Inhibition Of Electrical Activity Research Articles

Burst suppression and its relationship with anesthetics

Burst suppression (BS) is a sign of severe inhibition of electrical activity in the cerebral cortex. Anesthetic is a common reason of inducing BS. Hitherto, the mechanism underlying BS is unclear. The dose of anesthetic alone or in combination inducing BS is an important research target. This review presents current research advances of BS home and abroad, including the relationship between anesthetics and BS, the definition, judgment criteria and prognosis of BS. In the future, burst suppression ratio (BSR) can be used as a routine monitoring index for clinical anesthesia, making it easier for anesthesiologists to adjust the depth of anesthesia. Key words: Burst suppression; Burst suppression ratio; Anesthetics; Bispectral index

Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease, where neural progenitor cell (NPC) transplantation has been suggested as a potential neuroprotective therapeutic strategy. Since the effect of inflammation on NPCs is poorly known, their effect on the survival and functionality of human NPCs were studied. Treatment with interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ did not induced cytotoxicity, but IFN-γ treatment showed decreased proliferation and neuronal migration. By contrast, increased proliferation and inhibition of electrical activity were detected after TNF-α treatment. Treatments induced secretion of inflammatory factors. Inflammatory cytokines appear to modulate proliferation as well as the cellular and functional properties of human NPCs.

Electrical stimulation of cerebellar fastigial nucleus: mechanism of neuroprotection and prospects for clinical application against cerebral ischemia.

For around two decades, electrical fastigial nucleus stimulation (FNS) has been demonstrated to induce neuroprotection involving multiple mechanisms. In this review, we summarize the protective effects of FNS against cerebral ischemia through the inhibition of electrical activity around the lesion, excitotoxic damage on neurons, and brain inflammatory response, as well as apoptosis. Moreover, FNS has been reported to promote nerve tissue repair, reconstruction, and neurological rehabilitation and improve stroke-related complications including poststroke cognitive dysfunction, depression, and abnormal heart rate variability. We thus further discuss the potential of FNS for clinical applications. Given the absence of any risk of inducing sublethal damage, FNS may offer a new approach to preconditioned neuroprotection against cerebral ischemia.

Syndecan-4 and β1 integrin are regulated by electrical activity in skeletal muscle: Implications for cell adhesion

Syndecan-4 and integrins are involved in the cell migration and adhesion processes in several cell types. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is associated to focal adhesions in adherent cells and has been described as a marker of satellite cells in skeletal muscle. In this tissue, β1 integrin forms heterodimers with α5 and α6 during myoblast differentiation and with α7 in adult muscle. Here, we show that the levels of these two cell surface membrane molecules are regulated by spontaneous electrical activity during the differentiation of rat primary myoblasts. Syndecan-4 and β1 integrin protein levels decrease after the inhibition of electrical activity using tetrodotoxin (TTX). Syndecan-4 also decreases substantially in denervated rat tibialis anterior muscle. Indirect immunofluorescence analysis shows that syndecan-4 and β1 integrin co-localize with vinculin, a molecular marker of costameres in skeletal muscle myofibers. Co-localization is lost in inactive myotubes adopting a diffuse pattern, suggesting that the costameric organization is disrupted in TTX-treated myotubes. Moreover, the inhibition of spontaneous electrical activity decreases myotube cell adhesion. In summary, this work shows that syndecan-4 and β1 integrin protein levels and their localization in costameric structures are regulated by electrical activity and suggests that this regulatory mechanism influences the adhesion properties of skeletal myotubes during differentiation.

Inhibition of Electrical Activity by Retroviral Infection with Kir2.1 Transgenes Disrupts Electrical Differentiation of Motoneurons

Network-driven spontaneous electrical activity in the chicken spinal cord regulates a variety of developmental processes including neuronal differentiation and formation of neuromuscular structures. In this study we have examined the effect of chronic inhibition of spinal cord activity on motoneuron survival and differentiation. Early spinal cord activity in chick embryos was blocked using an avian replication-competent retroviral vector RCASBP (B) carrying the inward rectifier potassium channel Kir2.1. Chicken embryos were infected with one of the following constructs: RCASBP(B), RCASBP(B)-Kir2.1, or RCASBP(B)-GFP. Infection of chicken embryos at E2 resulted in widespread expression of the viral protein marker p27 gag throughout the spinal cord. Electrophysiological recordings revealed the presence of functional Kir2.1 channels in RCASBP(B)-Kir2.1 but not in RCASBP(B)-infected embryos. Kir2.1 expression significantly reduced the generation of spontaneous motor movements in chicken embryos developing in ovo. Suppression of spontaneous electrical activity was not due to a reduction in the number of surviving motoneurons or the number of synapses in hindlimb muscle tissue. Disruption of the normal pattern of activity in chicken embryos resulted in a significant downregulation in the functional expression of large-conductance Ca2+-dependent K+ channels. Reduction of spinal cord activity also generates a significant acceleration in the inactivation rate of A-type K+ currents without any significant change in current density. Kir2.1 expression did not affect the expression of voltage-gated Na+ channels or cell capacitance. These experiments demonstrate that chronic inhibition of chicken spinal cord activity causes a significant change in the electrical properties of developing motoneurons.

Transforming Growth Factor β (TGF-β) Signaling Is Regulated by Electrical Activity in Skeletal Muscle Cells: TGF-β TYPE I RECEPTOR IS TRANSCRIPTIONALLY REGULATED BY MYOTUBE EXCITABILITY

Transforming growth factor (TGF-beta) is involved in several cellular processes such as cell proliferation, differentiation, and apoptosis. At the cell surface, TGF-beta binds to serine-threonine kinase transmembrane receptors (type II and type I) to initiate Smad-dependent intracellular signaling cascades. During the early stages of skeletal muscle differentiation, myotubes start to evoke spontaneous electrical activity in association with contractions that arise following the maturation of the excitation-contraction apparatus. In this work, we report that TGF-beta-dependent signaling is regulated by electrical activity in developing rat primary myotubes, as determined by Smad2 phosphorylation, Smad4 nuclear translocation, and p3TPLux reporter activity. This electrical activity-dependent regulation is associated with changes in TGF-beta type I receptor (TbetaRI) levels, correlated with changes in transducing receptors at the cell membrane (measured through radiolabeling binding assays). The inhibition of electrical activity with tetrodotoxin, a voltage-dependent sodium channel blocker, increases TbetaRI levels via a transcription-dependent mechanism. In contrast, the promotion of electrical activity in myotube cultures, induced by the up-regulation of voltage-dependent sodium channels or by direct stimulation with extracellular electrodes, causes TbetaRI levels to decrease. Similar results were obtained in denervated adult muscles, suggesting that electrical activity-dependent regulation of TbetaRI also occurs in vivo. Additional results suggest that this activity-dependent regulation is mediated by myogenin. Altogether, these findings support the possibility for a novel regulatory mechanism acting on TGF-beta signaling cascade in skeletal muscle cells.

Evidence for the involvement of the cyclooxygenase-metabolic pathway in diclofenac-induced inhibition of spontaneous contraction of rat portal vein smooth muscle cells

The effects of diclofenac, a cyclooxygenase (COX) inhibitor, were investigated on spontaneous phasic contractions of longitudinal preparations of the rat portal vein. Diclofenac produced a concentration-dependent decrease in the amplitude of these spontaneous phasic contractions. Diclofenac (30 microM) decreased the amplitude of the spontaneous phasic increase in the F340/F380 ratio of Fura PE3, an indicator of intracellular Ca2+ concentration. It also reduced the number of action potentials in each burst discharge without changing the resting membrane potential of longitudinal smooth muscle cells. The extent of the distribution of Lucifer Yellow injected into a smooth muscle cell was decreased in the presence of diclofenac (30 microM). Both AH6809, a prostanoid EP receptor antagonist, and SQ22536, an adenylate cyclase inhibitor, decreased the amplitude of the spontaneous contractions. On the other hand, neither ozagrel, a thromboxane synthase inhibitor, nor SQ29548, a prostanoid TP receptor antagonist, significantly affected spontaneous contractions. These results indicate that diclofenac inhibits the amplitude of spontaneous contractions of the rat portal vein through inhibition of electrical activity, which may be related to an inhibition of the cyclooxygenase pathway.

Insulin activates ATP-sensitive K(+) channels in pancreatic beta-cells through a phosphatidylinositol 3-kinase-dependent pathway.

Insulin is known to regulate pancreatic beta-cell function through the activation of cell surface insulin receptors, phosphorylation of insulin receptor substrate (IRS)-1 and -2, and activation of phosphatidylinositol (PI) 3-kinase. However, an acute effect of insulin in modulating beta-cell electrical activity and its underlying ionic currents has not been reported. Using the perforated patch clamp technique, we found that insulin (1-600 nmol/l) but not IGF-1 (100 nmol/l) reversibly hyperpolarized single mouse beta-cells and inhibited their electrical activity. The dose-response relationship for insulin yielded a maximal change (mean +/- SE) in membrane potential of -13.6 +/- 2.0 mV (P < 0.001) and a 50% effective dose of 25.9 +/- 0.1 nmol/l (n = 63). Exposing patched beta-cells within intact islets to 200 nmol/l insulin produced similar results, hyperpolarizing islets from -47.7 +/- 3.3 to -65.6 +/- 3.7 mV (P < 0.0001, n = 11). In single cells, insulin-induced hyperpolarization was associated with a threefold increase in whole-cell conductance from 0.6 +/- 0.1 to 1.7 +/- 0.2 nS (P < 0.001, n = 10) and a shift in the current reversal potential from -25.7 +/- 2.5 to -63.7 +/- 1.0 mV (P < 0.001 vs. control, n = 9; calculated K(+) equilibrium potential = -90 mV). The effects of insulin were reversed by tolbutamide, which decreased cell conductance to 0.5 +/- 0.1 nS and shifted the current reversal potential to -25.2 +/- 2.3 mV. Insulin-induced beta-cell hyperpolarization was sufficient to abolish intracellular calcium concentration ([Ca(2+)](i)) oscillations measured in pancreatic islets exposed to 10 mmol/l glucose. The application of 100 nmol/l wortmannin to inactivate PI 3-kinase, a key enzyme in insulin signaling, was found to reverse the effects of 100 nmol/l insulin. In cell-attached patches, single ATP-sensitive K(+) (K(ATP)) channels were activated by bath-applied insulin and subsequently inhibited by wortmannin. Our data thus demonstrate that insulin activates the K(ATP) channels of single mouse pancreatic beta-cells and islets, resulting in membrane hyperpolarization, an inhibition of electrical activity, and the abolition of [Ca(2+)](i) oscillations. We thus propose that locally released insulin might serve as a negative feedback signal within the islet under physiological conditions.

Involvement of platelet activating factor in the endotoxin‐induced effects on gastrointestinal electrical activity and some haematological parameters in the conscious miniature pig

In conscious miniature pigs the influence of intravenous dose of lipopolysaccharide (LPS), 10 μg/kg over 10 min, with and without pretreatment with a platelet activating factor (PAF) antagonist, SAH 63‐675 10 mg/kg, on gastrointestinal electrical activity, arterial pressure and clinical and haematological parameters was studied. Dose of LPS provoked mild clinical signs and hypotension, which were prevented by PAF antagonism. The LPS induced leukocytosis and increase in mature neutrophils, however, were PAF independent. Pretreatment with the PAF antagonist attenuated the LPS‐provoked inhibition of electrical activity in the antrum, jejunum, ileum and caecum. These results suggest a beneficial effect of PAF antagonism in porcine endotoxaemia.

Role of nitric oxide in the contraction of circular muscle in the rat portal vein.

The role of nitric oxide in the electrical and mechanical activities of the rat portal vein was examined in circular muscle preparations with intact endothelium that were isolated from the longitudinal muscle layer. In contrast to the longitudinal muscle preparation, the circular muscle preparation did not show spontaneous phasic contraction. Inhibition of nitric oxide synthesis by Nomega-nitro-L-arginine (L-NNA) induced a tonic contraction. The contraction was inhibited by L-arginine, sodium nitroprusside or nifedipine. L-NNA did not induce contraction in endothelium-damaged preparations. The membrane potential of smooth muscle cells recorded in endothelium-intact preparations showed sporadic action potentials. L-NNA increased the frequency of action potentials without changing the resting membrane potential. The action potentials were inhibited by nifedipine. In the presence of L-NNA, sodium nitroprusside decreased the frequency of the action potentials without changing the resting membrane potential. These results indicated that contraction of rat portal vein circular muscles is inhibited tonically by nitric oxide, at least partly through inhibition of electrical activity.

Gramicidin-perforated patch revealed depolarizing effect of GABA in cultured frog melanotrophs.

1. In frog pituitary melanotrophs, GABA induces a transient stimulation followed by prolonged inhibition of hormone secretion. This biphasic effect is inconsistent with the elevation of cytosolic calcium and the inhibition of electrical activity also provoked by GABA in single melanotrophs. In the present study, standard patch-clamp configurations and gramicidin-perforated patches were used to investigate the physiological GABAA receptor-mediated response and intracellular chloride concentration ([Cl-]i) in cultured frog melanotrophs. 2. In the gramicidin-perforated patch configuration, 1 microM GABA caused a depolarization associated with an action potential discharge and a slight fall of membrane resistance. In contrast, at a higher concentration (10 microM) GABA elicited a depolarization accompanied by a transient volley of action potentials, followed by a sustained inhibitory plateau and a marked fall of membrane resistance. Isoguvacine mimicked the GABA-evoked responses, indicating a mediation by GABAA receptors. 3. In gramicidin-perforated cells, the depolarizing excitatory effect of 1 microM GABA was converted into a depolarizing inhibitory action when 0.4 microM allopregnanolone was added to the bath solution. 4. After gaining the whole-cell configuration, the amplitude and/or direction of the GABA-evoked current (IGABA) rapidly changed before stabilizing. After stabilization, the reversal potential of IGABA followed the values predicted by the Nernst equation for chloride ions when [Cl-]i was varied. 5. In gramicidin-perforated cells, the steady-state I-V relationships of 10 microM GABA- or isoguvacine-evoked currents yielded reversal potentials of -37.5 +/- 1.6 (n = 17) and -38.6 +/- 2.0 mV (n = 8), respectively. These values were close to those obtained by using a voltage-ramp protocol in the presence of Na+, K+ and Ca2+ channel blockers. The current evoked by 1 microM GABA also reversed at these potentials. 6. We conclude that, in frog pituitary melanotrophs, chloride is the exclusive charge carrier of IGABA. In intact cells, the reversal potential of IGABA is positive to the resting potential because of a relatively high [Cl-]i (26.5 mM). Under these conditions, GABA induces a chloride efflux responsible for a depolarization triggering action potentials. However, GABA at a high concentration or in the presence of the potentiating steroid allopregnanolone exerts a concomitant shunting effect leading to a rapid inhibition of the spontaneous firing.

The diabetogenic agent alloxan increases K+ permeability by a mechanism involving activation of ATP-sensitive K(+)-channels in mouse pancreatic beta-cells.

The effects of the diabetogenic agent, alloxan, on membrane potential, input resistance and electrical activity of normal mouse pancreatic beta-cells were studied. Tetraethylammonium (TEA), quinine and Glyburide were used to block K(+)-channels and to elucidate the mechanisms underlying alloxan's effects on beta-cell membrane potential. Exposure of the islet to alloxan (75-100 microM) in the presence of glucose (11 mM), produced a rapid (15 sec), transient inhibition of electrical activity, often accompanied by hyperpolarization of the membrane, and this was followed by recovery of the burst pattern. This early effect of alloxan was followed after approximately 15 min by a complete inhibition of electrical activity and hyperpolarization. The inhibition accompanied by hyperpolarization was associated with a decrease in input resistance, indicating increased K(+)-conductance. Both the transient and delayed effects of alloxan were blocked by glucose (33 mM), quinine and glyburide but not by other conditions which induce continuous electrical activity such as elevated external [K+] (10 mM), ouabain, K+ removal, or TEA (20 mM). The transient inhibition induced by alloxan may be due to a direct competition with glucose transport/metabolism since it did not occur when alpha-keto isocaproic acid (KIC) was used to induce electrical activity. The delayed inhibition may reflect indirect effects of accumulation of this agent or its metabolites within the cell. Since both effects of alloxan are blocked by glyburide they appear to involve activation of the ATP-sensitive K(+)-channel (K-ATP).

Glucose-induced increase in cytoplasmic pH in pancreatic beta-cells is mediated by Na+/H+ exchange, an effect not dependent on protein kinase C.

Glucose-induced changes in cytoplasmic pH (pHi) were investigated using pancreatic beta-cells isolated from obese hyperglycemic mice. Glucose, at concentrations above 3-5 mM, depolarized the beta-cell and increased pHi, cytoplasmic free Ca2+ ([Ca2+]i), and insulin release. This increase in pHi was dependent on the presence of extracellular Na+ and was inhibited by 5-(N-ethyl-N-isopropyl) amiloride, a blocker of Na+/H+ exchange. Stimulation of protein kinase C with phorbol ester also induced an alkalinization. However, when protein kinase C activity was down-regulated, glucose stimulation still induced alkalinization. At 20 mM glucose, 10 mM NH4Cl induced a marked rise in pHi, paralleled by repolarization, inhibition of electrical activity, and decreases in both [Ca2+]i and insulin release. Reduction in [Ca2+]i was prevented by 200 microM tolbutamide, but not by 10 mM tetraethylammonium. At 4 mM glucose, NH4Cl induced a transient increase in insulin release, without changing [Ca2+]i. Exposure of beta-cells to 10 mM sodium acetate caused a persistent decrease in pHi, an effect paralleled by a small transient increase in [Ca2+]i. Acidification per se did not change the beta-cell sensitivity to glucose, not excluding that the activity of the ATP-regulated K+ channels may be modulated by changes in pHi.

Inhibition of electrical activity in mouse pancreatic β-cells by the ATP/ADP translocase inhibitor, bongkrekic acid

Bongkrekic acid causes fatal food poisoning which is associated with hyperglycaemia. Here we demonstrate that bongkrekic acid, a potent inhibitor of the mitochondrial ATP/ADP translocase, inhibits glucose-induced electrical activity in the pancreatic β-cell through the simulation of ATP-sensitive potassium channel (K-ATP-channel) activity. By comparison of its effects with those of oligomycin, we suggest that bongkrekic acid acts by the inhibition of glucose metabolism and may induce hyperglycaemia by impairing β-cel function.

Neurophysiological events during the head critical period for prothoracicotropic hormone release in fourth-instar larvae of Manduca sexta

The initiation of larval moulting in the tobacco hornworm, Manduca sexta, involves an endocrine cascade that begins with the release of the cerebral prothoracicotropic hormone (PTTH) from the retrocerebral corpora allata. During the fourth larva instar of Manduca when the gated release of PTTH occurs, the in situ electrical activity of the nervi corporis cardiaci (NCC I + II), the paired nerve trunks from the brain that innervate the corpora cardiaca and more distal corpora allata, undergoes a distinct change in firing pattern. The initial change in pattern, from a steady firing, was a brief, intense burst of relatively large units followed by a short period (3–10 min) of completely suppressed activity. Next, bursting activity of several different units resumed, and depending upon the preparation, this event was either long or short in duration. This unique bursting pattern occurred at about the head critical period for PTTH release and was expressed by the brain-corpus cardiacum-allatum both in situ and in vitro. The complexity of the action potential patterns suggests that a variety of neurosecretory cell types may be involved in a coordinated, transient inhibition of electrical activity of the NCC I + II that is followed by selective disinhibition of a specific set of cerebral neurones that, based upon the release of PTTH from the corpus cardiacum-allatum preparations, culminates in PTTH release. That this neurophysiological event occurs at a precise time and occurs in vitro suggests that a pattern generator for the unique bursting firing and a clock mechanism controlling this event reside within the brain-corpus cardiacum-allatum. The significance of these results in relation to the neuroendocrinology of larval mounting is discussed.

Hypothalamic modulation of baroreceptor-induced inhibition of electrical activity in the renal nerve

Hypothalamic modulation of baroreceptor-induced inhibition of electrical activity in the renal nerve

Effects of Zn2+ on glucose-induced electrical activity and insulin release from mouse pancreatic islets.

The effects of Zn2+ and CO2+ on glucose-induced beta-cell electrical activity and on insulin release from microdissected mouse pancreatic islets were studied. In 11 mM glucose the electrical activity is characterized by a burst pattern with a bimodal distribution of spike amplitudes along the plateau phase. Zn2+ at 0.05 mM induced a reduction in the number of spikes during the bursts and preferentially blocked the large action potentials. Zn2+ at 0.1 mM and CO2+ at 1.0 mM completely inhibited the electrical activity in response to glucose. Zn2+ inhibition of electrical activity was poorly reversible, whereas CO2+ inhibition was rapidly and completely reversible. Zn2+ and CO2+ inhibited the glucose-stimulated insulin release from microdissected perifused islets. Half-maximal inhibition occurred at about 0.3 mM for both metals. Zn2+ also inhibited K+-induced insulin release in the absence of glucose, indicating that Zn2+ inhibition does not involve glucose metabolism. It is proposed that Zn2+ blocks the voltage-gated Ca2+ channels in pancreatic beta-cells.

Islet electrical pacemaker response to alpha-adrenergic stimulation.

To characterize the pancreatic islet cell responses to adrenergic stimulation, membrane potentials have been recorded from isolated, perifused mouse islets of Langerhans exposed to a steady glucose level of 200 mg/dl. Various doses of epinephrine HCl from 5 to 10,000 nM have been applied for 10--15-min test periods separated by 10--15-min control periods. Epinephrine produced a dose-dependent suppression of glucose-induced membrane electrical activity. Adding epinephrine (50--100 nM) reduced the plateau fraction (the fraction of each plateau/silent phase cycle spent in the plateau phase) from 0.41 +/- 0.03 (X +/- SEM, N = 13) to 0.28 +/- 0.08 (N = 5, P = 0.05) and more markedly reduced the plateau frequency from 2.56 +/- 0.32 (N = 13) to 0.80 +/- 0.23 min-1 (N = 5, P less than 0.02). Adding 10- and 100-fold higher concentrations of epinephrine had little additional effect. There was no effect of epinephrine on the membrane potential levels of the plateau and silent phase after a new steady state was achieved and no effect on the amplitude and waveform of the rapid spikes. The pattern of inhibition of the plateau/silent phase cycles by epinephrine is qualitatively different from the pattern seen during inhibition of electrical activity by reducing glucose level. This suggests that the electrical rhythm is controlled by more than one pathway. The persistence of electrical activity at very high levels of epinephrine (to 10,000 nM) suggests that electrical activity and, therefore, Ca2+ uptake can exist in the absence of insulin release.

Effect of stimulation of the medial and lateral zones of the respiratory center on electrical activity of the diaphragm, intercostal muscles, and phrenic neurons

Experiments on cats showed that the nucleus of the solitary tract displayed zones whose stimulation provoked separately stimulation or inhibition of the electrical activity of the phrenic neurons and the diaphragm. Stimulation in the nucleus ambiguus of such zones caused stimulation and inhibition of electrical activity of the intercostal inspiratory muscles. In stimulation of the corresponding zone in the giant cell nucleus the electrical activity of both groups of the inspiratory muscles proved to change. It is suggested that the action of stimulation of the giant cell nucleus zones on both groups of inspiratory muscles is mediated through the neurons of the solitary tract and the nucleus ambiguus.

Effects of noradrenaline on the membrane potential and ionic permeability of parenchymal cells in the liver of the guinea-pig.

CATECHOLAMINES exert most of their biological actions through two main types of pharmacological receptor which are usually described as α and β, following Ahlquist1. It has recently been shown that in smooth muscle the α receptors act by increasing the permeability of the cell membranes to inorganic ions2,3. In intestinal muscle, the permeability increase is chiefly to potassium and perhaps chloride so that the outcome is hyperpolarization and inhibition of electrical activity, whereas in most other kinds of smooth muscle it is likely that the permeability increase extends to Na and to Ca, as well as to K, so that the membrane potential falls, leading to excitation and contraction.