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Results for “Potassium Channel Blockers”

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PubMed1996

Altered contractility of rabbit penile corpus cavernosum smooth muscle by hypoxia.

PURPOSE: To investigate the effects of severe hypoxia on trabecular smooth muscle contractility. MATERIALS AND METHODS: Strips of rabbit corpus cavernosum were mounted in organ chambers to measure isometric tension. In some experiments intracellular free Ca2+ concentration and tension were measured by the intracellular fluorescent dye FURA-2 and isometric tension recording simultaneously. RESULTS: Contractions elicited by norepinephrine, endothelin-1 or potassium were attenuated under hypoxic conditions (pO2 approximately 10 mm. Hg). Strips contracted with 20 mM. K+ under normoxic conditions and then exposed to hypoxia consistently lost the potassium-induced tone. The hypoxia-induced relaxation was not affected by the removal of the endothelium, by treatment with the cyclooxygenase blocker, indomethacin, or with the guanylate cyclase blocker, methylene blue. The potassium channel opener, cromakalim, and adenosine relaxed potassium contracted strips; however, the potassium channel blockers glibenclamide, apamin, barium chloride and charybdotoxin or the adenosine receptor antagonist 8-(p-sulfonyl)theophylline were unable to prevent hypoxia-induced relaxation. Tetraethylammonium, a potassium channel blocker, and the depolarizing agents ouabain and high potassium (80 mM.), partially prevented hypoxia-induced relaxation. The calcium ionophore, ionomycin, had no effect on hypoxia-induced relaxations. Hypoxia, within 2 to 6 minutes, caused a large accumulation in intracellular calcium, concomitant with a loss of trabecular smooth muscle tone. Both these effects could be reproduced by inhibiting oxidative phosphorylation with 2,4,dinitrophenol. Reoxygenation resulted in an immediate recovery of both tone and intracellular calcium levels. Tissues under hypoxic conditions for 30 minutes had a 24% and 67% decrease in the ATP/ADP ratio and in creatine phosphate concentrations, respectively. CONCLUSION: Hypoxia causes a simultaneous increase in intracellular calcium and relaxation which, we propose, is the consequence of inhibition of oxidative phosphorylation with loss of high energy phosphates, necessary for the homeostasis of Ca2+ and the contractile mechanism of the cavernosal smooth muscle.

Adenosine Diphosphate↗

PubMed1994

Electrophysiological properties of neonatal mouse cardiac myocytes in primary culture.

1. The increasing utility of transgenic mice in molecular studies of the cardiovascular system has motivated us to characterize the ionic currents in neonatal mouse ventricular myocytes. 2. Cell capacitance measurements (30 +/- 1 pF, n = 73) confirmed visual impressions that neonatal mouse ventricular myocytes in primary culture are considerably smaller than freshly isolated adult ventricular myocytes. With the use of electron microscopy, mitochondria and sarcoplasmic reticulum were found in close association with myofibrils, but transverse tubules were not observed. 3. Action potential durations, measured at 50 and 90% repolarization, were 23 +/- 1 and 42 +/- 2 ms respectively (n = 46). Application of 4-aminopyridine (4-AP; 5 mM) prolonged action potential duration at 50% repolarization by 26 +/- 5% (n = 3). The brevity of the action potential is explained by the rapid activation of a transient outward K+ current upon voltage-clamp depolarization to plateau potentials. 4. Potassium currents identified include an inward rectifier, a large 4-AP-sensitive transient outward, a slowly inactivating 4-AP-insensitive outward, a slowly activating delayed rectifier and a small rapidly activating E-4031 (10 microM)-sensitive delayed rectifier K+ current. 5. Sodium currents (-305 +/- 50 pA pF-1, n = 21) were recorded in 40 mM Na+ with Ni2+ (1 mM) to block Ca2+ currents and with K+ replaced by Cs+. The relative insensitivity of the Na+ current to block by tetrodotoxin (IC50 = 2.2 +/- 0.3 microM, n = 4) is distinctive of the cardiac Na+ channel isoform. 6. Nitrendipine-insensitive (10 microM) Ba2+ currents elicited during steps from -90 to -30 mV measured -25 +/- 5 pA pF-1 (n = 7, 30 mM Ba2+). Decay of these currents was complete during 180 ms depolarizations, even with Ba2+ as the charge carrier. These currents were not present when the holding potential was set at -50 mV. These data support the presence of a low threshold, T-type Ca2+ current. 7. The maximal nitrendipine-sensitive L-type Ca2+ current density was -10 +/- 2 pA pF-1 (n = 8) in 2 mM Ca2+ and -38 +/- 5 pA pF-1 (n = 9) in 30 mM Ba2+. Exposure to isoprenaline (1 microM) resulted in an 82% increase (n = 3) in the amplitude of the Ba2+ currents elicited at 0 mV. 8. Neonatal mouse cardiac myocytes in primary culture possess surprisingly large inward currents given the brevity of their action potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1989

Interactions between dendrotoxin, a blocker of voltage-dependent potassium channels, and charybdotoxin, a blocker of calcium-activated potassium channels, at binding sites on neuronal membranes.

Dendrotoxin I (DpI) from black mamba venom (Dendroaspis polylepis) has high affinity binding sites on rat brain synaptic membranes. Native DpI displaced [125I]-DpI binding with a Ki of 1 x 10(-10) M, and over 90% of specific binding was displaceable. Charybdotoxin isolated from the Israeli scorpion venom (Leiurus quinquestriatus hebraeus), also displaced [125I]-DpI binding, with a Ki of approximately 3 x 10(-9) M, although the displacement curve was shallower than with native DpI. Both toxins are thought to be high affinity blockers of specific K+ currents. Charybdotoxin selectively blocks some types of Ca2+-activated K+ channels, whereas dendrotoxins only block certain voltage-dependent K+ channels. The interaction between the two types of toxin at the DpI binding site is unexpected and may suggest the presence of related binding sites on different K+ channel proteins.

Animals↗

PubMed2002

Changes in the expression and function of arterial potassium channels during hypertension.

Altered function of K+ channels associated with hypertension has been inferred from the effects of K+ channel blockers on contraction of arterial smooth muscle cells (SMCs) and from K+ efflux measurements. Of the classes of K+ channels known to exist in the smooth muscle, the contribution of voltage-gated (KV) and high-conductance, Ca2+ gated K+ (BKCa) channels to the regulation of arterial SMC contractile function has been the most studied in hypertension. The effects of selective and nonselective K+ channel blockers on tonic contraction suggest that these two K+ channel gene families contribute differently to total K+ conductance in arterial SMCs from normal and hypertensive subjects. Direct measurements of K+ channel properties by electrophysiological methods generally support this conclusion. Studies have demonstrated larger BKCa currents in SMCs from several arteries of hypertensive rats, which have been reported to result from a greater Ca2+ sensitivity of BKCa channels and/or from greater protein expression. Some, but not all, studies have shown decreased KV currents in arterial SMCs from hypertensive animals measured under Ca(2+)-replete conditions. However, when external Ca2+ is removed or when Ca2+ influx is inhibited, KV currents are larger in SMCs exposed to chronic hypertension. Gene expression studies of Shaker KV1 transcripts have shown that of the dominant species present in arterial SMCs, KV1.2 expression is higher, whereas KV1.5 is the same in SMCs from hypertensive compared to normal animals. This finding is consistent with the larger KV currents in vascular SMCs from hypertensive animals under low Ca2+ conditions and suggests that Ca2+ influx and/or intracellular Ca2+ per se exerts a greater inhibitory effect on KV currents in the myocytes from these animals. The pathways by which these K+ channel differences are produced during hypertension remain to be elucidated, as does the potential for these channel proteins to be targeted by novel antihypertensive therapies.

Animals↗

PubMed1996

Halothane and potassium channels in airway smooth muscle.

Earlier studies have suggested that halothane may relax smooth muscle in part by opening adenosine triphosphate-sensitive potassium (KATP) channels. We tested this hypothesis in vitro by examining the interaction of halothane with glibenclamide, a KATP channel blocker, and YM934, a KATP channel opener, in strips of canine tracheal smooth muscles mounted in an organ bath system. To examine the specificity of any effects of halothane on the KATP channel, we assessed the interaction of halothane with tetraethylammonium (TEA), an antagonist of the large-conductance, calcium-activated potassium channel. Experiments were conducted with drugs added before exposure to increasing concentrations of acetylcholine (ACh), and with drugs added after stable increases in force produced by ACh were achieved (ACh precontraction). Exposure to halothane 0.62 mmol litre-1 (equivalent to approximately 2 MAC) increased significantly the ED50 for ACh-induced contractions (by 0.24 (SEM 0.07) mumol litre-1). TEA 1 mmol litre-1 but not glibenclamide 10 mumol litre-1 significantly augmented this increase in ED50 (by an additional 0.17 (0.06) mumol litre-1). In strips precontracted with ACh, TEA, but not glibenclamide, potentiated concentration-dependent relaxation induced by halothane. Incubation with YM934 0.32 mumol litre-1 increased significantly the ED50 for ACh-induced contractions (from 0.12 (0.02) to 0.55 (0.11) mumol litre-1), an increase not affected by exposure to halothane 0.72 mmol litre-1. When added to strips precontracted with approximately ACh 0.3 mumol litre-1, YM934 produced concentration-dependent relaxation; halothane had little effect on this relaxation. These results do not support the hypothesis that halothane relaxes canine tracheal smooth muscle in part by opening KATP channels.

Acetylcholine↗

PubMed2005

Activation of mitochondrial ATP-sensitive potassium channels improves rotenone-related motor and neurochemical alterations in rats.

Our previous studies revealed that activation of mitochondrial ATP-sensitive potassium channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive potassium-channel opener, and diazoxide, a selective mitochondrial ATP-sensitive potassium-channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium-channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive potassium channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.

Animals↗

PubMed2006

The role of potassium channels in the vasodilatory effect of levosimendan in human internal thoracic arteries.

OBJECTIVE: We investigated the role of potassium channels in vasodilatory effect of levosimendan in human internal thoracic arteries. METHODS: Samples of redundant internal thoracic arteries obtained from patients undergoing a coronary artery bypass graft surgery were cut into 3 mm wide rings and suspended in 20 ml organ baths. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. RESULTS: Levosimendan (10(-8)-10(-5) M) or cromakalim (10(-8)-10(-5) M) produced concentration-dependent relaxation responses in human internal thoracic arteries precontracted by 10(-6) M phenylephrine. The relaxant responses to levosimendan did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of human internal thoracic artery rings with adenosine 3',5'-triphosphate (ATP)-dependent potassium channel blocker glibenclamide (10(-6) M) for 30 min significantly inhibited the relaxant responses to both levosimendan and cromakalim. The Ca2+-activated potassium channel blocker iberiotoxin (10(-7) M) also caused a significant but smaller inhibition on relaxant responses to levosimendan. Incubation of the rings with the voltage-dependent potassium channel blocker 4-aminopyridine (5 mM) for 10 min did not cause significant alterations in relaxant responses to levosimendan. CONCLUSIONS: The findings of this study suggested that levosimendan-induced relaxation responses in human internal thoracic arteries were depended on the activation of ATP-dependent and Ca2+-activated potassium channels.

Aged↗

PubMed1996

Identification of three separate binding sites on SHK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain.

Eighteen synthetic analogs of ShK toxin, a thirty-five residue K channel blocker derived from the sea anemone Stichodactyla helianthus, were prepared in order to identify functionally important residues. CD spectra of sixteen of the analogs were virtually identical with the spectrum of wild-type toxin, indicating that the conformations were not affected by the substitutions. A conserved residue, Lys22, is essential for ShK binding to rat brain K channels which are primarily of the Kv1.2 type. However, a cationic side chain at position 22 is not essential for binding to the human Jurkat T-lymphocyte Kv1.3 channel. While decreasing bulkiness at this position affected toxin affinity for the brain K channels, increasing bulkiness decreased toxin affinity for both brain and lymphocyte K channels. In contrast to the rat brain channels, ShK binding to Kv1.3 was sensitive to substitution at Lys9 and Arg11.

Amino Acid Sequence↗

PubMed2000

Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat.

Cation channels conduct calcium, sodium, and potassium, cations that are likely deleterious in the evolution of focal ischemic injury. Diffusion-weighted magnetic resonance imaging (DWI) is a powerful tool for evaluation of acute cerebral ischemia. We studied the effects of a novel, broad-spectrum inhibitor of several cation channels, LOE 908 MS, on acute ischemic lesion development with DWI and on cerebral infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem. Eighteen male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) and were randomly and blindly assigned to either LOE 908 MS (1 mg/kg bolus 30 min after MCAO and continuous i.v. infusion of 10 mg/kg for 4 h thereafter) or vehicle. Whole-brain DWI was done before initiation of treatment and repeated every 30 min for the next 3.5 h. The animals were reperfused in the magnetic resonance imaging (MRI) scanner 90 min after MCAO. At 24 h, the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. Physiological parameters, body weight, and premature mortality (3 in the placebo group and 1 in the treated group) did not differ between the groups. No hypotension, abnormal behavior, or other adverse effects were seen. Pretreatment, the DWI-derived %HLV did not differ between the groups (19.8 +/- 6.2 in the control group and 17.9 +/- 7.9 in the treated group), whereas at 4 h after MCAO, it was significantly smaller in the treated group (21.8 +/- 15.4 vs 40.4 +/- 15.5, p = 0.03). Postmortem, TTC-derived %HLV was significantly attenuated in the LOE 908 MS group (21.3 +/- 11.9 vs 50.1 +/- 10.7, p = 0.0001) and the neurological scores at 24 h were significantly better among the treated rats (2.1 +/- 1.5 vs 4.0 +/- 1.0, p < 0.02). LOE 908 MS significantly improved neurological outcome and reduced infarct size without observable effects in rats as demonstrated in vivo by DWI and confirmed postmortem by TTC staining. Blocking several distinct cation channels by LOE 908 MS showed significant neuroprotection.

Acetamides↗

PubMed1998

Inhibition of voltage-gated cationic channels in rat embryonic hypothalamic neurones and C1300 neuroblastoma cells by triphenylethylene antioestrogens.

The effect of the non-steroidal antioestrogens tamoxifen and toremifene on voltage-gated cationic currents was examined in primary cultures of rat hypothalamic neurones and the C1300 mouse neuroblastoma cell line using the whole-cell patch clamp technique. When applied to the external bathing solution both tamoxifen and toremifene were able to inhibit TTX-sensitive sodium currents with IC50 values of 1-2 microM and delayed rectifier type potassium currents (IC50, 2-3 microM). However, only toremifene showed a significant inhibition of the I(A) current (IC50 3 microM). Inhibition of voltage-gated cationic currents was significantly impaired when tamoxifen was applied in a serum-containing solution. The steroidal antioestrogen ICI 182,780 did not inhibit any of the currents at 10 microM.

Animals↗

PubMedDate not supplied

Block of NA+ and K+ currents in rat ventricular myocytes by quinacainol and quinidine.

1. The electrophysiological actions of quinacainol were investigated on sodium (I(Na)), transient outward (i(to)) and sustained-outward plateau (iKsus) potassium currents in rat isolated cardiac myocytes using the whole-cell patch-clamp technique and compared with quinidine. 2. Quinacainol blocked sodium currents in a concentration-dependent manner and with a potency similar to that of quinidine (mean (+/-SEM) EC50 50+/-12 vs 95+/-25 micromol/L for quinidine and quinacainol, respectively). However, quinacainol had a considerably prolonged onset and recovery from block compared with quinidine. 3. Neither quinacainol nor quinidine significantly changed the steady state voltage dependence of activation of sodium currents. Quinidine produced a hyperpolarizing shift in the voltage dependence for sodium current inactivation, but no such shift was observed with quinacainol at doses that produced a substantial current block. 4. Although quinacainol did not effectively block voltage-dependent potassium currents, even at concentrations as high as 1.5 mmol/L, quinidine, at a half-maximal sodium channel-blocking concentration, reduced peak i(to) current amplitude, increased the rate of inactivation of i(to) and blocked iKsus. 5. These results indicate that quinacainol, a quinidine analogue, blocks sodium currents in cardiac myocytes with little effect on i(to) or iKsus potassium currents, which suggests that quinacainol may be exerting class 1c anti-arrhythmic actions.

Animals↗

PubMed2006

Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons.

The use of oxaliplatin, a relatively new chemotherapeutic agent, is somewhat limited since it produces a specific peripheral neuropathy regarding other neurotoxic anticancer platinum analogues. In order to investigate the mechanism of such a peripheral neuropathy, the effects of 1-100 micromol/l oxaliplatin were assessed on the nodal ionic currents of single frog myelinated axons as a model of peripheral excitable membranes. Oxaliplatin decreased both Na(+) and K(+) currents in a dose-dependent manner and within 5-10 min, without producing any marked changes in the current kinetics. It was about three to eight times more effective in reducing the Na(+) than the K(+) current. In addition, it shifted the voltage-dependence of both Na(+) and K(+) conductances towards negative membrane potentials. A negative shift in the steady-state inactivation-voltage curve of the peak Na(+) current was also observed in the presence of oxaliplatin. These effects were not reversed by washing the myelinated axons with an oxaliplatin-free solution for at least 30 min. It is concluded that oxaliplatin modifies the voltage-dependent ionic channels mainly by altering the external surface membrane potential. The knowledge of such a mechanism may help to counteract the neurotoxic action of this anticancer agent.

Animals↗

PubMed2003

BTK-2, a new inhibitor of the Kv1.1 potassium channel purified from Indian scorpion Buthus tamulus.

A novel inhibitor of voltage-gated potassium channel was isolated and purified to homogeneity from the venom of the red scorpion Buthus tamulus. The primary sequence of this toxin, named BTK-2, as determined by peptide sequencing shows that it has 32 amino acid residues with six conserved cysteines. The molecular weight of the toxin was found to be 3452 Da. It was found to block the human potassium channel hKv1.1 (IC(50)=4.6 microM). BTK-2 shows 40-70% sequence similarity to the family of the short-chain toxins that specifically block potassium channels. Multiple sequence alignment helps to categorize the toxin in the ninth subfamily of the K+ channel blockers. The modeled structure of BTK-2 shows an alpha/beta scaffold similar to those of the other short scorpion toxins. Comparative analysis of the structure with those of the other toxins helps to identify the possible structure-function relationship that leads to the difference in the specificity of BTK-2 from that of the other scorpion toxins. The toxin can also be used to study the assembly of the hKv1.1 channel.

Amino Acid Sequence↗

PubMed2000

Activity-dependent maintenance of long-term potentiation at visual cortical inhibitory synapses.

Neural activity producing a transient increase in intracellular Ca(2+) concentration can induce long-term potentiation (LTP) at visual cortical inhibitory synapses similar to those seen at various excitatory synapses. Here we report that low-frequency neural activity is required to maintain LTP at these inhibitory synapses. Inhibitory responses of layer 5 cells evoked by layer 4 stimulation were studied in developing rat visual cortical slices under a pharmacological blockade of excitatory synaptic transmission using intracellular and whole-cell recording methods. Although LTP induced by high-frequency stimulation (HFS) persisted while test stimulation was applied at 0.1 Hz, it was not maintained in approximately two-thirds of cells after test stimulation was stopped for 30 min. In the rest of the cells, LTP seemed to be maintained by spontaneous presynaptic spikes, because presynaptic inhibitory cells discharged spontaneously in our experimental condition and because LTP was totally abolished by a temporary application of Na(+) channel blockers. Experiments applying various Ca(2+) channel blockers and Ca(2+) chelators after HFS demonstrated that LTP maintenance was mediated by presynaptic Ca(2+) entries through multiple types of high-threshold Ca(2+) channels, which activated Ca(2+)-dependent reactions different from those triggering transmitter release. The Ca(2+) entries associated with action potentials seemed to be regulated by presynaptic K(+) channels, presumably large-conductance Ca(2+)-activated K(+) channels, because the application of blockers for these channels facilitated LTP maintenance. In addition, noradrenaline facilitated the maintenance of LTP. These findings demonstrate a new mechanism by which neural activity regulates the continuation and termination of LTP at visual cortical inhibitory synapses.

Action Potentials↗

PubMed2006

Resonance (approximately 10 Hz) of excitatory networks in motor cortex: effects of voltage-dependent ion channel blockers.

The motor cortex generates synchronous network oscillations at frequencies between 7 and 14 Hz during disinhibition or low [Mg2+]o buffers, but the underlying mechanisms are poorly understood. These oscillations, termed here approximately 10 Hz oscillations, are generated by a purely excitatory network of interconnected pyramidal cells because they are robust in the absence of GABAergic transmission. It is likely that specific voltage-dependent currents expressed in those cells contribute to the generation of approximately 10 Hz oscillations. We tested the effects of different drugs known to suppress certain voltage-dependent currents. The results revealed that drugs that suppress the low-threshold calcium current and the hyperpolarization-activated cation current are not critically involved in the generation of approximately 10 Hz oscillations. Interestingly, drugs known to suppress the persistent sodium current abolished approximately 10 Hz oscillations. Furthermore, blockers of K+ channels had significant effects on the oscillations. In particular, blockers of the M-current abolished the oscillations. Also, blockers of both non-inactivating and slowly inactivating voltage-dependent K+ currents abolished approximately 10 Hz oscillations. The results indicate that specific voltage-dependent non-inactivating K+ currents, such as the M-current, and persistent sodium currents are critically involved in generating approximately 10 Hz oscillations of excitatory motor cortex networks.

Anesthetics, Local↗

PubMed2007

Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes.

Glial cell-mediated potassium and glutamate homeostases play important roles in the regulation of neuronal excitability. Diminished potassium and glutamate buffering capabilities of astrocytes result in hyperexcitability of neurons and abnormal synaptic transmission. The role of the different K+ channels in maintaining the membrane potential and buffering capabilities of cortical astrocytes has not yet been definitively determined due to the lack of specific K+ channel blockers. The purpose of the present study was to assess the role of the inward-rectifying K+ channel subunit Kir4.1 on potassium fluxes, glutamate uptake and membrane potential in cultured rat cortical astrocytes using RNAi, whole-cell patch clamp and a colorimetric assay. The membrane potentials of control cortical astrocytes had a bimodal distribution with peaks at -68 and -41 mV. This distribution became unimodal after knockdown of Kir4.1, with the mean membrane potential being shifted in the depolarizing direction (peak at -45 mV). The ability of Kir4.1-suppressed cells to mediate transmembrane potassium flow, as measured by the current response to voltage ramps or sequential application of different extracellular [K+], was dramatically impaired. In addition, glutamate uptake was inhibited by knock-down of Kir4.1-containing channels by RNA interference as well as by blockade of Kir channels with barium (100 microM). Together, these data indicate that Kir4.1 channels are primarily responsible for significant hyperpolarization of cortical astrocytes and are likely to play a major role in potassium buffering. Significant inhibition of glutamate clearance in astrocytes with knock-down of Kir4.1 highlights the role of membrane hyperpolarization in this process.

Animals↗

PubMed2005

The regulation of rotenone-induced inflammatory factor production by ATP-sensitive potassium channel expressed in BV-2 cells.

Our previous studies have demonstrated that activating ATP-sensitive potassium channel (K(ATP) channel), not only improved Parkinsonian behavior and neurochemical symptoms, but also reduced iNOS activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson's disease (PD). In this study, it was first shown that the subunits of K(ATP) channels are expressed in BV-2 cells, and then it was investigated whether K(ATP) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone. It was found that K(ATP) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and SUR 2A/2B. K(ATP) channel openers (KCOs) including pinacidil, diazoxide and iptakalim (Ipt) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells, decreased tumor necrosis factor alpha (TNF-alpha) production and the expression and activity of inducible isoform of nitric oxide synthase (iNOS). Either glibenclamide or 5-hydroxydecanoate acid (a selective mitochondrial K(ATP) channel blocker) could abolish the effects of KCOs, suggesting that K(ATP) channels, especially mitochondrial ATP-sensitive potassium channels (mitoK(ATP) channels), played a crucial role in preventing the activation of BV-2 cells, and subsequently the production of a variety of proinflammatory factors. Therefore, activation of K(ATP) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders.

ATP-Binding Cassette Transporters↗

PubMed1996

Mapping the block of a cloned human inward rectifier potassium channel by dofetilide.

Dofetilide, a methanesulfonanilide derivative, is a potent class III antiarrhythmic drug. Like other members of this class of K+ channel blockers, the sites in the channel to which the drug binds are unknown, although high and low affinity binding has been reported in cardiomyocytes. The most sensitive K+ channel target for dofetilide seems to be IKr, the rapid component of the repolarizing delayed rectifier K+ current. However, block of other K+ channels occurs at higher concentrations and is of special interest in regard to toxicity. Recently, we have demonstrated that hIRK, a cloned inward rectifier K+ channel (IRK) isolated from human atrium and expressed heterologously in Xenopus oocytes, is blocked by dofetilide. We report the localization of a site that is critical for dofetilide block in hIRK. We used chimeric constructs between hIRK and ROMK1, a related inward rectifier that is drug resistant. Substitution of hIRK-M2, the second putative transmembrane spanning segment of IRKs, with ROMK1-M2 increased unblocking of dofetilide by 10-20-fold in hIRK. Site-directed mutagenesis further pinpointed the effects to a single hydrophobic residue (I177) in M2. A reduction in hydrophobicity by the point mutation I177C increased recovery from block > 10-fold (1.17 sec in wild-type to 0.112 sec at -80 mV at physiological K+ concentrations), leading us to suggest that hydrophobic interactions are essential for dofetilide block in hIRK. A similar mechanism may explain dofetilide block in other ion channels, including IKr.

Anti-Arrhythmia Agents↗