) was inhibited by the selective TRPV4 antagonist HC-067047...
March 10, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28274924/dynamic-coupling-between-trpv4-and-ca-2-activated-sk1-3-and-ik1-k-channels-plays-a-critical-role-in-regulating-the-k-secretory-bk-channel-in-kidney-collecting-duct-cells
#9
Yue Li, Hongxiang Hu, Jin-Bin Tian, Michael X Zhu, Roger G O'Neil
The large-conductance Ca(2+)-activated K(+) channel, BK (KCNMA1), is expressed along the connecting tubule (CNT) and cortical collecting duct (CCD) where it underlies flow- and Ca(2+)-dependent K(+) secretion. Its activity is partially under the control of the mechanosensitive transient receptor potential vanilloid type 4 (TRPV4) Ca(2+)-permeable channel. Recently, we identified three small-/intermediate-conductance Ca(2+)-activated K(+) channels, SK1 (KCNN1), SK3 (KCNN3), and IK1 (KCNN4), with notably high Ca(2+)-binding affinities, that are expressed in CNT/CCD and may be regulated by TRPV4-mediated Ca(2+) influx...
June 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28155571/the-augmentation-of-bk-channel-activity-by-nitric-oxide-signaling-in-rat-cerebral-arteries-involves-co-localized-regulatory-elements
#10
Barry D Kyle, Ramesh C Mishra, Andrew P Braun
Large conductance, Ca(2+)-activated K(+) (BK) channels control cerebrovascular tone; however, the regulatory processes influencing these channels remain poorly understood. Here, we investigate the cellular mechanisms underlying the enhancement of BK current in rat cerebral arteries by nitric oxide (NO) signaling. In isolated cerebral myocytes, BK current magnitude was reversibly increased by sodium nitroprusside (SNP, 100 μM) and sensitive to the BK channel inhibitor, penitrem-A (100 nM). Fostriecin (30 nM), a protein phosphatase type 2A (PP2A) inhibitor, significantly prolonged the SNP-induced augmentation of BK current and a similar effect was produced by sildenafil (30 nM), a phosphodiesterase 5 (PDE5) inhibitor...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28133948/maternal-high-salt-diet-altered-adenosine-mediated-vasodilatation-via-pka-bk-channel-pathway-in-offspring-rats
#11
Jue Wu, Na Li, Yanping Liu, Weisheng Li, Axin He, Di Zhu, Xueqin Feng, Bailin Liu, Ruixiu Shi, Yujuan Zhang, Juanxiu Lv, Zhice Xu
SCOPE: High salt (HS) diets are related to cardiovascular diseases, and prenatal HS was suggested to increase risks of coronary artery diseases in the offspring. This study tested the hypothesis that prenatal HS may influence Adenosine-induced vasodilatation via protein kinase A (PKA) pathway in coronary arteries. METHODS AND RESULTS: Sprague-Dawley rats were fed with 8% salt diet for gestation, the control was fed with 0.3% salt diet. Coronary arteries from male adult offspring were tested for K(+) channels and Adenosine signal pathways...
January 29, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28041976/moving-pieces-in-a-cryptomic-puzzle-cryptide-from-tityus-serrulatus-ts3-nav-toxin-as-potential-agonist-of-muscarinic-receptors
#12
Cibele Rocha-Resende, Nádia Miricéia Leão, Maria Elena de Lima, Robson Augusto Santos, Adriano Monteiro de Castro Pimenta, Thiago Verano-Braga
Cryptome is as a subset of a given proteome containing bioactive cryptides embedded in larger peptides or proteins. We pinpointed a striking sequence similarity between two peptides from the Tityus serrulatus venom: Ts10 (KKDGYPVEYDRAY) and the N-terminal of Ts3 (KKDGYPVEYDNCAY). Ts3 (former Tityustoxin or TsIV) is an α-neurotoxin acting on voltage-gated sodium channels while Ts10 (former Peptide T) is a bradykinin-potentiating peptide and was originally reported as inhibitor of the angiotensin-converting enzyme (ACEi)...
December 29, 2016: Peptides
https://www.readbyqxmd.com/read/27827370/ethanol-sensitive-pacemaker-neurons-in-the-mouse-external-globus-pallidus
#13
Karina P Abrahao, Jessica H Chancey, C Savio Chan, David M Lovinger
Although ethanol is one of the most widely used drugs, we still lack a full understanding of which neuronal subtypes are affected by this drug. Pacemaker neurons exert powerful control over brain circuit function, but little is known about ethanol effects on these types of neurons. Neurons in the external globus pallidus (GPe) generate pacemaker activity that controls basal ganglia, circuitry associated with habitual and compulsive drug use. We performed patch-clamp recordings from GPe neurons and found that bath application of ethanol dose-dependently decreased the firing rate of low-frequency GPe neurons, but did not alter the firing of high-frequency neurons...
April 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27511837/control-of-sensory-neuron-excitability-by-serotonin-involves-5ht2c-receptors-and-ca-2-activated-chloride-channels
#14
Isabella Salzer, Enkhbileg Gantumur, Arsalan Yousuf, Stefan Boehm
Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron...
November 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27455901/effects-of-k-channel-openers-on-spontaneous-action-potentials-in-detrusor-smooth-muscle-of-the-guinea-pig-urinary-bladder
#15
Hiroaki Takagi, Hikaru Hashitani
The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM)...
October 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27421582/roles-of-ion-channels-in-regulation-of-acetylcholine-mediated-vasoconstrictions-in-umbilical-cords-of-rabbit-rats
#16
Zhoufeng Zhu, Jiaqi Tang, Xiuwen Zhou, Sharon Xiang, Xiaolin Zhu, Na Li, Ruixiu Shi, Yuan Zhong, Lubo Zhang, Miao Sun, Zhice Xu
We recently demonstrated that acetylcholine (ACh) produced reliable vasoconstrictions in the umbilical cords. This study investigated the possible mechanisms with different antagonists. ACh-mediated vasoconstrictions were decreased by voltage-operated calcium (Ca(2+)) channels antagonist nifedipine or inositol-1,4,5-trisphosphate-mediated Ca(2+) release antagonist 2-aminoethyl diphenylborinate, indicating that both extracellular and intracellular calcium modulated the ACh-stimulated umbilical contraction. Intracellular Ca(2+) concentrations were increased simultaneously with vasoconstrictions by ACh in the umbilical vessels...
July 12, 2016: Reproductive Toxicology
https://www.readbyqxmd.com/read/27298516/an-ep2-agonist-facilitates-nmda-induced-outward-currents-and-inhibits-dendritic-beading-through-activation-of-bk-channels-in-mouse-cortical-neurons
#17
Yoshinori Hayashi, Saori Morinaga, Xia Liu, Jing Zhang, Zhou Wu, Takeshi Yokoyama, Hiroshi Nakanishi
Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca(2+)-activated K(+) (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (I NMDA-OUT), which are associated with the BK channel activation...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/27238271/developing-molecular-pharmacology-of-bk-channels-for-therapeutic-benefit
#18
G J Kaczorowski, M L Garcia
High conductance, calcium-activated potassium (BK) channels (KCa1.1) are important in regulating physiologic responses in many types of tissues and, as such, present opportunities for development of new therapeutic agents. Both channel agonists and inhibitors could have therapeutic utility, depending on medical application under consideration. However, characterization of molecular pharmacology of BK channels is incomplete and has been difficult to accomplish because of paucity of chemical leads that are acceptable templates for Medicinal Chemistry investigation...
2016: International Review of Neurobiology
https://www.readbyqxmd.com/read/26944020/inflammatory-mediator-bradykinin-increases-population-of-sensory-neurons-expressing-functional-t-type-ca-2-channels
#19
Dongyang Huang, Ce Liang, Fan Zhang, Hongchao Men, Xiaona Du, Nikita Gamper, Hailin Zhang
T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude...
April 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26914408/endothelin-1-shifts-the-mediator-of-bradykinin-induced-relaxation-from-no-to-h2-o2-in-resistance-arteries-from-patients-with-cardiovascular-disease
#20
Thomas M Leurgans, Maria Bloksgaard, Jonathan R Brewer, Luis A Bagatolli, Maise H Fredgart, Kristoffer Rosenstand, Maria L Hansen, Lars M Rasmussen, Akhmadjon Irmukhamedov, Jo Gr De Mey
BACKGROUND AND PURPOSE: We tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endothelium-dependent vasodilator depend on the contractile stimulus. EXPERIMENTAL APPROACH: Arteries dissected from parietal pericardium of cardiothoracic surgery patients were studied by myography and imaging techniques. Segments were sub-maximally contracted by K(+) , the TxA2 analogue U46619 or endothelin-1 (ET-1). KEY RESULTS: Relaxing effects of Na-nitroprusside were comparable, but those of bradykinin (BK) were bigger in the presence of ET-1 compared with K(+) or U46619...
May 2016: British Journal of Pharmacology
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