Blockade Of Potassium Channels Research Articles

Unraveling neuroprotection with Kv1.3 potassium channel blockade by a scorpion venom peptide

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide’s potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12’s, offering insights into its pharmacological utility. The peptide’s impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions.

Knot data analysis using multiscale Gauss link integral

In the past decade, topological data analysis has emerged as a powerful algebraic topology approach in data science. Although knot theory and related subjects are a focus of study in mathematics, their success in practical applications is quite limited due to the lack of localization and quantization. We address these challenges by introducing knot data analysis (KDA), a paradigm that incorporates curve segmentation and multiscale analysis into the Gauss link integral. The resulting multiscale Gauss link integral (mGLI) recovers the global topological properties of knots and links at an appropriate scale and offers a multiscale geometric topology approach to capture the local structures and connectivities in data. By integration with machine learning or deep learning, the proposed mGLI significantly outperforms other state-of-the-art methods across various benchmark problems in 13 intricately complex biological datasets, including protein flexibility analysis, protein-ligand interactions, human Ether-à-go-go-Related Gene potassium channel blockade screening, and quantitative toxicity assessment. Our KDA opens a research area-knot deep learning-in data science.

Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 μM, preferentially blocked hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 μM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.

Cocaine Induced Cardiac Arrhythmias

An addictive drug that provides pleasure and reward is more likely to attack various parts of the body and affect health. Dangerous substances are also involved in cocaine processing. Not just the high dosage of cocaine but a lower quantity may also lead to severe health issues, which ultimately cause panic attacks, violent behavior, and tremors. However, long-term use of cocaine may lead to heart attack and is likely to cause sudden death. Cardiac arrhythmia or irregular heartbeat is highly associated with cocaine use. The potential causes of cocaine-associated arrhythmias, including sodium channel blockade, ischemia, and potassium channel blockade, and clinical manifestations that are influenced by acidosis, hyperthermia, hypoxia, and electrolyte abnormalities will be discussed.

Ectopic burst induced by blockade of axonal potassium channels on the mouse hippocampal mossy fiber.

A potassium channel blocker 4-AP has been shown to exert pronounced convulsive action to generate burst firings when applied to hippocampal slices. However, it remains unclear how the blockade of potassium channels leads to the generation of burst firings. One possibility is ectopic spiking from the sites different from those for physiological spike initiation at the axon initial segment, as suggested for several experimental models of epileptogenesis in vitro. To test for possible ectopic spiking at the distal axon by 4-AP application, direct recordings from large mossy fiber terminals were made with the loose-patch clamp technique in mouse hippocampal slices. To localize the action of 4-AP on the distal axon, focal perfusion, as well as micro-cut to disconnect soma and distal axons, were adopted. Focal application of 4-AP on the distal portion of mossy fibers reliably induced burst discharges of the mossy fiber terminals. Photochemical blockade of potassium channels at distal axons, by the application of RuBi-4-AP, a visible wavelength blue light-sensitive caged compound, and the illumination of blue light caused robust bursting activity originating from distal axons. Computer simulation suggested that local blockade of axonal potassium channels prolongs the duration of action potentials and thereby causes reverberating spiking activities at distal axons and subsequent antidromic propagation toward the soma. Taken together, it was suggested that local blockade of voltage-dependent potassium channels in distal axons by application of 4-AP is sufficient to cause a hyperexcitable state of hippocampal mossy fiber axons.

An opto-electronic control system for real-time complete (re)shaping of cardiac action potentials on a multicellular scale

Abstract Background Cardiomyocytes maintain a membrane potential (Vm), which fulfills essential regulatory roles in various biological functions, including not only action potential (AP) propagation and mechanical contraction, but also homeostatic regulation. In-depth studies into these roles have been severely hampered by the lack of research methods allowing full control over Vm, especially in multicellular cardiac preparations. Purpose We aimed to unlock new research possibilities by the development of an experimental system (APqr) capable of full Vm control, including instantaneous modulation of AP morphology on a multicellular level. Methods Immortalized human atrial myocytes (hiAMs) grown in monolayer format (n=7) were genetically modified to express the blue light-activatable cation channel Cheriff and the red light-sensitive inward chloride pump Jaws for depolarizing and hyperpolarizing effects, respectively. Real-time Vm readout was obtained by patch clamp electrophysiology. Dynamic Vm control was achieved by a custom closed-coop controller calculating Vm deviations from reference values. A 470-nm and a 617-nm LED were modulated by the controller in a Vm deviation-dependent manner, selectively activating Cheriff and Jaws. To explore the feasibility of AP restoration, electrical disturbances were introduced by non-selective potassium channel blockade (4-aminopyridine, 4AP, 200 µM) or by a preprogrammed blue-light pulse creating abnormal cation influx during the repolarization phase of the hiAM AP. Results 4AP induced a 82.4 ± 27.8 ms increase of AP duration at 90% repolarization (APD90) values in hiAM monolayers. Using APs recorded under control conditions (CTL) as reference, the APqr maneuver reduced this APD90 difference to 1.9 ± 3.1 ms. Similarly, APqr suppressed the effects of light-induced abnormal cation influx on APD90 (CTL: 342.9 ± 51.7 ms, blue-light pulse: 700.8 ± 64.5 ms, APqr: 338.3 ± 68 ms) effectively, with Vm deviation less than 2.5 mV in 96.7% of the time. APqr could also be applied for the enforcement of arbitrary AP shapes. In these experiments, the Vm references consisted of AP shapes of hiAM monolayers exposed to drugs with APD-prolonging (4AP) or shortening (carbachol) effects. APqr was able to enforce these reference APs, that were distinctly different from the endogenous AP shapes, on hiAM monolayers with great accuracy, with Vm deviations less than 2.5 mV in 95.8% and 94.4% of the time, respectively. Conclusions APqr restores AP morphologies in the presence of electrical perturbations of different origin without any prior knowledge about the disturbance and enforces arbitrary AP morphologies with high accuracy in an immediate and self-regulatory manner. Collectively, these results set the stage for in-depth investigations into the regulatory roles of Vm in healthy and diseased cardiomyocytes via the application of such real-time opto-electronic control systems.Real-time (re)shaping of cardiac APs

Calcium-gated potassium channel blockade via membrane-facing fenestrations.

Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.

Lack of knowledge regarding the misuse of domperidone in Pakistan and its serious consequences: short communication.

Domperidone is an antagonist of the peripheral dopamine (D2) receptor. It works as an antiemetic by blocking D2-receptors at the chemoreceptor trigger zone and as a gastroprokinetic drug by blocking GI tract D2-receptors. According to research, using domperidone significantly raises the risk of cardiac arrhythmia and sudden cardiac death by 70%, most likely through prolonging the QT interval. Blockade of hERG voltage-gated potassium channels is thought to be the reason. Here in Pakistan, this drug is being prescribed by every other physician and even patients frequently self-medicate themselves with it. Due to the serious side effects of this medication, extreme caution should be exercised when prescribing it, especially to the elderly, those who have underlying QT prolongation, those taking medications known to prolong QT, and even more so in pregnant women as there is some evidence that domperidone crosses into breast milk in small amounts and causes an irregular heartbeat in the baby. At least we, on our part, can limit the usage of the drug only with a prescription and, where necessary, if not completely, stop it.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Ameliorated Neurogenesis Deficits in Dentate Gyrus May Underly the Pronounced Antidepressant Effect of TREK-1 Potassium Channel Blockade in Rats with Depressive-like Behavior.

Depression is considered to be the most common mental disorder and is probed by several studies that chronic mild stress contributes to depression, and fortunately, most antidepressants ameliorate depressive-like behavior accompanied with reversed hippocampal neurogenesis defects. In our present study, we confirmed that different antidepressants repaired the stress-induced neuronal and behavioral deficits by modulating adult hippocampal neurogenesis. Antidepressant treatment restored the adult hippocampal neurodegeneration, which was impaired by chronic unpredicted mild stress displaying decreased proliferation and neuronal differentiation but increased apoptosis of newly formed neurons in dentate gyrus. Notably, sucrose preference ratio significantly correlated with both neuronal differentiation proportion and newborn apoptosis proportion, suggesting a mechanistic relationship between neurogenesis and behavior. Indeed, the neotype TREK-1 potassium channel blocker expressed an earlier and pronounced antidepressant manifestation compared to the traditional selective serotonin-reuptake inhibitors fluoxetine. We therefore conclude that the administration of TREK-1 potassium channel antagonism can reverse the depressive deficits caused by chronic stress quickly via regulation of adult hippocampal neurogenesis.

Treatment with senicapoc, a KCa 3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (KCa 3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. KCa 3.1 channel knockout (Kccn4-/- ) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the KCa 3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO2 /FiO2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO2 /FiO2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4-/- mice. Pretreatment with senicapoc (10-70 mg·kg-1 ) prevented the reduction in PaO2 /FiO2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg-1 ) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg-1 senicapoc also improved the PaO2 /FiO2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Genetic deficiency of KCa 3.1 channels and senicapoc improved the PaO2 /FiO2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking KCa 3.1 channels is a potential treatment in ARDS-like disease.

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/− rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/− rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/− rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.

Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs, based on high and low expression, with a conserved distribution pattern across the animals examined. We trained a convolutional neural network to recognize the parvalbumin subtypes and create maps of whole cerebellar distribution and find that PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing through differences in ion channel composition. It is proposed that ion channels drive the diversity in PC intrinsic firing phenotype and parvalbumin calcium buffering provides capacity for the highest firing rates observed. These findings open new avenues for detailed classification of PC subtypes.

Hydrogen sulfide attenuates induction and prevents progress of the 6-hydroxydopamine-induced Parkinsonism in rat through activation of ATP-sensitive potassium channels and suppression of ER stress

PurposeStudies argue in favor of hydrogen sulfide (H2S) as the next potent therapeutic agent for neurodegenerative diseases. In present study, we investigated the effect of long term treatment with NaHS (as donor of H2S) on induction and progress of the 6-hydroxydopamine (6-OHDA) -induced Parkinsonism in rat. MethodsThe 6-OHDA was injected into medial forebrain bundle of right hemisphere by stereotaxic surgery. Behavioral tests and treatments were carried out to eight weeks after the toxin. Immunohistochemistry and western blotting were carried out to evaluate the survival of tyrosine hydroxylase (TH) -positive neurons in substantia nigra (SN) and also expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of endoplasmic reticulum (ER) stress, in striatum and SN. ResultsEight weeks assessment of the behavioral symptoms showed that NaHS especially at dose of 100 μmol/kg attenuates remarkably induction of the Parkinsonism and prevents its progress. NaHS also increased the survival of TH- positive neurons and suppressed 6-OHDA- induced overexpression of GRP78 and CHOP. Blockade of ATP-sensitive potassium (K-ATP) channels with glibenclamide (Glib) prevented markedly the effect of NaHS on both the induction phase and survival of TH- positive neurons. But Glib did not affect the preventing effect of NaHS on the progress phase and its suppressing effect on the overexpression of ER stress markers. ConclusionH2S attenuates induction of the 6-OHDA- induced Parkinsonism and also increases the survival of dopaminergic neurons through activation of K-ATP channels. H2S also prevents progress of the Parkinsonism probably through suppression of ER stress.

Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain.

Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Nav1.8 and CGRPα. Ablating neurons expressing Nav1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of Kv1 voltage-gated potassium channels. Thus, silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.

Calcium Transients and Transmitter Secretion in Different Parts of Frog Nerve Endings in Different Conditions of Calcium Ion Influx

Experiments on frog neuromuscular preparations were performed to study the characteristics of the calcium response and the quantum secretion of acetylcholine in different pats of extended nerve terminals in different conditions of calcium influx. A calcium-sensitive fluorescent dye was used to analyze Ca2+ influx (Ca2+ transients) into the proximal and distal parts of nerve endings in conditions of increased K+ ion content, in response to blockers of N- and L-type calcium channels, and on blockade of calcium-activated potassium channels. These studies showed that at a uniform distribution density of voltage-gated calcium channels along nerve endings, the proximal-to-distal decrement in calcium transients and quantum secretion intensity persisted in conditions of additional opening of voltage-gated calcium channels by potassium depolarization, on “thinning” of these channels using specific blockers, but changed on blockade of calcium-activated potassium channels.

Guidance on Short-Term Management of Atrial Fibrillation in Coronavirus Disease 2019.

Atrial fibrillation is a common clinical manifestation in hospitalized patients with coronavirus disease 2019 (COVID‐19). Medications used to treat atrial fibrillation, such as antiarrhythmic drugs and anticoagulants, may have significant drug interactions with emerging COVID‐19 treatments. Common unintended nontherapeutic target effects of COVID‐19 treatment include potassium channel blockade, cytochrome P 450 isoenzyme inhibition or activation, and P‐glycoprotein inhibition. Drug‐drug interactions with antiarrhythmic drugs and anticoagulants in these patients may lead to significant bradycardia, ventricular arrhythmias, or severe bleeding. It is important for clinicians to be aware of these interactions, drug metabolism changes, and clinical consequences when choosing antiarrhythmic drugs and anticoagulants for COVID‐19 patients with atrial fibrillation. The objective of this review is to provide a practical guide for clinicians who are managing COVID‐19 patients with concomitant atrial fibrillation.

Chloroquine, hydroxychloroquine and COVID-19

The media have featured the antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) to treat coronavirus (COVID-19). Political leaders have touted their use and recommended availability to the public. These anti-inflammatory agents have substantial human toxicity with a narrow therapeutic window. CQ and HCQ poisoning cause myocardial depression and profound hypotension due to vasodilation. Bradycardia and ventricular escape rhythms arise from impaired myocardial automaticity and conductivity due to sodium and potassium channel blockade. With cardiotoxicity, ECGs may show widened QRS, atrioventricular heart block and QT interval prolongation. CQ may also cause seizures, often refractory to standard treatment. Of concern is pediatric poisoning, where 1-2 pills of CQ or HCQ can cause serious and potentially fatal toxicity in a toddler. The treatment of CQ/HCQ poisoning includes high-dose intravenous diazepam postulated to have positive ionotropic and antidysrhythmic properties that may antagonize the cardiotoxic effects of CQ. Infusions of epinephrine titrated to treat unstable hypotension, as well as potassium for severe hypokalemia may be required. Current scientific evidence does not support treatment or prophylactic use of these agents for COVID-19 disease. Regulatory and public health authorities recognize that CQ/HCQ may offer little clinical benefit and only add risk requiring further investigation before wider public distribution.

Aristoteline, an Indole-Alkaloid, Induces Relaxation by Activating Potassium Channels and Blocking Calcium Channels in Isolated Rat Aorta.

Alkaloids derived from plants have shown great medicinal benefits, and are often reported for their use in cardiovascular disease management. Aristotelia chilensis (Molina) Stuntz (Maqui) has shown important medicinal properties in traditional useage. In this study, we evaluated the effect of the indole-alkaloid aristoteline (ARI), isolated from leaves of Maqui, on vascular reactivity of isolated aortic rings from normotensive rats. ARI induced relaxation (100%) in a concentration-dependent manner in intact or denuded-endothelium aortic rings pre-contracted with phenylephrine (PE; 1 μM). However, a specific soluble guanylyl cyclase inhibitor (ODQ; 1 μM) significantly reduced the relaxation to ARI in aortic rings pre-contracted with PE. In the presence of ARI, the contraction induced by KCl or PE was significantly (p < 0.05) decreased. Interestingly, the potassium channel blockade with 10 μM BaCl2 (Kir), 10 μM glibenclamide (KATP), 1 mM tetraethylammonium (TEA; KCa1.1), or 1 mM 4-aminopyridine (4-AP; Kv) significantly (p < 0.05) reduced the ARI-induced relaxation. ARI significantly (p < 0.05) reduced the contractile response to agonist of CaV1.2 channels (Bay K8644; 10 nM), likely reducing the influx of extracellular calcium through plasma membrane. The mechanisms associated with this process suggest an activation of the potassium channels, a calcium-induced antagonism and endothelium independent vasodilation that possibly involves the nitric oxide-independent soluble guanylate cyclase pathway.

Blockade of voltage-gated potassium channels ameliorates diabetes-associated cognitive dysfunction in vivo and in vitro

The voltage-gated potassium (Kv) channel blockers tetraethylammonium (TEA) and 4-aminopyridine (4-AP) have shown beneficial effects on some neurological disorders. But their involvements in diabetes-associated cognitive dysfunction are still unknown. The present study aims to investigate whether the blockade of Kv channels by TEA and 4-AP alleviate cognitive decline in diabetes. In vivo, the effects of TEA and 4-AP (5 mg/kg body weight per day, 1 mg/kg body weight per day intraperitoneal injected for 4 weeks, respectively) were investigated in streptozotocin-induced C57BL/6 diabetic mice. In vitro study, we investigated the effects of TEA and 4-AP on the high glucose (HG) -stimulated primary cortical neurons. The results showed that TEA and 4-AP ameliorated the cognitive decline of diabetic mice in the Morris water maze test, improved the ultrastructure of pancreatic β cells, hippocampal neurons and synapses, decreased oxidative stress, modulated apoptosis-related proteins, and activated phosphatidylinositol 3-kinase (PI3K)/ Protein kinase-B (PKB or Akt) signaling pathway. In the HG-stimulated primary cultured cortical neurons, TEA and 4-AP increased the cell viability, decreased oxidative stress; prevented apoptosis and activated PI3K/Akt signaling pathway. Additionally, the PI3K inhibitor LY294002 partially abolished the effects of TEA and 4-AP. These findings indicate that the blockade of Kv channels by TEA and 4-AP ameliorates the diabetes-associated cognitive dysfunction via PI3K/Akt pathway, suggesting that targeting Kv channels could be a promising strategy for the treatments of cognitive impairments in diabetes.