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PubMed2000

Clinical differences between the newer antiarrhythmic agents.

In the light of studies demonstrating the serious safety problems of antiarrhythmic agents with class I activity, research and development efforts have focused largely on drugs with a class III mechanism of action. Most of the newer agents target the rapid component of the delayed rectifier potassium current (I(Kr)). In the case of dofetilide, the mechanism of action is relatively pure, with single I(Kr) channel blocking activity. Other agents have a wider spectrum of activity. Azimilide blocks both the rapid I(Kr) and slow I(Ks) potassium currents and ibutilide also augments the inward sodium current. Clinical investigation of these agents has shown them to be effective antiarrhythmic drugs with a number of advantages over existing agents, particularly in terms of safety. Dronedarone and tedisamil also have multichannel blocking actions and are in earlier stages of clinical development. Until now, therapeutic choices have been limited and far from ideal. It is hoped that the availability of the newer class III agents will at least provide greater choice of therapy and hopefully will bring us closer to therapeutic ideals in the management of arrhythmia.

Amiodarone↗
PubMed2003

Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel.

Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans, however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking. The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current (IKr) encoded by HERG (the human ether-a-go-go-related gene) at drug concentrations, temperature and ionic conditions mimicking those occurring in human subjects. Potassium currents in HEK 293 cells stably transfected with HERG were recorded using a whole cell voltage clamp method. Exposure of cells to erythromycin reduced the HERG encoded potassium current in a concentration dependent manner with an IC50 of 38.9 +/- 1.2 microM and Hill Slope factor of 0.4 +/- 0.1. Clarithromycin produced a similar concentration-dependent block with an IC50 of 45.7 +/- 1.1 microM and Hill Slope factor of 1.0 +/- 0.1. Erythromycin (25-250 microM) and clarithromycin (5 or 25 microM) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol. The results of this study document that both erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations.

Action Potentials↗
PubMed2006

Topics on the Na+/Ca2+ exchanger: involvement of Na+/Ca2+ exchange system in cardiac triggered activity.

Sodium-calcium exchange (NCX) is one of the major regulators of intracellular Ca(2+) concentration in cardiac myocytes. The bi-directional and electrogenic property of NCX raises a question about whether NCX is involved in arrhythmias. We reviewed the role of NCX in cardiac triggered activity in limited experimental conditions: the digitalis-induced arrhythmia, the arrhythmia caused from sustained opening of sodium channel, and the arrhythmia caused from the inhibition of inwardly rectifying potassium current. Effects of NCX inhibitors on ventricular arrhythmias recorded on ECG or the delayed afterdepolarizations and triggered activity recorded by the current clamp method were evaluated. As an NCX inhibitor, we preferred to use SEA0400 instead of KB-R 7943. For a precise analysis, a computational reconstruction of action potential with the Luo and Rudy model was applied. The cardiac NCX system seems to play a role only in the digitalis-induced arrhythmia and may not be involved in other arrhythmias. This review highlights the relationship between triggered activity and an NCX system and also suggests the physiologic and pathologic aspect of the NCX system in cardiac arrhythmias.

Animals↗
PubMed2003

Effects of caffeine on potassium currents in isolated rat ventricular myocytes.

Rapid exposure of cardiac muscle to high concentrations of caffeine releases Ca(2+) from the sarcoplasmic reticulum (SR). This Ca(2+) is then extruded from the cell by the Na(+)/Ca(2+) exchanger. Measurement of the current carried by the exchanger (I(Na/Ca)) can therefore be used to estimate of the Ca(2+) content of the SR. Previous studies have shown that caffeine, however, can also inhibit K(+) currents. We therefore investigated whether the inhibitory effects of caffeine on these currents could contaminate measurements of I(Na/Ca). Caffeine caused partial inhibition of the inward rectifier K(+) current (I(K1)): the outward current at -40 mV was 1.15+/-0.24 pA/pF in control and decreased to 0.34+/-0.15 pA/pF in the presence of 10 mmol/l caffeine (P<0.05, n=15). This was similar to the effect of caffeine on the holding current observed at -40 mV in the absence of K(+) channel block and could therefore account for the contaminating effects of caffeine observed during measurements of I(Na/Ca). Moreover, caffeine also partially inhibited the transient outward ( I(to)) and the delayed rectifier (I(K)) K(+) currents.

Animals↗
PubMed1993

Inward rectification of the minK potassium channel.

The minK protein induces a slowly activating voltage-dependent potassium current when expressed in Xenopus oocytes. We have used macroscopic minK currents to determine the open channel current-voltage relationship for the channel, and have found that the minK current is inwardly rectifying. The channel passes inward current at least 20-fold more readily than outward current. Both rat and human minK exhibit this property. The rectification of minK is similar to that reported for a slow component of the cardiac delayed rectifier, strengthening the hypothesis that minK is responsible for that current.

Amino Acid Sequence↗
PubMed1998

The Androctonus australis garzoni scorpion venom contains toxins that selectively affect voltage-dependent K(+)-channels in cerebellum granular cells.

A purified peptide from Androctonus australis Garzoni venom (AaG) affects selectively a K(+)-current recorded from cerebellum granular cells. This current is characterized by fast activating and inactivating kinetics similar to an IA-type current. Addition of 2 microM peptide Aa1 (from Androctonus australis, toxin 1) to the external side of the channel suppressed completely and in a selective manner the IA-type current, with an IC50 value of 130 nM, whereas in the same conditions, the other potassium current, identified as delayed rectifier (Id), was not affected. Additionally, we show that another partially purified peptide (III-12) from the same venom was able to block reversibly both K(+)-currents.

Animals↗
PubMed1991

Shaker, Shal, Shab, and Shaw express independent K+ current systems.

Although many K+ channel genes encoding homologous subunits have been cloned, a central question remains: how do these subunits associate to produce the diversity of K+ currents observed in living cells? Previous work has shown that different subunits encoded by the Shaker gene subfamily are able to form heteromultimers, which add to the diversity of currents. However, the unrestrained mixing of subunits from all genes to form hybrid channels would be undesirable for some cells that clearly require functionally discrete K+ currents. We show that Drosophila Shaker, Shal, Shab, and Shaw subunits form functional homomultimers, but that a molecular barrier to heteropolymerization is present. Coexpression of all four K+ channel systems does not alter their individual properties in any way. These experiments also demonstrate that multiple, independent A-current systems together with multiple, independent delayed rectifier systems can coexist in single cells.

Animals↗
PubMed2003

Human amylin actions on rat cholinergic basal forebrain neurons: antagonism of beta-amyloid effects.

Human amylin (hAmylin), a 37-amino acid pancreatic peptide, and amyloid beta protein (A beta), a 39-43 amino acid peptide, abundantly deposited in the brains of Alzheimer's patients, induce neurotoxicity in hippocampal and cortical cultures. Although the mechanism of this neurotoxicity is unknown, both peptides are capable of modulating ion channel function that may result in a disruption of cellular homeostasis. In this study, we examined the effects of hAmylin on whole cell currents in chemically identified neurons from the rat basal forebrain and the interactions of hAmylin-induced responses with those of A beta. Whole cell patch-clamp recordings were performed on enzymatically dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. Bath application of hAmylin (1 nM to 5 microM) resulted in a dose-dependent reduction in whole cell currents in a voltage range between -30 and +30 mV. Single-cell RT-PCR analysis reveal that all DBB neurons responding to hAmylin or A beta were cholinergic. Using specific ion channel blockers, we identified hAmylin and A beta effects on whole cell currents to be mediated, in part, by calcium-dependent conductances. Human amylin also depressed the transient outward (IA) and the delayed rectifier (IK) potassium currents. The hAmylin effects on whole cell currents could be occluded by A beta and vice versa. Human amylin and A beta responses could be blocked with AC187 (50 nM to 1 microM), a specific antagonist for the amylin receptor. The present study indicates that hAmylin, like A beta, is capable of modulating ion channel function in cholinergic basal forebrain neurons. Furthermore, the two peptides may share a common mechanism of action. The ability of an amylin antagonist to block the responses evoked by hAmylin and A beta may provide a novel therapeutic approach for Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Molecular cloning and characterization of LKv1, a novel voltage-gated potassium channel in leech.

We have cloned a novel voltage-gated K channel, LKv1, in two species of leech. The properties of LKv1 expressed in transiently transfected HEK293 cells is that of a delayed rectifier current. LKv1 may be a major modulator of excitability in leech neurons, since antibody localization studies show that LKv1 is expressed in the soma and axons of all neurons in both the central and peripheral nervous systems. Comparison of the biophysical and pharmacological properties of LKv1 with native voltage-gated conductances in leech neurons suggests that LKv1 may correspond to the previously characterized delayed rectifier current, I(K). Phylogenetic analysis of LKv1 shows that it is related to the Shaker subfamily of voltage-gated K channels although it occupies a separate branch from that of the monophyletic Shaker clade composed of the flatworm, Aplysia, Drosophila, and mammalian Shaker homologs as well as from that of two recently identified Shaker-related K channels in jellyfish. Thus, this analysis indicates that this group of voltage-gated K channels contains several evolutionarily divergent lineages.

Amino Acid Sequence↗
PubMed2003

Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo.

BACKGROUND AND PURPOSE: In light of recent evidence suggesting that an upregulation of K+ efflux mediated by outward delayed rectifier (I(K)) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of I(K) channels might be neuroprotective against hypoxia/ischemia-induced neuronal death. METHODS: Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K+ channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion. RESULTS: The K+ channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked I(K) without affecting N-methyl-D-aspartate receptor-mediated current or voltage-gated Ca2+ currents. Both TEA and a lipophilic K+ channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo. CONCLUSIONS: These data are consistent with the idea that K+ channel-mediated K+ efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K+ efflux through K+ channels may constitute a therapeutic approach for the treatment of stroke.

Animals↗
PubMed1996

Two temporally overlapping "delayed-rectifiers" determine the voltage-dependent potassium current phenotype in cultured hippocampal interneurons.

1. Whole cell voltage-clamp recordings were used to characterize the calcium-independent "delayed-rectifier" potassium currents of gamma-aminobutyric acid (GABA)-positive stratum radiatum-lacunosum-moleculare (st. L-M) interneurons in primary culture derived from neonate rats [postnatal day 5-7 (P5-P7)]. 2. Two distinct current phenotypes were observed, which we termed "sustained" and "slowly inactivating." Despite possessing similar voltage-dependent activation properties, current differed in their time-dependent inactivation properties and their kinetics of activation and deactivation. The phenotypes of the observed currents did not change during the time in vitro. The total current phenotype observed in any cell likely resulted from the temporal overlap of the two current components expressed in different relative proportions. 3. Externally applied 4-aminopyridine (4-AP) selectively blocked the slowly inactivating current component, by a use-dependent, but voltage-independent mechanism, suggesting that channel activation is required for 4-AP to interact with its binding site. In contrast, the sustained current component was unaffected by 4-AP. 4. Both the slowly inactivating and sustained current phenotypes were sensitive to externally applied tetraethylammonium (TEA). The IC50 of block by TEA was lower in cells expressing predominantly the sustained current components. 5. Currents recorded in the presence of internally applied TEA were of a slowly inactivating phenotype, suggesting that [TEA]i preferentially blocked the sustained current component. 6. When test pulses were preceded by a prepulse to -100 mV, a transient A-type current component was observed, but in contrast to pyramidal neurons and other interneuron types, this transient current contributed only a minor component to the total initial peak current. 7. In conclusion, two distinct, temporally overlapping potassium current phenotypes were observed on st. L-M interneurons. The overall phenotype was determined by the relative proportion of each current component. The absence of a prominent transient current suggests that the two delayed-rectifier currents play a critical role in determining the firing characteristics of these interneurons.

4-Aminopyridine↗
PubMed2002

Activation of NMDA receptors linked to modulation of voltage-gated ion channels and functional implications.

Catfish (Ictalurus punctatus) cone horizontal cells contain N-methyl-d-aspartate (NMDA) receptors, the function of which has yet to be determined. In the present study, we have examined the effect of NMDA receptor activation on voltage-gated ion channel activity. NMDA receptor activation produced a long-term downregulation of voltage-gated sodium and calcium currents but had no effect on the delayed rectifying potassium current. NMDA's effect was eliminated in the presence of AP-7. To determine whether NMDA receptor activation had functional implications, isolated catfish cone horizontal cells were current clamped to mimic the cell's physiological response. When horizontal cells were depolarized, they elicited a single depolarizing overshoot and maintained a depolarized steady state membrane potential. NMDA reduced the amplitude of the depolarizing overshoot and increased the depolarized steady-state membrane potential. Both effects of NMDA were eliminated in the presence of AP-7. These results support the hypothesis that activation of NMDA receptors in catfish horizontal cells may affect the type of visual information conveyed through the distal retina.

Animals↗
PubMed1988

Lineage-specific development of calcium currents during embryogenesis.

The development of electrophysiological properties of isolated, identified ascidian blastomeres was followed from the fertilized egg to the neurula, and the stage at which cells of different lineages first express different functional ion channel populations was determined. Little has been known about such events because of the difficulties of making voltage-clamp recordings from small embryonic cells and of identifying their developmental fates in dissociated preparations. The problem of small cell size was circumvented by using the whole-cell patch clamp, and identification was facilitated by the use of a species of ascidian, Boltenia villosa, in which endogenous pigment marks cells of specific developmental fates. Within approximately 3 hours after gastrulation, muscle-lineage blastomeres in these embryos developed a voltage-dependent calcium current while surrounding blastomeres of other lineages did not. At about the same time, all cells developed delayed outward potassium currents and lost the inwardly rectifying potassium currents present at earlier stages.

Animals↗
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↗
PubMed1992

Potassium channel modulation in rat portal vein by ATP depletion: a comparison with the effects of levcromakalim (BRL 38227).

1. The effects of levcromakalim and of adenosine 5'-triphosphate (ATP) depletion on membrane potential and ionic currents were studied in freshly-dispersed smooth muscle cells of rat portal vein by use of combined voltage- and current-clamp techniques. 2. Levcromakalim (1 microM) induced a glibenclamide-sensitive, non-inactivating K-current (IKCO) and simultaneously inhibited the slow, transient outward, delayed rectifier K-current (ITO). Levcromakalim also hyperpolarized the portal vein cells by approximately 20 mV. 3. Reduction of intracellular ATP by removal of glucose and carboxylic acids from the recording pipette and of glucose from the bath fluid, induced a slowly-developing, non-inactivating and glibenclamide-sensitive K-current (Imet) within 60-300 s after breaking the membrane patch. Imet reached peak amplitude after 300-900 s, remained at a plateau for 200-800 s and then slowly ran down. At the peak of Imet, the cells were hyperpolarized by approximately 20 mV and their input conductance was increased by 42%. 4. At the time of maximum development of Imet, the delayed rectifier current, ITO, was reduced by 48%. 5. In the absence of glucose and carboxylic acids, addition of 1 microM free ATP to the recording pipette almost doubled the magnitude of Imet. At a holding potential of -10 mV, Imet was increased from 124 +/- 11 pA to 228 +/- 54 pA whereas the time-course of development and run-down of Imet was unaffected. 6. During the development and after the run-down of Imet, levcromakalim (1-10 microM) failed to induce IKCO. 7. Stationary fluctuation analysis of the current noise associated with Imet revealed a unitary conductance of between 10-20 pS in a physiological potassium gradient. A second contaminating current with an underlying unitary conductance of approximately 150 pS remained after Imet had run down. 8. It is concluded that IKCO induced by levcromakalim and Imet are carried by the same population of relatively small conductance, glibenclamide-sensitive K-channels. The open state of these is increased by procedures designed to lower intracellular ATP concentrations. 9. The simultaneous inhibition of the delayed rectifier current (ITO) by both levcromakalim and during the development of Imet is highly significant. It suggests that levcromakalim could modify the interaction of ATP with sites linked to more than one type of K-channel. This results in the opening of those channels which underlie IKCO (and which are normally inhibited by ATP binding) together with the modulation of phosphorylation-dependent channels such as those which underlie ITO.

Adenosine Triphosphate↗
PubMed1999

The weaver GIRK2 mutation leads to decreased levels of serum thyroid hormone: characterization of the effect on midbrain dopaminergic neuron survival.

The selective neurodegenerative changes occurring in the weaver mutant cerebellum and midbrain are linked to a point mutation in an inward rectifying potassium channel (GIRK2). However, given that GIRK2 is widely expressed in the CNS, it is not understood why this mutation only leads to neuroanatomically selective and developmentally specific neuronal cell death. Here we show that the phenotype of the weaver mutant mouse includes hypothyroidism, which is associated with delays in somatic development and decreased expression of striatal transforming growth factor alpha (TGF-alpha). Since thyroid hormone has major effects on brain development, further studies were performed to address whether some of pathological changes detected the weaver mutant mouse are due to the reduced thyroid hormone levels. We observed that daily thyroid hormone replacement was able to stimulate somatic growth and restore TGF-alpha expression to wild-type levels, indicating that while these mice are responsive to thyroid hormone they possibly have a defect in the ability to regulate its release at the level of the hypothalamic pituitary axis. However, when we assessed whether thyroid hormone replacement could rescue midbrain dopaminergic neurons we found that this treatment accelerated rather than attenuated neurodegeneration. We did not observe that thyroid hormone was able to directly regulate expression of GIRK2 mRNA levels in the midbrain and therefore, speculate that the mechanism by which thyroid hormone accelerates midbrain dopaminergic neurodegeneration is by enhancing the maturation of the striatonigral inputs. In summary, we detected reduced levels of serum thyroid hormone in the weaver mutant mouse, which appears to be responsible for delays in somatic growth and the onset of neurodegenerative changes in the midbrain.

Animals↗
PubMed2000

[The role of sulphonylurea derivatives in treatment of diabetes type 2. The role of glimepiride].

Type 2 diabetes is characterised by some kind of duality. In its pathogenesis an important role have as well genetic as environmental factors. Both of them influence the insulin secretion at the one side and the insulin resistance at the other one. Very important group of antidiabetic drugs are sulphonylureas. They bind to the sulphonylurea receptor localized at the potassium channel in the cellular membrane. Contemporary sulphonylurea derivatives should be characterised by rather weak binding with the receptor, action during mealtime only (prandial regulation of glycemia), not to strong insulin secretion and for the quality of life reason once daily application. This criteria are fulfilled by e.g. slow-releasing preparations of glipizide and glikiazide and also by glimepiride.

ATP-Binding Cassette Transporters↗
PubMed2003

In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits.

OBJECTIVES: Women have longer rate-corrected QT intervals (QTc) and are at higher risk for developing life-threatening torsades de pointes ventricular arrhythmias than men, especially after taking medications that block cardiac human ether-a-go-go-related gene (HERG)-encoded K(+) channels. The purpose of the present study was to determine if the male sex steroid hormone, dihydrotestosterone (DHT), influences QT intervals in orchiectomized (Orch) male rabbits. METHODS: ECG and whole-cell patch-clamp analyses were employed to evaluate cardiac repolarization and K(+) currents in hearts isolated from orchiectomized (Orch) male New Zealand White rabbits receiving subcutaneous sustained release pellets for either dihydrotestosterone (DHT) or placebo. The efficacy of the treatment paradigm was monitored by measuring plasma DHT concentrations before and after the treatment period (10-14 days). RESULTS: The results show that rate- and drug-induced QT-lengthening is attenuated in hearts from DHT-treated rabbits relative to placebo-treated controls. No significant changes in QRS were observed in response to DHT, thereby indicating that DHT influences QT primarily through an effect on ventricular repolarization. In addition, hearts from DHT-treated rabbits displayed significantly less QT lengthening in response to quinidine challenge compared to placebo controls. Current densities for two important cardiac repolarizing K(+) currents, I(K1) and I(Kr), were found to be significantly increased in ventricular myocardium of DHT-treated rabbits. Further, the half-maximal voltage of activation (V(1/2)) for I(Kr) was significantly shifted to more negative potentials in myocytes from DHT vs. placebo hearts (21.2+/-1.2 vs. 30.2+/-1.4 mV, respectively, n=12, P<0.001). Corresponding changes in rabbit ether-a-go-go-related gene (RERG) mRNA were not found when examined by Northern blot hybridization. CONCLUSIONS: These results suggest that the presence of male sex steroid hormones in male rabbits helps to suppress rate- and drug-induced delays in cardiac repolarization. DHT action produces increased current densities for I(K1) and I(Kr) and a left-shift in the V(1/2) for I(Kr) that could account, at least in part, for the observed QTc differences between males and females. Since little change was seen in ventricular RERG gene expression, DHT action in the heart may influence I(Kr) via post-transcriptional and/or post-translational mechanisms.

Animals↗