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Results for “Delayed Rectifier Potassium Channels”

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PubMed2002

The antiarrhythmic drug BRL-32872.

BRL-32872 is a new antiarrhythmic drug with balanced class-III and class-IV actions as categorized by the Vaughan-Williams classification. BRL-32872 blocks the rapid component of the cardiac delayed rectifier potassium channel IK(r) (IC(50) = 28 nM) and its molecular correlate HERG ("Human-ether-a-go-go related gene," IC(50) of 19.8 nM in cell lines) at low concentrations. It also inhibits the L-type calcium current (ICa) at higher concentrations (IC(50) = 2.8 microM). This dual concentration-dependent profile of action at higher concentrations may possibly prevent "torsades de pointes" ventricular arrhythmias, which is a dangerous side effect of many other class-III antiarrhythmic drugs. With BRL-32872, an excessive prolongation of the action potential duration and consecutive QTc prolongation is prevented by a concentration-dependent increase of calcium channel block, resulting in the so-called "bell-shaped" profile of antiarrhythmic drug action. BRL-32872 is very effective in the treatment of ventricular arrhythmias in animal models of cardiac ischemia. In the ischemic hearts of animals the drug significantly reduced early afterdepolarization and ventricular tachycardia. The antiarrhythmic effect of BRL-32872 has not yet been demonstrated in humans.

Action Potentials↗

PubMed1994

Ionic currents during action potentials in mammalian skeletal muscle fibers analyzed with loose patch clamp.

The loose patch-clamp technique was applied to analyze transmembrane currents during propagating action potentials in superficial fibers of musculi extensor digitorum longus of the mouse in vitro. Experimentally three components were identified in the transmembrane current: 1) a capacitive, 2) an inward sodium, and 3) an outward potassium current. Other components were negligible. The capacitive current was similar in shape to the first derivative of the intracellularly measured action potential. Tetrodotoxin, tetraethylammonium, and 4-aminopyridine, applied in the pipette, were used to identify the contribution in the current by sodium and potassium ions. With extracellularly applied depolarization steps only a sodium current was observed, not a potassium current. Occasionally found outward currents were artifactual. The behaviour of delayed rectifier potassium channels in muscle fiber membranes is discussed in the light of these unexpected findings. We conclude that potassium channel activity contributing to and measured during action potential generation is in some way inaccessible to loose patch extracellular voltage-clamp stimulation and that loose patch action current recording is a useful noninvasive method to analyze membrane conductances involved in action potential generation.

4-Aminopyridine↗

PubMed1998

Modulation of K+ currents in monocytes by VCAM-1 and E-selectin on activated human endothelium.

Resting membrane potential (RMP) and whole cell currents were recorded in human THP-1 monocytes adherent to polystyrene, unstimulated human umbilical vein endothelial cells (HUVECs), lipopolysaccharide (LPS)-treated HUVECs, immobilized E-selectin, or vascular cell adhesion molecule 1 (VCAM-1) using the patch-clamp technique. RMP after 5 h on polystyrene was -24.3 +/- 1.7 mV (n = 42) with delayed rectifier K+ (Idr) and Cl- currents (ICl) present in >75% of the cells. Inwardly rectifying K+ currents (Iir) were present in only 14% of THP-1 cells. Adherence to unstimulated HUVECs or E-selectin for 5 h had no effect on Iir or ICl but decreased Idr. Five hours after adherence to LPS-treated HUVECs, outward currents were unchanged, but Iir was present in 81% of THP-1 cells. A twofold increase in Iir and a hyperpolarization (-41.3 +/- 3.7 mV, n = 16) were abolished by pretreatment of THP-1 cells with cycloheximide, a protein synthesis inhibitor, or herbimycin A, a tyrosine kinase inhibitor, or by pretreatment of the LPS-treated HUVECs with anti-VCAM-1. Only a brief (15-min) interaction between THP-1 cells and LPS-treated HUVECs was required to induce Iir expression 5 h later. THP-1 cells adherent to VCAM-1 exhibited similar conductances to cells adherent to LPS-treated HUVECs. Thus engagement of specific integrins results in selective modulation of different K+ conductances.

Cell Adhesion↗

PubMed2000

Inducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q-T phenotype.

We created a mouse model with a prolonged Q-T interval and spontaneous arrhythmias by overexpressing the NH(2) terminus and first transmembrane segment (Kv1.1N206Tag) of a delayed rectifier potassium channel (LQT(+/-) mouse). Analyses were performed using whole cell recordings of cardiac myocytes, surface electrocardiography, and programmed electrical stimulation. Action potential duration (APD) was prolonged to the same extent and was more highly variable in myocytes derived from LQT(+/-) and LQT(+/+) mice than in myocytes derived from wild-type (WT) FVB mice. Under ketamine anesthesia, the Q-T interval of both LQT(+/+) and LQT(+/-) mice was comparably prolonged versus that of WT mice. Stimulation of the right ventricle using an intracardiac catheter induced polymorphic ventricular tachyarrhythmias in 50% of the LQT(+/-) mice and 36% of the LQT(+/+) mice, whereas polymorphic ventricular tachyarrhythmias were not inducible in WT mice. The analyses of LQT(+/-) and LQT(+/+) mice indicate that prolongation of the Q-T interval in LQT mice is associated with prolonged APD, increased dispersion of APD among cardiocytes, and inducibility of polymorphic ventricular tachycardia, providing the substrate for spontaneous arrhythmias in these animals.

Action Potentials↗

PubMedDate not supplied

Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo).

Episodic ataxia (EA) is a rare, disabling condition of autosomal dominant inheritance, but it is not a distinct clinical entity. Synonyms are familial periodic ataxia or hereditary paroxysmal cerebellar ataxia. Family members have a similar clinical syndrome; however, the syndrome varies considerably from family to family. At least two groups of disorders have been separated clinically: (1) episodic ataxia type 1 (EA-1), which manifests without vertigo and is associated with 'interictal' myokymia, and (2) episodic ataxia type 2 (EA-2), which often manifests with vertigo and is associated with 'interictal' nystagmus. EA-1 and EA-2 have been identified as channelopathies. EA-1 is due to different heterozygous missense point mutations in a voltage-gated (delayed rectifier) potassium channel gene (KCNA1/Kv1.1) on chromosome 12p13, whereas EA-2 is caused by mutations of the cerebral P/Q-type calcium channel alpha 1 subunit gene CACNL1A4 localized on chromosome 19p, which is highly expressed in the cerebellum. The diagnosis of EA-1 and EA-2 is important, since they can be easily treated and are often mislabeled. As effective as acetazolamide is in preventing attacks, prospective studies still have to prove whether it can prevent progressive ataxia in EA-2 or even improve chronic cerebellar deficits.

Acetazolamide↗

PubMed1993

Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome.

BACKGROUND: Erythromycin is known to prolong ventricular repolarization and has been associated with the occurrence of torsades de pointes. In this study, we have investigated potential mechanisms in vivo and in vitro for induction of an acquired long QT syndrome by erythromycin. METHODS AND RESULTS: Ventricular electrograms and endocardial monophasic action potentials were recorded in anesthetized open-chest dogs before and after administration of 40 to 120 mg/kg of erythromycin lactobionate. Conventional microelectrode techniques were used to record transmembrane action potentials in isolated dog Purkinje fibers and papillary muscles. Erythromycin at concentrations > 20 mg/L prolonged action potential duration. At higher concentrations (100 to 200 mg/L), erythromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro. The effects of erythromycin on repolarization were more marked in Purkinje fibers than in papillary muscle. Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker. Pretreatment with prazosin or tetrodotoxin had no effect on erythromycin-induced changes in action potential duration. CONCLUSIONS: These pharmacological studies suggest that erythromycin prolongs repolarization to a large extent by block of IK. In turn, prolongation of action potential duration resulting from erythromycin's actions on IK may promote the development of EADs. The induction of ventricular arrhythmias observed clinically after exposure to erythromycin may be related to the development of EADs. The rarity of occurrence of ventricular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.

Action Potentials↗

PubMed1997

Modulation of the Electrophysiologic Actions of E-4031 and Dofetilide by Hyperkalemia and Acidosis in Rabbit Ventricular Myocytes.

BACKGROUND: E-4031 and dofetilide are new class III antiarrhythmic agents that inhibit the rapid component of the delayed rectifier potassium channel (I(Kr)); however, the effectiveness of many antiarrhythmic drugs in ischemic conditions is uncertain. METHODS AND RESULTS: We modeled two components of ischemia, hyperkalemia (9.6 mM) and acidosis (pH 6.8), in voltage-clamped single rabbit ventricular myocytes to help determine the effect of ischemia on the action of these two drugs. In physiologic solution both E-4031 and dofetilide blocked I(Kr) and significantly reduced total outward current. In hyperkalemic solution, both E-4031 and dofetilide showed significantly reduced blockade of I(Kr), while in acidotic solution dofetilide showed significantly reduced blockade of I(Kr) and E-4031 showed a trend to reduced blockade. Neither drug significantly reduced total outward current in hyperkalemic or acidotic solutions. CONCLUSIONS: In these conditions, E-4031 and dofetilide demonstrate reduced blockade of I(Kr), resulting in loss of class III effect. Furthermore, the complete loss of blocking effect on total outward current during simulated ischemia suggests increases of other repolarizing currents also contribute to loss of class III effect.

Journal Article↗

PubMed2005

A place for high-throughput electrophysiology in cardiac safety: screening hERG cell lines and novel compounds with the ion works HTTM system.

Several commercially available pharmaceutical compounds have been shown to block the IKr current of the cardiac action potential. This effect can cause a prolongation of the electrocardiogram QT interval and a delay in ventricular repolarization. The Food and Drug Administration recommends that all new potential drug candidates be assessed for IKr block to avoid a potentially lethal cardiac arrhythmia known as torsades de pointes. Direct compound interaction with the human ether-a-go-go- related gene (hERG) product, a delayed rectifier potassium channel, has been identified as a molecular mechanism of IKr block. One strategy to identify compounds with hERG liability is to monitor hERG current inhibition using electrophysiology techniques. The authors describe the Ion Works HT instrument as a tool for screening cell lines expressing hERG channels. Based on current amplitude and stability criteria, a cell line was selected and used to perform a 300-compound screen. The screen was able to identify compounds with hERG activity within projects that spanned different therapeutic areas. The cell line selection and optimization, as well as the screening abilities of the Ion Works HT system, provide a powerful means of assessing hERGactive compounds early in the drug discovery pipeline.

Action Potentials↗

PubMed2006

Physiologic regulation of a tetrodotoxin-sensitive sodium influx that mediates a slow afterdepolarization potential in gonadotropin-releasing hormone neurons: possible implications for the central regulation of fertility.

The brain controls fertility through release of gonadotropin-releasing hormone (GnRH), but the mechanisms underlying action potential patterning and GnRH release are not understood. We investigated whether GnRH neurons exhibit afterdepolarizing potentials (ADPs) and whether these are modified by reproductive state. Whole-cell current-clamp recordings of GnRH neurons in brain slices from ovariectomized mice revealed a slow ADP (sADP) after action potentials generated by brief current injection. Generating two or four spikes enhanced sADP amplitude and duration. sADP amplitude was not affected by blocking selected neurotransmitter/neuromodulator receptors, delayed-rectifier potassium channels, calcium-dependent cation channels, or hyperpolarization-activated cation channels but was halved by the calcium channel blocker cadmium and abolished by tetrodotoxin. Cadmium also reduced peak latency. Intrinsic mechanisms underlying the sADP were investigated using voltage-clamp protocols simulating action potential waveforms. A single action potential produced an inward current, which increased after double and quadruple stimulation. Cadmium did not affect current amplitude but reduced peak latency. Pretreatment with blockers of calcium-activated potassium currents (I(KCa)) reproduced this shift and blocked subsequent cadmium-induced changes, suggesting cadmium changes latency indirectly by blocking I(KCa). Tetrodotoxin abolished the inward current, suggesting that it is carried by sodium. In contrast, I(KCa) blockers increased the inward current, indicating that I(KCa) may oppose generation of the sADP. Strong sADPs were suprathreshold, generating repetitive spontaneous firing. I(ADP), sADP, and excitability were enhanced by in vivo estradiol, which triggers a preovulatory surge of GnRH release. Physiological feedback modification of this inward current and resulting sADP may modulate action potential firing and subsequent GnRH release.

Action Potentials↗

PubMed2003

Ziprasidone in the management of schizophrenia : the QT interval issue in context.

Ziprasidone is a new atypical antipsychotic recently marketed in a number of countries. Its main advantage over other atypical and typical drugs is its low propensity for causing weight gain. However, ziprasidone has been shown to prolong to some extent the cardiac corrected QT (QTc) interval, a property shared by a number of other antipsychotics. Prolongation of the QTc interval is linked to the ventricular tachyarrhythmia torsade de pointes, which is occasionally fatal, although the precise association between QTc changes and risk of sudden cardiac death has not been determined. QTc prolongation is certainly linked in some way to an increased risk of sudden cardiac death, and this may explain the recent, somewhat preliminary, reports of increased risk associated with use of some antipsychotics. Ziprasidone prolongs QTc to a moderate degree, though to a greater extent than quetiapine, risperidone, olanzapine and haloperidol. There is also preliminary evidence that ziprasidone blocks the delayed potassium rectifier channel in cardiac cells. Because of this, and despite the fact that no increased risk of arrhythmia or sudden death has been demonstrated for ziprasidone, some caution is required. Ziprasidone should be avoided in patients with some types of cardiac disease and with uncontrolled electrolyte disturbance. Coprescription of ziprasidone with other drugs that prolong the QT interval should be avoided where possible. When cross-tapering with other antipsychotics, care should be taken to avoid high total load of antipsychotics, and cross-tapering with drugs known to prolong QT interval at normal clinical doses should be avoided. Under most clinical circumstances, however, ziprasidone may be safely used without ECG monitoring or other special precautions. Its effect on QT interval and possible effect on risk of arrhythmia should be balanced with the observation that the drug has a more favourable effect on bodyweight and glucose homeostasis (and so perhaps cardiac risk) than many other antipsychotics.

Antipsychotic Agents↗

PubMed2001

Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage.

Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

Animals↗

PubMed2001

Role of I(K) and I(f) in the pacemaker mechanisms of sino-atrial node myocytes.

The role of I(K) (delayed rectifier current) and I(f) (hyperpolarization-activated current) in dominant and subsidiary pacemaker ranges was studied in single myocytes isolated from the guinea pig sino-atrial node by means of a perforated patch-clamp technique. In the dominant pacemaker range (approx. -55 to -40 mV), I(K) tails are present whereas I(f) is not activated. In the subsidiary pacemaker range (approx. -80 to -70 mV), I(f) is large whereas I(K) is minimal and reversing. The threshold for I(f) activation is more negative at short time intervals. Larger or longer depolarizations to -40 mV and +20 mV deactivate I(f) more and are followed by faster reactivation of I(f). Steps of 200-300 ms duration to +20 mV completely deactivate I(f). The slope conductance decreases during depolarizations at -40 and +20 mV and quickly re-increases after the steps. The I(f) deactivation range is between -70 and +10 mV, with a V(1/2) of -35 mV. Depolarizations from -80 to +20 mV at a rate of 120/min limit the subsequent I(f) reactivation owing to the short diastole. We conclude that I(K) plays a predominant role in the dominant pacemaker range and I(f) does so in the subsidiary pacemaker range. Either pacemaker mechanism is used by sino-atrial node cells depending on the diastolic potential range. A previous depolarization markedly increases the amplitude and rate of I(f) reactivation.

Action Potentials↗

PubMed1993

[Effects of panaxatriol saponins (PTS) isolated from panax notoginseng on the action potential and delayed rectifier current (Ix) in sheep cardiac Purkinje fibers].

The electrophysiological effects of PTS in sheep cardiac Purkinje fibers were studied. PTS was shown to increase the duration of action potential (APD30, APD50 and APD90) at the concentrations of 2.5 micrograms/ml and 5.0 micrograms/ml. However, the amplitude of action potential (APA) remained unchanged. The result of using double microelectrode voltage clamp method showed that PTS (1.25-10.0 micrograms/ml) depressed the delayed (outward) rectifier current (Ix) in time- and dose-dependent manners, when the holding potential was held at +20 mV, the command potential was held at +10 mV, 0.2 Hz and the clamping time at 1-1.5 s. It may be concluded that the effect of PTS on APD is mainly related to blocking the delayed rectifier potassium channel.

Action Potentials↗

PubMedDate not supplied

Sensitivity of the slow component of the delayed rectifier potassium current (IKs) to potassium channel blockers: implications for clinical reverse use-dependent effects.

The slow delayed rectifier potassium current (I(Ks)) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I(Ks) and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of I(Ks). A two-electrode voltage clamp technique was performed to investigate the I(Ks). We demonstrated that quinidine, sotalol and procainamide had no effects on I(Ks) up to a concentration of 300 microM while amiodarone inhibited I(Ks) in a concentration-dependent manner starting from 10 microM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. I(Ks) is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of I(Ks) at clinical concentrations contributes to the clinical reverse use-dependent effects.

Amiodarone↗

PubMed2006

Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current.

We have identified a series of diphenyl phosphine oxide (DPO) compounds that are potent frequency-dependent inhibitors of cloned human Kv1.5 (hKv1.5) channels. DPO inhibited hKv1.5 expressed in Chinese hamster ovary cells in a concentration-dependent manner preferentially during channel activation and slowed the deactivating tail current, consistent with a predominant open-channel blocking mechanism. Varying kinetics of DPO interaction with Kv1.5 channels resulted in differing potencies and frequency dependencies of inhibition that were comparable for both expressed hKv1.5 current and native ultrarapidly activating delayed rectifier potassium current (IKur) in human atrial myocytes. Selectivity of DPO versus other cardiac K+ channels was demonstrated in human atrial myocytes (IKur versus transient outward potassium current) and guinea pig ventricular myocytes [IKur versus rapidly activating delayed rectifier potassium current (IKr), slowly activating delayed rectifier potassium current (IKs) and inward rectifier potassium current (IK1), and one compound (DPO-1) was shown to be 15-fold more selective for Kv1.5 versus Kv3.1 channels expressed in Xenopus oocytes. DPO-1 also prolonged action potentials of isolated human atrial but not ventricular myocytes, in contrast to the effect of a selective IKr blocker. The selectivity and kinetics of inhibition hKv1.5 and IKur by DPO and the resulting selective prolongation of atrial repolarization could provide an effective profile for treatment of supraventricular arrhythmias.

Action Potentials↗

PubMed1993

2,3-Butanedione monoxime (BDM) inhibition of delayed rectifier DRK1 (Kv2.1) potassium channels expressed in Xenopus oocytes.

DRK1 is a cloned K+ channel from rat brain with consensus sites for protein kinase-dependent phosphorylation that might be expected to be functionally regulated by phosphorylation. 2,3-Butane-dione-monoxime (BDM) chemically removes phosphate groups from many proteins, and its action on DRK1 channels was examined after expression of DRK1 cRNA in Xenopus oocytes. In two-microelectrode voltage-clamp experiments, the application of BDM to the bath inhibited DRK1 current (ki = 16.6 mM, H = 0.96) rapidly and reversibly, with a time course similar to the time course of solution change within the bath. DRK1 current was inhibited at all potentials; the time course of current activation, deactivation and inactivation were unaffected by BDM. In inside-out patch-clamp experiments, the application of BDM to the cytoplasmic surface similarly inhibited channel activity rapidly and reversibly (ki = 10.7 mM, H = 1.01) in the absence of rephosphorylating substrates. These results are inconsistent with a phosphatase effect, because such an effect should be irreversible in cell-free, ATP-free patches. Instead, the results suggest that BDM can inhibit DRK1 channels directly from inside or outside of the membrane.

Animals↗

PubMed1996

Homogeneous development of electrical excitability via heterogeneous ion channel expression.

Synchronous differentiation of delayed-rectifier potassium current regulates electrical excitability and calcium entry in motor, sensory, and interneurons of the developing amphibian spinal cord. Although Kv1 and Kv2 potassium channel transcripts are detectable in these cells, it is not known which transcript contributes to functional expression. Overexpression of a Kv1 dominant-negative subunit indicates that 20% of neurons have only Kv1 potassium currents. In other neurons, non-Kv1 channels function because the dominant-negative subunit either only partially suppresses or has no effect on current. Thus, diverse embryonic neurons coordinate differentiation of excitability yet rely on heterogeneous potassium channel gene expression.

Animals↗

PubMed2001

New channel blocker BIIA388CL blocks delayed rectifier, but not A-type potassium current in central neurons.

A new substance (R,S)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-yl)-2-cyclohexyl-N-(3,3-diphenylpropyl)-acetamide hydrochloride (BIIA388Cl), which demonstrates neuroprotective properties in animal models, was examined for its action on K(+) currents in acutely isolated rat hippocampal neurons using the patch-clamp/concentration clamp techniques in the whole-cell configuration. The delayed rectifier K(+)-current (I(DR)) was strongly inhibited by externally applied BIIA388Cl, while the transient A-current (I(A)) remained virtually unaffected. Block of I(DR) by the pre-applied BIIA388Cl was revealed as a rapid decay of the current indicating direct interaction of the drug with the open state of the channel. The removal of the block upon repolarization was also rapid (tau=22 ms). The dose-response relationship for the blocking action of BIIA388Cl revealed an IC(50) value of 300 nM for the peak I(DR), whereas the IC(50) value for I(DR) measured 300 ms after the onset of depolarization was 120 nM. The blocking action of BIIA388Cl on I(A) was at least 200 times less potent. These data allow us to conclude that BIIA388Cl is an effective and selective blocker of I(DR). This current is the main pathway for the loss of intracellular potassium by depolarized neurons. Selective obstruction of this pathway could be useful for neuroprotection.

Animals↗