SEARCH · PubMed Health

Results for “Potassium Channel Blockers”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2000

Effects of sodium and potassium channel blockers on hyperinflation-induced slowly adapting pulmonary stretch receptor stimulation in the rat.

The excitatory responses of slowly adapting pulmonary stretch receptor (SAR) activity to hyperinflation (inflation volume = 3 tidal volumes) for approximately 10 respiratory cycles were examined before and after administration of flecainide, a Na+ channel blocker, and 4-aminoprydine (4-AP), a K+ channel blocker. The experiments were performed in anesthetized, artificially ventilated rats after unilateral vagotomy. During hyperinflation the SARs increased their activity during inflation and decreased their discharge during deflation. The magnitude of increased SAR activity during inflation became more prominent as compared to that of decreased receptor activity during deflation. Flecainide treatment (6 mg/kg) that was sufficient to block veratridine (50 microg/kg)-induced SAR stimulation did not significantly alter the excitatory response of SAR activity to hyperinflation. Subsequent administration of 3 mg/kg flecainide (a total dose, 9 mg/kg) resulted in a greater inhibition of hyperinflation-induced SAR stimulation. Although administration of 4-AP (2 mg/kg) usually stimulated SAR activity, particularly in the deflation phase, in the control ventilation, 4-AP treatment had no significant effect on hyperinflation-induced SAR stimulation. These results suggest that the excitatory effect of hyperinflation on SAR activity may not be involved in the activation of either flecainide-sensitive Na+ channels or 4-AP-sensitive K+ channels.

Animals↗

PubMed2006

Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, with a relative sparing of axons. In MS patients, many neurologic signs and symptoms have been attributed to the underlying conduction deficits. The idea that neurologic function might be improved if conduction could be restored in CNS demyelinated axons led to the testing of potassium (K(+)) channel blockers as a symptomatic treatment. To date, only 2 broad-spectrum K(+) channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been tested in MS patients. Although both 4-AP and 3,4-DAP produce clear neurologic benefits, their use has been limited by toxicity. Here we review the current status of basic science and clinical research related to the therapeutic targeting of voltage-gated K(+) channels (K(v)) in MS. By bringing together 3 distinct but interrelated disciplines, we aim to provide perspective on a vast body of work highlighting the lengthy and ongoing process entailed in translating fundamental K(v) channel knowledge into new clinical treatments for patients with MS and other demyelinating diseases. Covered are (1) K(v) channel nomenclature, structure, function, and pharmacology; (2) classic and current experimental morphology and neurophysiology studies of demyelination and conduction deficits; and (3) a comprehensive overview of clinical trials utilizing 4-AP and 3,4-DAP in MS patients.

4-Aminopyridine↗

PubMed1996

Cicutoxin from Cicuta virosa--a new and potent potassium channel blocker in T lymphocytes.

The effect of cicutoxin, the poisonous principle of the genus Cicuta, on K+ currents of activated T lymphocytes was investigated using the patch clamp technique. Cicutoxin produced a dose-dependent [5 x 10(-6) to 7 x 10(-5) mol/l] and completely reversible block of K+ currents with an EC50 of 1.8 x 10(-5) mol/l. A maximum block of 71% was achieved with cicutoxin at a concentration of 7 x 10(-5) mol/l. Since previous studies have shown that T lymphocyte proliferation is associated with K+ currents, the effect of cicutoxin on T lymphocyte proliferation was studied by means of 3H-thymidine uptake assays. At noncytotoxic concentrations [10(-7) to 5 x 10(-5) mol/l] cicutoxin reduced the 3H-thymidine incorporation dose-dependently. In conclusion, cicutoxin is a potent K+ current blocker which inhibits K+ channel-dependent proliferation of naive and memory T lymphocytes.

Alkynes↗

PubMed1999

Differential effects of potassium channel blockers on the activity of the locomotor network in neonatal rat.

The role played by various K+ channels during locomotor activity was studied using an in vitro neonatal rat spinal cord preparation. Locomotor-like activity was elicited by bath-applying serotonin (5-HT) and N-methyl-d-l-aspartate (NMA). Four different K+ channel blockers were tested by adding them to the superfusing saline. Each of the K+ channel blockers elicited a characteristic motor pattern with specific temporal parameters. Cs+ and tetraethyl ammonium both decreased the motor period, but had opposite effects on the burst amplitude. Apamin increased both the motor period and the burst amplitude. A dose-response relationship was established for the K+ channel blockers. The blockers elicited an unstable rhythmic activity, contrary to what occurred under control conditions. We also found that due to the specific changes that they elicit, the various blockers produce selective changes in the burst ratio. These results suggest that the various K+ channels contribute differently to the generation of locomotor activity.

4-Aminopyridine↗

PubMed1998

Differential atrial versus ventricular activities of class III potassium channel blockers.

The atrial versus ventricular activities of Class III agents with differing K+ channel blocking profiles were assessed in vitro in ferret atrial and right ventricular papillary muscles. In concentration-effective refractory period (ERP) response studies at 2 Hz and 32 degreesC, the selective IKr blockers dofetilide, E-4031 and d-sotalol, as well as ibutilide, an IKr blocker also reported to enhance inward Na+ current, displayed markedly greater efficacies in increasing atrial ERP (+90-110%) versus ventricular ERP (+10-20%). RP58866, a blocker of IK1 and IKr, and tedisamil, primarily a blocker of Ito and IKr, increased atrial ERP with approximately 10-fold greater potencies than ventricular ERP, but with similar efficacies for both tissues (+60-80% with RP58866; +150-160% with tedisamil). Azimilide, a blocker of IKr and IKs, and indapamide, a blocker of IKs, displayed essentially "balanced" activities, increasing atrial and ventricular ERP with equivalent potencies and efficacies (+40-60% increases for both tissues). Frequency-dependence profiles at 32 degrees C varied between atrial and ventricular tissues, and there was no general correspondence between atrial versus ventricular selectivity and frequency-dependence profiles. In the papillary muscle preparation, increasing temperature from 32 degrees C to 37 degrees C altered both magnitude and frequency dependence of response to K+ channel blockers. These findings support the potential to selectively modulate atrial versus ventricular refractoriness with the targeting of appropriate K+ channel subtypes, and further demonstrate the differential frequency and temperature dependence of varying K+ channel subtype blockade. Ultimately, the identification and targeting of an appropriate K+ channel subtype or mix of subtypes may result in the achievement of optimal atrial-selective activity for the treatment of supraventricular arrhythmias.

Animals↗

PubMed1997

Effects of potassium channel blockers on the acetylcholine-induced currents in dissociated outer hair cells of guinea pig cochlea.

Much physiological evidence is available to show that acetylcholine (ACh) hyperpolarizes the outer hair cells (OHCs) of guinea pig cochlea and induces Ca2+-activated K+ currents. In this study, using the nystatin perforated patch-clamp technique, we investigated the effects of various K+ channel blockers on the ACh-induced currents (I[ACh]) in dissociated OHCs of guinea pig cochlea. The I(ACh) were inhibited by apamin in a concentration-dependent manner. The half-maximal inhibitory concentration for apamin on the ACh-induced response was 1.59 x 10(-9) M. Charybdotoxin and iberiotoxin had no inhibitory effect on the I(ACh) The inhibitory potency of the various K+ channel blockers on the I(ACh) was as follows: apamin >> quinine approximately quinidine approximately d-tubocurarine > tetraethylammonium chloride > 4-aminopyridine approximately Ba2+ > Cs2+. It is proposed that the Ca2+-activated K+ channels of mammalian cochlear OHCs should be classified as small conductance Ca2+-activated K+ (SK) channels according to their pharmacological properties.

4-Aminopyridine↗

PubMed1995

Differential effects of potassium channel blockers on extracellular concentrations of dopamine and 5-HT in the striatum of conscious rats.

1. The selective Ca(2+)-activated K+ channel blocker apamin increased extracellular 5-hydroxytryptamine (5-HT) concentrations in the striatum when administered through the microdialysis probe at doses of 0.1 mM and 1 mM. Extracellular dopamine concentrations increased only at the highest dose administered (1 mM). 2. Mast cell degranulating peptide (MCDP), which blocks the dendrotoxin sensitive delayed rectifier (DR) current, increased extracellular concentrations of dopamine at dose of 10 microM-100 microM but had no effect on 5-HT. 3. The non selective K+ channel blocker tetraethylammonium (TEA) induced a dose-dependent (1 mM-10 mM) increase in extracellular dopamine concentrations and an increase in 5-HT which showed little or no dose-dependency. 4. 4-Aminopyridine (4-AP), a blocker with some similar characteristics to MCDP, increased extracellular dopamine concentrations at doses of 10 microM-1 mM, but had no effect on 5-HT. 5. These findings suggest that dopamine release may be modulated by DR-like current and/or A-current K+ channels. However, in view of the similar effects of MCDP and 4-AP at the concentrations used it is more likely that the dendrotoxin-sensitive DR-like current is involved. In contrast, 5-HT release appears to be modulated by Ca(2+)-activated K+ channels.

4-Aminopyridine↗

PubMed2004

Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons.

K+ and Cl- homeostasis have been implicated in cell volume regulation and apoptosis. We addressed the hypothesis that K+ and Cl- efflux may contribute to apoptotic cell shrinkage and apoptotic death in cultured cortical neurons. CLC-2 and CLC-3 chloride channels were detected in cultured cortical neurons. The Cl- channel blockers 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) inhibited the outwardly rectifying Cl- current, prevented apoptotic cell shrinkage, and mildly attenuated cell death induced by staurosporine, C2-ceramide, or serum deprivation. Cl- channel blockers, however, at concentrations that prevented cell shrinkage had no significant effects on caspase activation and/or DNA fragmentation. Cell death in the presence of a Cl- channel blocker was still sensitive to blockade by the caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk). Electron microscopy revealed that, although DIDS prevented apoptotic cell shrinkage, certain apoptotic ultrastructural alterations still took place in injured neurons. On the other hand, the K+ channel blocker tetraethylammonium (TEA), clofilium, or the caspase inhibitor z-VAD-fmk prevented cell shrinkage as well as caspase activation and/or DNA damage, and showed stronger neuroprotection against apoptotic alterations and cell death. The results indicate that neurons may undergo apoptotic process without cell shrinkage and imply distinct roles for Cl- and K+ homeostasis in regulating different apoptotic events.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2006

Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide.

In some clinical settings it is necessary to inject large volumes of local anesthetic--and consequently very high doses--in order to provide an adequate level of block. Subsequent absorption of these high doses, or inadvertent intravenous administration of even small doses, has led to systemic toxicity. Thus, it is desirable to develop adjuvants that are inert alone, but would enhance the potency and/or efficacy of local anesthetics to improve their safety. Adelta/C fibers possess K(+) channels identified as sustained delayed rectifier type K(DR) currents and transient A-type K(A) currents. In the heart, the class III antiarrhythmic drug ibutilide blocks the cardiac component of the rapid delayed rectifying K(+) current (IKr). Experiments were conducted to determine whether co-administration of the K(+) channel blocker ibutilide would enhance the local anesthetic bupivacaine in mice. After injecting bupivacaine mixed with vehicle or ibutilide in the popliteal region of mice, paw withdrawal latencies were determined by applying the plantar aspect of a single hind-paw to the surface a 55 degrees C hot-plate device. 0.5% Bupivacaine+ibutilide (7.8x10(-5) M) elicited significantly longer hot-plate latencies than 0.5% bupivacaine+vehicle. In addition, bupivacaine was 2.6-fold more potent when co-administered with ibutilide rather than vehicle. Epinephrine extends the tissue concentrations of local anesthetics by inducing localized vasoconstriction. Epinephrine augmented the enhancement by ibutilide of bupivacaine's potency by 6.8-fold. In summary, ibutilide may enhance the effects of bupivacaine by blocking K(+) channels on sensory nociceptive nerves.

Adrenergic alpha-Agonists↗

PubMed2004

Solution structure of BmKK2, a new potassium channel blocker from the venom of chinese scorpion Buthus martensi Karsch.

A natural K+ channel blocker, BmKK2 (a member of scorpion toxin subfamily alpha-KTx 14), which is composed of 31 amino acid residues and purified from the venom of the Chinese scorpion Buthus martensi Karsch, was characterized using whole-cell patch-clamp recording in rat hippocampal neurons. The three dimensional structure of BmKK2 was determined with two-dimensional NMR spectroscopy and molecular modelling techniques. In solution this toxin adopted a common alpha/beta-motif, but showed distinct local conformation in the loop between alpha-helix and beta-sheet in comparison with typical short-chain scorpion toxins (e.g., CTX and NTX). Also, the alpha helix is shorter and the beta-sheet element is smaller (each strand consisted only two residues). The unusual structural feature of BmKK2 was attributed to the shorter loop between the alpha-helix and beta-sheet and the presence of two consecutive Pro residues at position 21 and 22 in the loop. Moreover, two models of BmKK2/hKv1.3 channel and BmKK2/rSK2 channel complexes were simulated with docking calculations. The results demonstrated the existence of a alpha-mode binding between the toxin and the channels. The model of BmKK2/rSK2 channel complex exhibited favorable contacts both in electrostatic and hydrophobic, including a network of five hydrogen bonds and bigger interface containing seven pairs of inter-residue interactions. In contrast, the model of BmKK2/hKv1.3 channel complex, containing only three pairs of inter-residue interactions, exhibited poor contacts and smaller interface. The results well explained its lower activity towards Kv channel, and predicted that it may prefer a type of SK channel with a narrower entryway as its specific receptor.

Amino Acid Sequence↗

PubMed1993

Diuretic action of potassium channel blockers.

The availability of specific potassium channel blockers has made it possible to examine their effects along the nephron on fluid and electrolyte excretion. Recent experiments indicate that they modulate transepithelial sodium and potassium transport. In the thick ascending limb, potassium channel blockers, by interfering with potassium recycling across the apical cell membrane, reduce the activity of the sodium-2chloride-potassium cotransporter. In the initial and cortical collecting duct their inhibitory action on ATP-sensitive potassium channels reduces potassium secretion. Accordingly, tissue-specific potassium channel blockers are promising diuretic agents that may induce diuresis by inhibiting tubular sodium transport with only minimal loss of potassium.

Animals↗

PubMed2003

[Effects of potassium channel blockers on the proliferation of rat bronchial smooth muscle cells].

AIM: To investigate the effects of blockers of the three kinds of potassium channels: voltage-dependent K+ channel(KV), calcium-activated K+ channel(KCa) and ATP-sensitive K+ channel(KATP), on the proliferation of rat bronchial smooth muscle cells (BSMCs). METHODS: The effects of three kinds of potassium channel blockers on the proliferation of BSMCs were detected by MTT method, immunocytochemistry staining and flow-cytometry. Their effects on the dynamic changes of Ca2+ concentration in BSMCs were investigated by the fluorophotometry of Fura-2/AM. RESULTS: The KV blocker 4-aminopyridine (4-AP) was shown to significantly increase the expression of proliferating cell nucleus antigen in cultured rat BSMCs (P < 0.01), but the KCa blocker tetraethylammonium (TEA) and KATP blocker glibenclamide(Glib) did not show such effect (P > 0.05). 4-AP was found to significantly increase the optical density value of the cultured BSMCs (P < 0.01) by MTT method and the numbers of S + G2M BSMCs(P < 0.05) by flow-cytometry. TEA and Glib did not show such effects. 4-AP significantly increased the Ca2+ concentration in cultured BSMCs(P < 0.01). TEA and Glib did not show such effects. CONCLUSION: This result suggests that inhibition of KV activity can increase intracellular Ca2+ and proliferation of rat BSMCs, but inhibition of KCa and KATP showed no effect.

4-Aminopyridine↗

PubMed2005

1,4-Diazabicyclo[2.2.2]octane derivatives: a novel class of voltage-gated potassium channel blockers.

Voltage-gated potassium (Kv) channels are targets for therapeutic drugs in the treatment of pathologic conditions including cardiac arrhythmia and epilepsy. In this study, we synthesized three classes of novel polyammonium compounds incorporating the bicyclic unit 1,4-diazabicyclo[2.2.2]octane (DABCO) and tested their action on three representative mammalian Kv channels (Kv2.1, Kv3.4, and Kv4.2) expressed in Xenopus laevis oocytes. Nonsubstituted DABCO did not block the Kv channels tested. Simple DABCO monostrings and diDABCO strings inhibited Kv2.1 and Kv3.4 channels, with potency increasing with string length for both these DABCO classes. Both Kv2.1 and Kv3.4 were most sensitive to C16 monostrings, with IC50 values of 1.9 and 0.6 microM, respectively. For compounds comprising two DABCO groups separated by an aromatic ring, inhibition depended upon relative positioning of the two DABCO groups, and only the para form (JC638.2alpha) was active, blocking Kv2.1 with an IC50 of 186 microM. Kv4.2 channels were relatively insensitive to all compounds tested. Unlike the tetraethylammonium ion (TEA), neither JC638.2alpha nor C16 monostring TA279 produced block when applied intracellularly via the recording electrode to Kv2.1 channels expressed in Chinese hamster ovary cells, suggesting against an internal site of action. However, JC638.2alpha protected an introduced cysteine (K356C) in the Kv2.1 outer pore from permanent modification by methanethiosulfonate ethyltrimethylammonium (MTSET). These data suggest that JC638.2alpha occupies an external binding site similar to that of TEA in the Kv2.1 outer pore, but with much higher affinity than TEA. These DABCO salts represent a new class of Kv channel blockers, some with higher potencies than any previously described quaternary ammonium ions. The potential for synthesis of an array of modular derivatives suggests that DABCO compounds hold promise as probes of Kv channel structure and identity and as potential therapeutic agents.

Animals↗

PubMed2001

Effects of the potassium channel blocker barium on sodium and potassium transport in the rat loop of Henle in vivo.

In vitro evidence suggests that the 'recycling' of K(+) ions through luminal K(+) channels in the thick ascending limb of the loop of Henle (TALH) is essential for the normal operation of the luminal Na(+)-K(+)-2Cl(-) co-transporter. In the present study these channels were investigated in vivo by perfusing superficial loops of Henle in anaesthetised rats with and without the K(+) channel blocker barium. Using a standard perfusate, intraluminal barium (5 mmol l(-1)) reduced sodium reabsorption (J(Na)) from 1887 +/- 50 to 1319 +/- 53 pmol min(-1) (P < 0.001). When the experiment was repeated using a low-Na(+) perfusate, designed to inhibit reabsorption in the pars recta (the initial segment of the loop of Henle), a similar reduction in J(Na) was observed (from 698 +/- 47 to 149 +/- 23 pmol min(-1), P < 0.001), strongly suggesting that the effect of barium is localised to the TALH. The magnitude of the reduction in J(Na) during blockade of K(+) channels confirms the importance of K(+) recycling in facilitating Na(+) reabsorption in the TALH in vivo. However, the reduction in J(Na) was not associated with a fall in the K(+) concentration of the fluid collected at the early distal tubule. When bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) co-transporter, was included in the low-Na(+) perfusate, net K(+) secretion was observed. Addition of barium to this perfusate reduced, but did not abolish, the secretion, suggesting that bumetanide-induced K(+) secretion results partly from paracellular transport. Experimental Physiology (2001) 86.4, 469-474.

Animals↗

PubMed2001

Designed peptide analogues of the potassium channel blocker ShK toxin.

ShK toxin, a potassium channel blocker from the sea anemone Stichodactyla helianthus, is a 35-residue polypeptide cross-linked by 3 disulfide bridges. In an effort to generate truncated peptidic analogues of this potent channel blocker, we have evaluated three analogues, one in which the native sequence was truncated and then stabilized by the introduction of additional covalent links (a non-native disulfide and two lactam bridges), and two in which non-native structural scaffolds stabilized by disulfide and/or lactam bridges were modified to include key amino acid residues from the native toxin. The effect of introducing a lactam bridge in the first helix of ShK toxin (to create cyclo14/18[Lys14,Asp18]ShK) was also examined to confirm that this modification was compatible with activity. All four analogues were tested in vitro for their ability to block Kv1.3 potassium channels in Xenopus oocytes, and their solution structures were determined using 1H NMR spectroscopy. The lactam bridge in full-length ShK is well tolerated, with only a 5-fold reduction in binding to Kv1.3. The truncated and stabilized analogue was inactive, apparently due to a combination of slight deviations from the native structure and alterations to side chains required for binding. One of the peptide scaffolds was also inactive because it failed to adopt the required structure, but the other had a K(d) of 92 microM. This active peptide incorporated mimics of Lys22 and Tyr23, which are essential for activity in ShK, and an Arg residue that could mimic Arg11 or Arg24 in the native toxin. Modification of this peptide should produce a more potent, low molecular weight peptidic analogue which will be useful not only for further in vitro and in vivo studies of the effect of blocking Kv1.3, but also for mapping the interactions with the pore and vestibule of this K(+) channel that are required for potent blockade.

Amino Acid Sequence↗

PubMed1986

Autoreceptor-mediated changes in dopaminergic terminal excitability: effects of potassium channel blockers.

The effects of the potassium channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), on autoreceptor-mediated changes in dopaminergic terminal excitability were examined in urethane-anesthetized rats. Local infusions of 4-AP or TEA into neostriatal terminal fields of nigral dopaminergic neurons led to marked decreases in terminal excitability, as measured by the increase in stimulating current required to activate the neurons antidromically from the site of the infusion. The decreased excitability resulting from 4-AP could be reversed by subsequent i.v. injection of haloperidol, and was blocked in rats that had been depleted of endogenous dopamine by prior treatment with alpha-methyl-p-tyrosine (AMpT). Thus, the decrease in excitability elicited by the potassium channel-blockers was indirect, and apparently due to increased autoreceptor stimulation resulting from enhanced transmitter release. In addition, co-infusion of 4-AP and apomorphine in AMpT-treated animals led to decreased terminal excitability that did not differ from the effects of apomorphine alone, indicating that 4-AP did not block the effects of exogenous autoreceptor agonist administration. These results provide in situ electrophysiological evidence that autoreceptor-mediated processes occurring at dopaminergic terminals are not mediated by 4-AP- or TEA-sensitive potassium channels. Furthermore, our findings suggest that, as in other types of presynaptic terminals, blockade of voltage-sensitive potassium channels in dopamine terminals leads to enhanced release of transmitter.

4-Aminopyridine↗

PubMed2004

[Ion channels and demyelination: basis of a treatment of experimental autoimmune encephalomyelitis (EAE) by potassium channel blockers].

Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound action potential decreased probably because conduction block occurred. Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by dendrotoxin-I or kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during demyelinating diseases. In a T-cell line reactive to myelin basic protein antigen, which is used to adoptively transfer experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response, cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type hypersensitivity response to myelin basic protein prevents and treats adoptive experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent immunosuppressive agents with beneficial symptomatic effects in experimental autoimmune encephalomyelitis.

Action Potentials↗

PubMed1998

Suppression of reperfusion arrhythmias by preconditioning is inhibited by an ATP-sensitive potassium channel blocker, 5-hydroxydecanoate, but not by protein kinase C blockers in the rat.

It has been suggested that preconditioning (PC) against infarction in the rat heart is mediated by opening of ATP-sensitive potassium (KATP) channels, which may be induced by receptor-triggered activation of protein kinase C (PKC). However, the mechanism of suppression of reperfusion arrhythmias by PC remains unclear. This study first examined whether suppression of reperfusion arrhythmias by PC requires the activation of KATP channels, PKC, and opioid receptors. In anesthetized rats, reperfusion arrhythmias were induced by occluding the left main coronary artery for 5 min and subsequent reperfusion. In untreated control rats, the incidence of reperfusion ventricular tachycardia (VT) was 100%, and 80% of the VT deteriorated to ventricular fibrillation (VF). PC with 2-min ischemia/5-min reperfusion reduced the incidences of VT and VF to 30% and 0, respectively. Although a KATP channel blocker, 5-hydroxydecanoate (5-HD), alone caused no significant effect on the incidence of reperfusion VT, this agent blocked the suppression of reperfusion VT by PC (VT incidence, 91%). The incidence of reperfusion VF in the 5-HD-treated rats tended to be lower than that in the untreated controls and was not different between preconditioned and nonpreconditioned groups (30 vs. 27%). PKC inhibitors staurosporine and calphostin C modified neither reperfusion arrhythmias nor the antiarrhythmic effect of PC on reperfusion VT and VF. Naloxone (6 mg/kg, i.v.) did not alter the incidence or duration of VT in the nonpreconditioned heart. However, suppression of reperfusion VT by PC was prevented by naloxone (VT incidence, 70%). The incidence of reperfusion VF was similarly low in the naloxone-treated rats in both nonpreconditioned and preconditioned groups (20% vs. 0). In the second series of experiments, the effect of 5-HD on repetitive PC was assessed. Repetitive PC was performed with three cycles of 2-min ischemia/5-min reperfusion, which totally abolished reperfusion VT and VF. This antiarrhythmic effect of repetitive PC was not inhibited by 5-HD. These results suggest that KATP channels and opioid receptors may be partly involved in suppression of reperfusion arrhythmias, although their roles may be compensated for by other antiarrhythmic mechanisms in repetitive PC. In contrast with PC against infarction, PKC is unlikely to play a major role in PC against reperfusion arrhythmias in the rat.

Adenosine Triphosphate↗