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1.
J Vet Med Sci ; 81(9): 1266-1272, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31292350

RESUMO

The aim of the present study was to clarify roles of ATP-dependent potassium channels (KATP channels) in motility of the striated muscle portion in the esophagus. An isolated segment of the rat esophagus was placed in an organ bath and mechanical responses were recorded using a force transducer. Electrical stimulation of the vagus nerve evoked contractile response of striated muscle in the esophageal segment. Application of glibenclamide, an antagonist of KATP channels, increased amplitude of vagally mediated twitch contractions of the rat esophagus. On the other hand, minoxidil, an agonist of KATP channels, decreased amplitude of twitch contractions. RT-PCR revealed the expression of subunits of KATP channels in esophageal tissue. In addition, immunopositivity for subunits of KATP channels was observed in the striated muscle cells of the esophageal muscle layer. These findings indicate that KATP channels contribute to motor regulation of striated muscle in the rat esophagus.


Assuntos
Esôfago/inervação , Contração Muscular/fisiologia , Músculo Estriado/fisiologia , Canais de Potássio/fisiologia , Trifosfato de Adenosina , Animais , Estimulação Elétrica , Esôfago/efeitos dos fármacos , Glibureto/farmacologia , Masculino , Minoxidil/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Estriado/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Ratos Sprague-Dawley , Nervo Vago/fisiologia
2.
Georgian Med News ; (288): 163-166, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31101798

RESUMO

Considering the incidence, high risk of progression and severe consequences of renal pathology, a preventive therapy as well as correction of kidney dysfunction are issues of a great importance today. An essential condition for an improvement of nephroprotection is a determination of new mechanisms of disturbances and restoration of homeostatic kidney processes. A unique physiological role of ATP-dependent potassium (KATP) channels and their participation in adaptive-compensatory reactions substantiate the feasibility of search for effective nephroprotectors among pharmacological modulators of their activity. The goal of research - to generalize available scientific data concerning the influence of KATP channels activators on kidneys for prospective administration of these pharmacological class representatives in nephroprotection. Analysis of renal effects of KATP channels activators allows stating a fact of perspectivity of the further studies of these pharmacological class representatives as the potential nephroprotectors in glomerular and tubular damage of the nephron.


Assuntos
Nefropatias , Néfrons , Preparações Farmacêuticas , Canais de Potássio , Trifosfato de Adenosina , Humanos , Nefropatias/prevenção & controle , Néfrons/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Estudos Prospectivos
3.
ChemMedChem ; 14(9): 952-964, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30861620

RESUMO

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure-activity relationship studies were performed to evaluate the KV 7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV 7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50 =1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.


Assuntos
Aminopiridinas/farmacologia , Carbamatos/farmacologia , Fenilenodiaminas/farmacologia , Canais de Potássio/efeitos dos fármacos , Aminopiridinas/química , Carbamatos/química , Células HEK293 , Humanos , Oxirredução , Fenilenodiaminas/química
4.
J Neurochem ; 148(1): 29-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295919

RESUMO

Methamphetamine (Meth) is a potent and commonly abused psychostimulant. Meth alters neuron and astrocyte activity; yet the underlying mechanism(s) is not fully understood. Here we assessed the impact of acute Meth on human fetal astrocytes (HFAs) using whole-cell patch-clamping. We found that HFAs displayed a large voltage-gated K+ efflux (IKv ) through Kv /Kv -like channels during membrane depolarization, and a smaller K+ influx (Ikir ) via inward-rectifying Kir /Kir -like channels during membrane hyperpolarization. Meth at a 'recreational' (20 µM) or toxic/fatal (100 µM) concentration depolarized resting membrane potential (RMP) and suppressed IKv/Kv-like . These changes were associated with a decreased time constant (Ƭ), and mimicked by blocking the two-pore domain K+ (K2P )/K2P -like and Kv /Kv -like channels, respectively. Meth also diminished IKir/Kir-like , but only at toxic/fatal levels. Given that Meth is a potent agonist for the trace amine-associated receptor type-1 (TAAR1), and TAAR1-coupled cAMP/cAMP-activated protein kinase (PKA) cascade, we further evaluated whether the Meth impact on K+ efflux was mediated by this pathway. We found that antagonizing TAAR1 with N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) reversed Meth-induced suppression of IKv/Kv-like ; and inhibiting PKA activity by H89 abolished Meth effects on suppressing IKv/Kv-like . Antagonizing TAAR1 might also attenuate Meth-induced RMP depolarization. Voltage-gated Ca2+ currents were not detected in HFAs. These novel findings demonstrate that Meth suppresses IKv/Kv-like by facilitating the TAAR1/Gs /cAMP/PKA cascade and altering the kinetics of Kv /Kv -like channel gating, but reduces K2P /K2P -like channel activity through other pathway(s), in HFAs. Given that Meth-induced decrease in astrocytic K+ efflux through K2P /K2P -like and Kv /Kv -like channels reduces extracellular K+ levels, such reduction could consequently contribute to a decreased excitability of surrounding neurons. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Astrócitos/efeitos dos fármacos , Metanfetamina/toxicidade , Canais de Potássio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Estimulantes do Sistema Nervoso Central/toxicidade , Feto , Humanos , Potenciais da Membrana/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos
5.
eNeuro ; 5(5)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406178

RESUMO

HCN1 compartmentalization in CA1 pyramidal cells, essential for hippocampal information processing, is believed to be controlled by the extracellular matrix protein Reelin. Expression of Reelin, in turn, is stimulated by 17ß-estradiol (E2). In this study, we therefore tested whether E2 regulates the compartmentalization of HCN1 in CA1 via Reelin. In organotypic entorhino-hippocampal cultures, we found that E2 promotes HCN1 distal dendritic enrichment via the G protein-coupled estrogen receptor GPER1, but apparently independent of Reelin, because GST-RAP, known to reduce Reelin signaling, did not prevent E2-induced HCN1 enrichment in distal CA1. We therefore re-examined the role of Reelin for the regulation of HCN1 compartmentalization and could not detect effects of reduced Reelin signaling on HCN1 distribution in CA1, either in the (developmental) slice culture model or in tamoxifen-inducible conditional reelin knockout mice during adulthood. We conclude that for HCN1 channel compartmentalization in CA1 pyramidal cells, Reelin is not as essential as previously proposed, and E2 effects on HCN1 distribution in CA1 are mediated by mechanisms that do not involve Reelin. Because HCN1 localization was not altered at different phases of the estrous cycle, gonadally derived estradiol is unlikely to regulate HCN1 channel compartmentalization, while the pattern of immunoreactivity of aromatase, the final enzyme of estradiol synthesis, argues for a role of local hippocampal E2 synthesis.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Dendritos/efeitos dos fármacos , Estrogênios/farmacologia , Proteínas da Matriz Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Animais , Dendritos/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Estrogênios/metabolismo , Hipocampo/metabolismo , Neurônios/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Células Piramidais/metabolismo , Ratos Wistar
6.
J Appl Oral Sci ; 26: e20180048, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30304126

RESUMO

OBJECTIVE: Periodontitis is associated with endothelial dysfunction, which is clinically characterized by a reduction in endothelium-dependent relaxation. However, we have previously shown that impairment in endothelium-dependent relaxation is transient. Therefore, we evaluated which mediators are involved in endothelium-dependent relaxation recovery. MATERIAL AND METHODS: Rats were subjected to ligature-induced experimental periodontitis. Twenty-one days after the procedure, the animals were prepared for blood pressure recording, and the responses to acetylcholine or sodium nitroprusside were obtained before and 30 minutes after injection of a nitric oxide synthase inhibitor (L-NAME), cyclooxygenase inhibitor (Indomethacin, SC-550 and NS- 398), or calcium-dependent potassium channel blockers (apamin plus TRAM- 34). The maxilla and mandible were removed for bone loss analysis. Blood and gingivae were obtained for C-reactive protein (CRP) and myeloperoxidase (MPO) measurement, respectively. RESULTS: Experimental periodontitis induces bone loss and an increase in the gingival MPO and plasmatic CRP. Periodontitis also reduced endothelium-dependent vasodilation, a hallmark of endothelial dysfunction, 14 days after the procedure. However, the response was restored at day 21. We found that endothelium-dependent vasodilation at day 21 in ligature animals was mediated, at least in part, by the activation of endothelial calcium-activated potassium channels. CONCLUSIONS: Periodontitis induces impairment in endothelial-dependent relaxation; this impairment recovers, even in the presence of periodontitis. The recovery is mediated by the activation of endothelial calcium-activated potassium channels in ligature animals. Although important for maintenance of vascular homeostasis, this effect could mask the lack of NO, which has other beneficial properties.


Assuntos
Óxido Nítrico/metabolismo , Periodontite/metabolismo , Periodontite/fisiopatologia , Canais de Potássio/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Proteína C-Reativa/análise , Inibidores de Ciclo-Oxigenase/farmacologia , Ligadura , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Peroxidase/análise , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
7.
Toxicol Appl Pharmacol ; 359: 62-69, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30244120

RESUMO

We investigated the potential effects of monosodium glutamate (MSG)-induced obesity with regards to nitric oxide and prostanoid production, as well as potassium channel function, in rat thoracic arteries. Newborn male Wistar rats were injected intraperitoneally with typically reported MSG (4.0 mg/g) once daily for 4 consecutive days. At 90 days postnatal, the rats were sacrificed and the thoracic aortas were evaluated for vascular responses and for prostanoid production. Nitric oxide was studied with calcium ionophore (A23187), acetylcholine (ACh) and sodium nitroprusside (SNP). The release of prostanoids was measured under basal and ACh-stimulated conditions, and the vasomotor effect of exogenous thromboxane A2 mimetic, U46619 was assessed. Potassium channel activities were analyzed using an NS1619 opener for BKCa channels and pinacidil for KATP channels. Arteries from MSG-obese rats exhibited a reduced maximal contraction to potassium chloride and hyper-responsiveness to U46619, suggesting that MSG also alters the responsiveness of vascular smooth muscles. The endothelium-dependent relaxation to ACh and A23817 was attenuated, suggesting low nitric oxide bioavailability. The hypersensitivity of arteries to an exogenous nitric oxide donor, SNP, occurred. The secondary contraction to A23817 was augmented, suggesting increased activation of the prostanoid receptor. The prostanoid release was increased in both basal- and acetylcholine-stimulated rings. In addition, down-regulation of KATP and BKCa channels influenced hyperpolarizing mechanisms. Our findings suggest that increased prostanoid production and hypersensitivity to thromboxane A2 together with down-regulation of potassium channels and low nitric oxide bioavailability may contribute to the increase in blood pressure found in adult MSG-obese male rats.


Assuntos
Aditivos Alimentares/toxicidade , Óxido Nítrico/metabolismo , Obesidade/induzido quimicamente , Obesidade/patologia , Canais de Potássio/efeitos dos fármacos , Prostaglandinas/metabolismo , Glutamato de Sódio/toxicidade , Artérias Torácicas/efeitos dos fármacos , Artérias Torácicas/patologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/patologia , Regulação para Baixo/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Wistar , Artérias Torácicas/metabolismo , Tromboxano A2/farmacologia , Vasoconstritores/farmacologia
8.
Peptides ; 108: 14-18, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30121363

RESUMO

Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human ß-defensins hBD1 and hBD2 point to complex interactions between human ß-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC50 value of 187.6 ±â€¯25.7 nM; 1 µM hBD4 inhibited 34.0 ±â€¯0.2% of Kv1.3 channel currents. Moreover, 1 µM hBD3 inhibited 50.6 ±â€¯3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human ß-defensin family is a novel group of potassium channel inhibitors with diverse types of human ß-defensin-potassium channel interactions.


Assuntos
Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , beta-Defensinas/farmacologia , Células HEK293 , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Cinética , Canal de Potássio Kv1.2/antagonistas & inibidores , Canal de Potássio Kv1.2/metabolismo , Canal de Potássio Kv1.3/antagonistas & inibidores , Canal de Potássio Kv1.3/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , beta-Defensinas/metabolismo
9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(10): 1246-1256, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077007

RESUMO

The pannexin-1 (Panx1) channel has been reported to mediate the release of ATP that is involved in local tissue inflammation, obesity, and many chronic degenerative diseases. It remains unknown whether Panx1 is present in podocytes and whether this channel in podocytes mediates ATP release leading to glomerular inflammation or fibrosis. To answer these questions, we first characterized the expression of Panx channels in podocytes. Among the three known pannexins, Panx1 was the most enriched in podocytes, either cultured or native in mouse glomeruli. Using a Port-a-Patch planar patch-clamp system, we recorded a large voltage-gated outward current through podocyte membrane under the Cs+in/Na+out gradient. Substitution of gluconate or aspartate for chloride in the bath solution blocked voltage-gated outward currents and shifted the reversal potential of Panx1 currents to the right, indicating the anion permeability of this channel. Pharmacologically, the recorded voltage-gated outward currents were substantially attenuated by specific Panx1 channel inhibitors. Given the anti-inflammatory and intracellular ATP restorative effects of adiponectin, we tested whether this adipokine inhibits Panx1 channel activity to block ATP release. Adiponectin blocked Panx1 channel activity in podocytes. Mechanistically, inhibition of acid ceramidase (AC) remarkably enhanced Panx1 channel activity under control conditions and prevented the inhibition of Panx1 channel by adiponectin. Correspondingly, intracellular addition of AC products, sphingosine or sphingosine-1-phosphate (S1P), blocked Panx1 channel activity, while elevation of intracellular ceramide had no effect on Panx1 channel activity. These results suggest that adiponectin inhibits Panx1 channel activity in podocytes through activation of AC and associated elevation of intracellular S1P.


Assuntos
Ceramidase Ácida/metabolismo , Adiponectina/metabolismo , Conexinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Podócitos/citologia , Trifosfato de Adenosina/metabolismo , Animais , Ácido Aspártico/farmacologia , Células Cultivadas , Ativação Enzimática , Gluconatos/farmacologia , Lisofosfolipídeos/metabolismo , Camundongos , Podócitos/metabolismo , Canais de Potássio/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo
10.
ACS Chem Neurosci ; 9(12): 3153-3165, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30089357

RESUMO

K2P potassium channels generate leak currents that stabilize the resting membrane potential of excitable cells. Various K2P channels are implicated in pain, ischemia, depression, migraine, and anesthetic responses, making this family an attractive target for small molecule modulator development efforts. BL-1249, a compound from the fenamate class of nonsteroidal anti-inflammatory drugs is known to activate K2P2.1(TREK-1), the founding member of the thermo- and mechanosensitive TREK subfamily; however, its mechanism of action and effects on other K2P channels are not well-defined. Here, we demonstrate that BL-1249 extracellular application activates all TREK subfamily members but has no effect on other K2P subfamilies. Patch clamp experiments demonstrate that, similar to the diverse range of other chemical and physical TREK subfamily gating cues, BL-1249 stimulates the selectivity filter "C-type" gate that controls K2P function. BL-1249 displays selectivity among the TREK subfamily, activating K2P2.1(TREK-1) and K2P10.1(TREK-2) ∼10-fold more potently than K2P4.1(TRAAK). Investigation of mutants and K2P2.1(TREK-1)/K2P4.1(TRAAK) chimeras highlight the key roles of the C-terminal tail in BL-1249 action and identify the M2/M3 transmembrane helix interface as a key site of BL-1249 selectivity. Synthesis and characterization of a set of BL-1249 analogs demonstrates that both the tetrazole and opposing tetralin moieties are critical for function, whereas the conformational mobility between the two ring systems impacts selectivity. Together, our findings underscore the landscape of modes by which small molecules can affect K2P channels and provide crucial information for the development of better and more selective K2P modulators of the TREK subfamily.


Assuntos
Canais de Potássio de Domínios Poros em Tandem/efeitos dos fármacos , Tetra-Hidronaftalenos/farmacologia , Tetrazóis/farmacologia , Animais , Células HEK293 , Humanos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Oócitos , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Xenopus laevis
11.
Immunity ; 49(1): 56-65.e4, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29958799

RESUMO

Potassium (K+) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K+ channel (K2P) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6-/- macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K+ efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.


Assuntos
Inflamassomos/metabolismo , Inflamação/fisiopatologia , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Caspase 1/deficiência , Caspase 1/metabolismo , Linhagem Celular , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/fisiopatologia , Macrófagos/transplante , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/deficiência , Quinina/farmacologia , RNA Interferente Pequeno/farmacologia , Receptores Purinérgicos P2X7/deficiência , Receptores Purinérgicos P2X7/metabolismo , Sepse/metabolismo , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
12.
Expert Opin Ther Targets ; 22(5): 439-451, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29697308

RESUMO

INTRODUCTION: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K+ channel inhibitors. A combination of K+ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K+ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Desenho de Drogas , Genótipo , Humanos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia
13.
J Neurosci ; 38(19): 4505-4520, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29650696

RESUMO

Neuropeptide Y (NPY) expression is tightly linked with the development of stress resilience in rodents and humans. Local NPY injections targeting the basolateral amygdala (BLA) produce long-term behavioral stress resilience in male rats via an unknown mechanism. Previously, we showed that activation of NPY Y1 receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current, Ih The present studies tested whether NPY treatment induces stress resilience by modulating Ih NPY (10 pmol) was delivered daily for 5 d bilaterally into the BLA to induce resilience; thereafter, the electrophysiological properties of PNs and the expression of Ih in the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration. In vitro intracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 weeks (2W) and 4 weeks (4W) after NPY treatment. At 2W, spontaneous IPSC frequencies were increased, whereas at 4W, resting Ih was markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knock-down of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased SI beginning 2W after injection and induced stress resilience. NPY treatment induced sequential, complementary changes in the inputs to BLA PNs and their postsynaptic properties that reduce excitability, a mechanism that contributes to less anxious behavior. Furthermore, HCN1 knock-down mimicked the increases in SI and stress resilience observed with NPY, indicating the importance of Ih in stress-related behavior.SIGNIFICANCE STATEMENT Resilience improves mental health outcomes in response to adverse situations. Neuropeptide Y (NPY) is associated with decreased stress responses and the expression of resilience in rodents and humans. Single or repeated injections of NPY into the basolateral amygdala (BLA) buffer negative behavioral effects of stress and induce resilience in rats, respectively. Here, we demonstrate that repeated administration of NPY into the BLA unfolds several cellular mechanisms that decrease the activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel HCN1. Moreover, shRNA knock-down of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating that this channel may be a possible target for therapy.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Canais de Potássio/efeitos dos fármacos , Resiliência Psicológica/efeitos dos fármacos , Tonsila do Cerebelo/citologia , Animais , Ansiedade/genética , Ansiedade/psicologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Relações Interpessoais , Masculino , Microinjeções , Neuropeptídeo Y/administração & dosagem , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Mol Cell Neurosci ; 88: 330-341, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29524627

RESUMO

The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca2+ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases. Small-conductance Ca2+-activated K+ (SK) channels regulate the intrinsic firing patterns in different central neurons and are essential regulators of the intracellular Ca2+ homeostasis. However, the role of SK channels for the intrinsic pacemaking of LC neurons in mice is still unclear. Therefore we performed qPCR expression analysis as well as patch clamp recordings of in vitro brainstem slices, for instance testing SK channel blockers and activators like apamin and NS309, respectively. Although we found a transcriptional expression of SK1, SK2 and SK3 channels, SK2 was the predominantly expressed subunit in mouse LC neurons. Using perforated-patch clamp experiments, we found that SK channels are essential regulators of the intrinsic pacemaking of LC neurons, mediating a large fraction of the afterhyperpolarization (AHP) in these cells. Consistent with a previous observation that a concerted action of L- and T-type Cav channels is essential for the pacemaking of LC neurons, we found that SK channel activation, and the respective AHP amplitude, is primarily coupled to Ca2+ influx via these types of Ca2+ channels. Our study identified SK2 channels as drug targets for the tuning of the pacemaker frequency in disorders involving a dysregulation of the LC.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Locus Cerúleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Marca-Passo Artificial , Canais de Potássio/metabolismo
15.
J Clin Psychopharmacol ; 38(3): 243-246, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29601316

RESUMO

BACKGROUND: Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission. METHODS: This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The primary clinical outcome measure was change in Montgomery-Asberg Depression Rating Scale score from baseline to posttreatment. Quantitative insulin sensitivity check index, as well as concomitant imaging measures (electroencephalography, proton magnetic resonance spectroscopy, magnetoencephalography), were used as potential surrogate markers of target (KATP channel) engagement. RESULTS: The study was halted due to severe adverse effects. Given the small sample size, statistical evaluation of the effect of diazoxide on Montgomery-Asberg Depression Rating Scale scores or the imaging measures was not pursued. Visual inspection of the quantitative insulin sensitivity check index test revealed no evidence of target engagement. CONCLUSIONS: Although the results are negative, they are an important addition to the literature in this rapidly changing field.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Diazóxido/administração & dosagem , Canais de Potássio/efeitos dos fármacos , Adulto , Idoso , Estudos Cross-Over , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Diazóxido/efeitos adversos , Diazóxido/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Canais de Potássio/metabolismo , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
16.
PLoS One ; 13(2): e0192699, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29474372

RESUMO

The membrane potential helps determine pulmonary artery smooth muscle cell (PASMC) contraction. The Kv7 channel activators, retigabine and flupirtine, are thought to dilate pulmonary arteries by hyperpolarising PASMC. Zinc pyrithione activates Kv7 channels by a mechanism distinct from retigabine and with different Kv7 subunit selectivity. This study aimed to determine if zinc pyrithione selectively activates Kv7 channels in rat PASMC to evoke pulmonary artery dilation. Zinc pyrithione relaxed pulmonary arteries with half-maximal effect at 4.3µM. At 10µM it activated pronounced voltage-dependent K+ current and hyperpolarized PASMCs by around 10mV. Tetraethylammonium ions (TEA, 10mM) and paxilline (1µM) abolished both the current and hyperpolarisation. XE991 (10µM) blocked the hyperpolarization and reduced the current by 30%. Iberiotoxin (50nM) had no effect on the hyperpolarisation, but reduced the current by 40%. The XE991-sensitive current activated with an exponential time course (time constant 17ms), whereas the iberiotoxin-sensitive current followed a bi-exponential time course (time constants 6 and 57ms), suggesting that the drugs blocked different components of the zinc pyrithione-induced current. Zinc pyrithione therefore appears to activate at least two types of K+ channel in PASMC; an XE991, TEA and paxilline-sensitive Kv7 channel and a TEA, paxilline and iberiotoxin-sensitive BKCa channel. Both could contribute to the relaxing effect of zinc pyrithione on pulmonary artery.


Assuntos
Compostos Organometálicos/farmacologia , Canais de Potássio/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Piridinas/farmacologia , Animais , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Artéria Pulmonar/fisiologia , Ratos , Ratos Sprague-Dawley
17.
Acta Med Iran ; 56(1): 14-20, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29436790

RESUMO

Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100% of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P<0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P<0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P<0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure.


Assuntos
Anticonvulsivantes/administração & dosagem , Carbamatos/envenenamento , Cromakalim/administração & dosagem , Intoxicação por Organofosfatos/complicações , Convulsões/prevenção & controle , Animais , Diclorvós/administração & dosagem , Relação Dose-Resposta a Droga , Glibureto/administração & dosagem , Masculino , Camundongos , Fisostigmina/administração & dosagem , Canais de Potássio/efeitos dos fármacos , Convulsões/induzido quimicamente
18.
J Neurophysiol ; 119(5): 1912-1923, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29412775

RESUMO

The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD; however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K+ currents and GABAA and NMDA receptors in the hippocampal slice preparation. Blocking glycolysis with the glucose derivative 2-deoxy-d-glucose (2-DG; 10 mM) gave a fast reduction of the frequency of interictal discharge (IED) consistent with findings in other in vitro models. However, this was followed by the induction of seizure-like discharges in area CA1 and CA3. Substituting glucose with sucrose (glucopenia) had effects similar to those of 2-DG, whereas substitution with l-lactate or pyruvate reduced the IED but had a less proconvulsant effect. Blockade of ATP-sensitive K+ channels, glycine or adenosine 1 receptors, or depletion of the endogenous anticonvulsant compound glutathione did not prevent the actions of 2-DG. Baclofen (2 µM) reproduced the effect of 2-DG on IED activity. The proconvulsant effect of 2-DG could be reproduced by blocking the oxidative phosphorylation with the complex I toxin rotenone (4 µM). The data suggest that inhibition of IED, induced by 2-DG and glucopenia, is a direct consequence of impairment of glycolysis, likely exerted via a decreased recurrent excitatory synaptic transmission in area CA3. The accompanying proconvulsant effect is caused by an excitatory mechanism, depending on impairment of oxidative phosphorylation. NEW & NOTEWORTHY This study reveals two opposing effects of 2-deoxy-d-glucose (2-DG) and glucopenia on in vitro epileptiform discharge observed during combined blockade of K+ currents and GABAA receptors. Interictal-like activity is inhibited by a mechanism that selectively depends on impairment of glycolysis and that results from a decrease in the strength of excitatory recurrent synaptic transmission in area CA3. In contrast, 2-DG and glucopenia facilitate ictal-like activity by an excitatory mechanism, depending on impairment of mitochondrial oxidative phosphorylation.


Assuntos
Antimetabólitos/farmacologia , Desoxiglucose/farmacologia , Epilepsia/metabolismo , GABAérgicos/farmacologia , Glicólise , Hipocampo , Mitocôndrias , Fosforilação Oxidativa , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Glicólise/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Ratos Wistar
19.
Neurochem Res ; 43(1): 27-40, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28444636

RESUMO

Action potentials are fundamental to relaying information from region to region in the nervous system. Changes in action potential firing patterns in neural circuits influence how the brain processes information. In our previous study, we focused on interneuron/perineuronal astrocyte pairs in the hippocampal CA1 region and reported that direct depolarization of perineuronal astrocytes modulated the firing pattern of interneurons. In the current study, we investigated the morphological and electrophysiological properties of perineuronal oligodendrocytes, and examined their modulatory effects on interneuronal firing in the CA1 region. Perineuronal oligodendrocytes only had a few processes, which were crooked, intricately twisted, and twined around the soma and proximal region of the main processes of adjacent interneurons. Whole-cell current patterns of perineuronal oligodendrocytes were homogenous and the current-voltage relationship showed remarkable outward rectification. Although the K+ channel blockers, tetraethylammonium and 4-aminopyridine, clearly blocked outward currents, Ba2+ did not significantly alter whole-cell currents. Unlike perineuronal astrocytes, the depolarization of perineuronal oligodendrocytes had no effect on interneuronal firing; however, when the interneurons were firing at a higher frequency, the hyperpolarization of perineuronal oligodendrocytes suppressed their action potentials. The suppressive effects of perineuronal oligodendrocytes were inhibited in the presence of a low concentration of tetraethylammonium, which selectively blocked deep and fast afterhyperpolarization. These results suggest that perineuronal oligodendrocytes suppress interneuronal firing through their influence on K+ channels, which are responsible for deep and fast afterhyperpolarization.


Assuntos
Hipocampo/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Canais de Potássio/metabolismo , Potenciais de Ação/fisiologia , Animais , Interneurônios/metabolismo , Potenciais da Membrana/fisiologia , Canais de Potássio/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Ratos Sprague-Dawley
20.
J Cardiovasc Pharmacol Ther ; 23(2): 119-129, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28946759

RESUMO

The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K+ channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K+ channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.


Assuntos
Cardiopatias/metabolismo , Frequência Cardíaca , Coração , Miócitos Cardíacos/metabolismo , Canais de Potássio/metabolismo , Potenciais de Ação , Animais , Antiarrítmicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio/efeitos dos fármacos
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