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PubMed2001

Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development.

The repolarization phase of the cardiac action potential is dependent on transmembrane K(+) currents. The slow (I(Ks)) and fast (I(Kr)) components of the delayed-rectifier cardiac K(+) current are generated by pore-forming alpha subunits KCNQ1 and KCNH2, respectively, in association with regulatory beta-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the beta-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that alpha subunits are homogeneously distributed within the myocardium, whereas the beta subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K(+) currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential beta-subunit distribution.

Animals↗
PubMed2003

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium.

Atrial fibrillation is one of the common arrhythmias associated with hyperthyroidism. This study examined the effects of thyroid hormone (T3) on mRNA expression and currents of major ionic channels determining the action potential duration (APD) in the rat atrium using the RNase protection assay and the whole-cell patch-clamp technique, respectively. T3 increased the Kv1.5 mRNA expression and decreased the L-type calcium channel mRNA expression, while the Kv4.2 mRNA expression did not change. APD was shorter in hyperthyroid than in euthyroid myocytes. The ultrarapid delayed rectifier potassium currents were remarkably increased in hyperthyroid than in euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid than in euthyroid myocytes. T3 shifted the current-voltage relationship for calcium currents negatively. In conclusion, T3 increased the outward currents and decreased the inward currents. The resultant changes of ionic currents shortened APD, providing a substrate for atrial fibrillation.

Action Potentials↗
PubMed2005

A single residue in the S6 transmembrane domain governs the differential flecainide sensitivity of voltage-gated potassium channels.

Flecainide has been used to differentiate Kv4.2-based transient-outward K(+)-currents (flecainide-sensitive) from Kv1.4-based (flecainide-insensitive). We found that flecainide also inhibits ultrarapid delayed rectifier (I(Kur)) currents in Xenopus laevis oocytes carried by Kv3.1 subunits (IC(50), 28.3 +/- 1.3 microM) more strongly than Kv1.5 currents corresponding to human I(Kur) (IC(50), 237.1 +/- 6.2 microM). The present study examined molecular motifs underlying differential flecainide sensitivity. An initial chimeric approach pointed to a role for S6 and/or carboxyl-terminal sites in Kv3.1/Kv1.5 sensitivity differences. We then looked for homologous amino acid residues of the two sensitive subunits (Kv4.2 and Kv3.1) different from homologous residues for insensitive subunits (Kv1.4 and Kv1.5). Three candidate sites were identified: two in the S5-S6 linker and one in the S6 segment. Mutation of the proximal S5-S6 linker site failed to alter flecainide sensitivity. Mutation at the more distal site in Kv1.5 (V481L) modestly increased sensitivity, but the reciprocal Kv3.1 mutation (L401V) had no effect. S6 mutants caused marked changes: flecainide sensitivity decreased approximately 8-fold for Kv3.1 L422I (IC(50), 213 +/- 9 microM) and increased approximately 7-fold for Kv1.5 I502L (IC(50), 35.6 +/- 1.9 microM). Corresponding mutations reversed flecainide sensitivity of Kv1.4 and Kv4.2; L392I decreased Kv4.2 sensitivity by approximately 17-fold (IC(50) of 37.4 +/- 6.9 to 628 +/- 36 microM); I547L increased Kv1.4 sensitivity by approximately 15-fold (IC(50) of 706 +/- 37 to 40.9 +/- 7.3 microM). Our observations indicate that the flecainide sensitivity differences among these four voltage-gated K(+)-channels are determined by whether an isoleucine or a leucine is present at a specific amino acid location.

Amino Acid Sequence↗
PubMed2005

Anaesthetics and the rate corrected interval: learning from droperidol?

PURPOSE OF REVIEW: Understanding of the long QT syndrome continues to evolve. Anaesthesia in patients with untreated long QT syndrome carries a risk of perioperative malignant ventricular arrhythmias. Genotypically susceptible individuals may have a normal rate-corrected QT interval and present with torsade de pointes intraoperatively. The likelihood of arrhythmias can be reduced by careful preoperative preparation. Perioperative disturbances in physiological homeostasis and drugs administered can prolong the rate-corrected QT interval. RECENT FINDINGS: Seven ion channel genes have been discovered and over 300 mutations identified. For acquired long QT syndrome, the main issue is the blockade of a slow component of delayed rectifier potassium ion current. Preclinical tests are recommended to assess potential new drugs for QT prolongation. Drugs not increasing the transmural dispersion of repolarization have little potential to induce arrhythmias despite prolonging the QT interval. Diagnostic DNA testing is used to screen families. Although gene-based specific therapy is preliminary, molecular genetic analysis could be useful to unravel subclinical mutations. Future therapeutic strategies include the use of sodium antagonists, potassium channel activators and protein kinase inhibitors. SUMMARY: Droperidol can lead to serious cardiac arrhythmias from QT prolongation. Recent advances in the pathophysiology of congenital and acquired long QT syndrome are reviewed. Preclinical tests assessing potential new drugs for QT prolongation are briefly discussed. Considerations for the management of these patients during perioperative phases are explored. The optimal treatment of the long QT syndrome is presented along with a glimpse into future possibilities in this field.

Journal Article↗
PubMed1996

Identification and properties of an ATP-sensitive K+ current in rabbit sino-atrial node pacemaker cells.

1. Single myocytes were isolated from rabbit sino-atrial (SA) node by enzymatic dissociation. Spontaneous pacemaker activity, whole-cell and single-channel currents were recorded under conditions known to modulate ATP-sensitive K+ (KATP) channels. 2. The KATP channel openers, cromakalim and pinacidil, slowed or abolished the pacemaker activity, and caused hyperpolarization of the maximum diastolic potential (MDP). Glibenclamide, a KATP channel blocker, reversed these effects. Cromakalim- and pinacidil-activated currents reversed near the potassium equilibrium potential, EK. Glibenclamide had no effect on the L-type calcium current, ICa(L), the hyperpolarization-activated inward current, If, or the delayed rectifier potassium current, IK. 3. Sodium cyanide, which inhibits mitochondrial ATP production, induced a macroscopic current that reversed near EK and was blocked by glibenclamide. 4. In excised, inside-out patches from SA node cells, single KATP channels showed a slope conductance of 52 +/- 8 pS (mean +/- S.D.) when measurements were made at negative voltages in symmetric, 140 mM K+. Channels from ventricular myocytes showed a somewhat larger slope conductance (70 +/- 5 pS). 5. Raising the intracellular ATP concentration caused a concentration-dependent reduction in the open probability of the KATP channels (IC50, 16 microM; Hill coefficient, approximately 1; at both pH 7.4 and 6.8). 6. In excised inside-out patches, cromakalim or pinacidil induced significant increases in KATP channel activity in the presence of 50 microM or 1 mM intracellular ATP. This channel activity was blocked by glibenclamide. 7. Our results suggest that sino-atrial node cells express a distinct isoform of KATP channel which may play an important role in pharmacological and pathophysiological modulation of pacemaker activity.

Action Potentials↗
PubMed2006

Effects of female steroid hormones on A-type K+ currents in murine colon.

Idiopathic constipation is higher in women of reproductive age than postmenopausal women or men, suggesting that female steroid hormones influence gastrointestinal motility. How female hormones affect motility is unclear. Colonic motility is regulated by ion channels in colonic myocytes. Voltage-dependent K(+) channels serve to set the excitability of colonic muscles. We investigated regulation of Kv 4.3 channel expression in response to acute or chronic changes in female hormones. Patch clamp experiments and quantitative PCR were used to compare outward currents and transcript expression in colonic myocytes from male, non-pregnant, pregnant and ovariectomized mice. Groups of ovariectomized mice received injections of oestrogen or progesterone to investigate the effects of hormone replacement. The capacitance of colonic myocytes from non-pregnant females was larger than in males. Net outward current density in male and ovariectomized mice was higher than in non-pregnant females and oestrogen-treated ovariectomized mice. Current densities in late pregnancy were lower than in female controls. Progesterone had no effect on outward currents. A-type currents were decreased in non-pregnant females compared with ovariectomized mice, and were further decreased by pregnancy or oestrogen replacement. Kv 4.3 transcripts did not differ significantly between groups; however, expression of the potassium channel interacting protein KChIP1 was elevated in ovariectomized mice compared with female controls and oestrogen-treated ovariectomized mice. Delayed rectifier currents were not affected by oestrogen. In the mouse colon, oestrogen suppresses A-type currents, which are important for regulating excitability. These observations suggest a possible link between female hormones and altered colonic motility associated with menses, pregnancy and menopause.

Animals↗
PubMed2002

Von Hippel-Lindau tumor suppressor protein transforms human neuroblastoma cells into functional neuron-like cells.

Von Hippel-Lindau (VHL) tumor suppressor protein is expressed in neurons of the central nervous system and plays an important role during the neuronal differentiation of central nervous system progenitor cells. To elucidate the neuronal differentiating potential of VHL protein in neuroblastoma cells, we overexpressed or inhibited VHL protein in human neuroblastoma cells (SY-SH5Y), and examined the morphological change, expressions of neuronal markers, and electrophysiological functions. Here we show that with VHL gene transduction SY-SH5Y cells stably expressing the VHL protein had neurite-like processes with varicosities, showed the distinct expression of the neuronal markers neuropeptide Y and neurofilament 200, acquired regulated neurosecretion competence in response to depolarizing and cholinergic stimuli, and had large voltage-gated fast sodium currents and delayed rectifier potassium (Kv) currents compatible with those of functional neurons. In addition, they displayed inactivated ether-á-go-go potassium channels related to the promotion of the cell cycle and to the termination of differentiation. Also, by treatment with retinoic acid, they rapidly underwent cell death related to apoptosis. These findings suggest that the induction of neuronal function by VHL protein is associated with down-regulation of the cell cycle. In contrast, the inhibition of endogenous expression of VHL protein with antisense-orientated VHL gene transduction reduced such neuronal properties inherent to these cells, including the capacity for activation of ether-á-go-go channels. In conclusion, VHL protein has a neuronal differentiating potential to transform neuroblastoma cells into functional neuron-like cells. Our finding of the neuronal differentiation of neuroblastoma cells under the control of the VHL gene may contribute to the development of clinical techniques for neuronal regeneration in the case of intractable neuronal diseases and for differentiation therapy against neuroblastomas.

Apoptosis↗
PubMed1997

Regulation of expression of the [3H]-dofetilide binding site associated with the delayed rectifier K+ channel by dexamethasone in neonatal mouse ventricle.

Developmental shortening of cardiac action potential duration in mouse appears to result, at least in part, from replacement of the rapid component of the delayed rectifying potassium current (IKr) with the transient outward current (ItO1). This developmental decrease in the IKr current density was paralleled by a loss of the high affinity [3H]-dofetilide binding site and loss of prolongation of action potential duration by dofetilide. Since glucocorticoid treatment prevented the developmental shortening of action potential duration in rats in the perinatal period, we hypothesized that chronic dexamethasone treatment would alter the developmental loss of IKr channel expression in mice. Accordingly, 10-day-old mice were randomly allocated to chronic in vivo dexamethasone treatment (1 mg/kg) or placebo treatment for 3-5 days. At 15 days of life, transmembrane action potentials were recorded in right ventricular endocardium and [3H]-dofetilide equilibrium binding studies were performed. The baseline action potential duration in the dexamethasone-treated animals was significantly greater than that in the control group (66+/-3 v 54+/-10 ms, respectively; P<0.01). Moreover, dofetilide significantly prolonged action potential duration in the dexamethasone-treated animals, but had no effect on the placebo-treated group (P<0.01). In addition, a high affinity [3H]-dofetilide binding site (Kd 96+/-21 nM and Bmax 69+/-13 fmoles/mg protein) was observed in the dexamethasone-treated group (n=5), whereas no specific [3H]-dofetilide binding was observed in the placebo-treated group. In conclusion, dexamethasone modulates developmental regulation of IKr channel expression in mouse ventricle.

Action Potentials↗
PubMed1987

Potassium channels in mouse neonate dorsal root ganglion cells: a patch-clamp study.

Isolated neurons from mouse neonate dorsal root ganglia were analyzed using both whole-cell clamp and single-channel recording techniques and presented a complex repertoire of potassium (K) channels. Different types of potassium channels have been found: calcium-activated K channel presenting a large unit conductance of 260 pS in symmetrical K; voltage-dependent K channels of 130 pS without calcium-dependence; two types of inward rectifying K channels (90 and 120 pS in symmetrical K); low probability K channels; delayed rectifier channels and non-selective cationic channels.

Animals↗
PubMed2002

Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain.

The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a). Coexpression of KChIP4a with Kv4 alpha-subunits abolishes fast inactivation of the Kv4 currents in various cell types, including cerebellar granule neurons. Kinetic analysis shows that the KIS domain delays Kv4.3 opening, but once the channel is open, it disrupts rapid inactivation and slows Kv4.3 closing. Accordingly, KChIP4a increases the open probability of single Kv4.3 channels. The net effects of KChIP4a and KChIP1-3 on Kv4 gating are quite different. When both KChIP4a and KChIP1 are present, the Kv4.3 current shows mixed inactivation profiles dependent on KChIP4a/KChIP1 ratios. The KIS domain effectively converts the A-type Kv4 current to a slowly inactivating delayed rectifier-type potassium current. This conversion is opposite to that mediated by the Kv1-specific "ball" domain of the Kv beta 1 subunit. Together, these results demonstrate that specific auxiliary subunits with distinct functions actively modulate gating of potassium channels that govern membrane excitability.

Amino Acid Sequence↗
PubMed1994

Voltage-activated potassium currents in isolated motor neurons from the jellyfish Polyorchis penicillatus.

1. We describe two voltage-activated potassium currents in the swim motor neurons (SMNs) of the hydrozoan jellyfish, Polyorchis penicillatus. Recordings from neurons isolated in primary cultures were made using the tight-seal, whole-cell technique. 2. One current, IK-fast, turned on rapidly (time to peak = 6-15 ms), was half-activated at -10 to 0 mV, decayed with two exponential phases (tau were approximately 70 ms and approximately 1 s), and was half-inactivated by prepulses around -53 mV. It likely plays an important role in regulating the duration of SMN action potentials. IK-fast has features shared by delayed rectifiers and A-like currents in other invertebrates and vertebrates. 3. Another current, IK-slow, elicited from a holding potential of -30 mV, exhibited a slow onset (tau = 65-250 ms), was half-activated approximately +24 mV, exhibited a shallower voltage dependence than IK-fast, and did not inactivate. It was slower than most known delayed rectifiers.

Action Potentials↗
PubMed1999

Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole.

INTRODUCTION: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go-related gene (HERG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears in serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels. METHODS AND RESULTS: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent. Norastemizole also blocked HERG current; however, block was incomplete and required higher drug concentrations (half-maximal block of 27.7 nM). CONCLUSIONS: Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.

Astemizole↗
PubMed1997

Involvement of voltage-dependent potassium channels in the EDHF-mediated relaxation of rat hepatic artery.

1. In the rat hepatic artery, the acetylcholine-induced relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is abolished by a combination of apamin and charybdotoxin, inhibitors of small (SKCa) and large (BKCa) conductance calcium-sensitive potassium (K)-channels, respectively, but not by each toxin alone. The selective BKCa inhibitor iberiotoxin cannot replace charybdotoxin in this combination. Since delayed rectifier K-channels (KV) represent another target for charybdotoxin, we explored the possible involvement of KV in EDHF-mediated relaxation in this artery. 2. The KV inhibitors, agitoxin-2 (0.3 microM), kaliotoxin (0.3 microM), beta-dendrotoxin (0.3 microM), dofetilide (1 microM) and terikalant (10 microM), each in combination with apamin (0.3 microM) had no effect on the EDHF-mediated relaxation induced by acetylcholine in the presence of N omega-nitro-L-arginine (0.3 mM) and indomethacin (10 microM), inhibitors of nitric oxide (NO) synthase and cyclo-oxygenase, respectively (n = 2-3). Although the KV inhibitor margatoxin (0.3 microM) was also without effect (n = 5), the combination of margatoxin and apamin produced a small inhibition of the response (pEC50 and Emax values were 7.5 +/- 0.0 and 95 +/- 1% in the absence and 7.0 +/- 0.1 and 81 +/- 6% in the presence of margatoxin plus apamin, respectively; n = 6; P < 0.05). 3. Ciclazindol (10 microM) partially inhibited the EDHF-mediated relaxation by shifting the acetylcholine-concentration-response curve 12 fold to the right (n = 6; P < 0.05) and abolished the response when combined with apamin (0.3 microM; n = 6). This combination did not inhibit acetylcholine-induced relaxations mediated by endothelium-derived NO (n = 5). 4. A 4-aminopyridine-sensitive delayed rectifier current (IK(V)) was identified in freshly-isolated single smooth muscle cells from rat hepatic artery. None of the cells displayed a rapidly-activating and -inactivating A-type current. Neither charybdotoxin (0.3 microM; n = 3) nor ciclazindol (10 microM; n = 5), alone or in combination with apamin (0.3 microM; n = 4-5), had an effect on IK(V). A tenfold higher concentration of ciclazindol (0.1 mM, n = 4) markedly inhibited IK(V), but this effect was not increased in the additional presence of apamin (0.3 microM; n = 2). 5. By use of membranes prepared from rat brain cortex. [125I]-charybdotoxin binding was consistent with an interaction at a single site with a KD of approximately 25 pM. [125I]-charybdotoxin binding was unaffected by iberiotoxin (0.1 microM, n = 6), but was increased by apamin in a concentration-dependent manner (Emax 43 +/- 10%, P < 0.05 and pEC50 7.1 +/- 0.2; n = 7-8). Agitoxin-2 (10 nM) displaced [125I]-charybdotoxin binding by 91 +/- 3% (n = 6) and prevented the effect of apamin (1 microM; n = 6). 6. It is concluded that the EDHF-mediated relaxation in the rat hepatic artery is not mediated by the opening of either KV or BKCa. Instead, the target K-channels for EDHF seem to be structurally related to both KV and BKCa. The possibility that a subtype of SKCa may be the target for EDHF is discussed.

4-Aminopyridine↗
PubMed1990

Single delayed rectifier channels in frog atrial cells. Effects of beta-adrenergic stimulation.

The patch-clamp technique with two pipettes was used to record single delayed K+ channels (cell-attached electrode) and to control the potential and the composition of the intracellular compartment (whole-cell electrode). With 30 microM cAMP in the cell and physiological potassium concentrations inside and outside the patch, a channel carrying an outward current was characterized. Its open probability was very low and the channel was recorded in only 5% of patches under control conditions. Increasing intracellular cAMP increased the probability of finding a channel in a patch 10-fold. The channel had the characteristics expected of a delayed rectifier channel. The time-course of its ensemble average resembled the whole-cell current in the same cell. The current-voltage relationship exhibited inward rectification, with a slope conductance of 20 pS in the linear portion and a reversal potential close to EK. Both the open- and the closed-time distributions were described by the sum of two exponentials, suggesting a complicated gating scheme involving two closed states and two open states. The beta-adrenergic stimulation did not change the conductance of the channel, but increased its probability of opening.

Animals↗
PubMed2005

Pattern of Kv beta subunit expression in macrophages depends upon proliferation and the mode of activation.

Voltage-dependent potassium channels (Kv) in leukocytes are involved in the immune response. In bone marrow-derived macrophages (BMDM), proliferation and activation induce delayed rectifier K+ currents, generated by Kv1.3, via transcriptional, translational, and posttranslational controls. Furthermore, modulatory Kv beta subunits coassociate with Kv alpha subunits, increasing channel diversity and function. In this study we have identified Kv beta subunits in mouse BMDM, studied their regulation during proliferation and activation, and analyzed K+ current parameters influenced by these proteins. BMDM express all isoforms of Kv beta1 (Kv beta1.1, Kv beta1.2, and Kv beta1.3) and Kv beta2 (Kv beta2.1), but not Kv beta4, the alternatively spliced murine Kv beta3 variant. M-CSF-dependent proliferation induced all Kv beta isoforms. However, LPS- and TNF-alpha-induced activation differentially regulated these subunits. Although LPS increased Kv beta1.3, reduced Kv beta1.2, and maintained Kv beta1.1 mRNA levels constant, TNF-alpha up-regulated Kv beta1.1, down-regulated Kv beta1.2, and left Kv beta1.3 expression unchanged. Moreover, in contrast to TNF-alpha, M-CSF- and LPS- up-regulated Kv beta2.1. K+ currents from M-CSF- and LPS-stimulated BMDM exhibited faster inactivation, whereas TNF-alpha increased tau values. Although in M-CSF-stimulated cells the half-inactivation voltage shifted to more positive potentials, the incubation with LPS and TNF-alpha resulted in a hyperpolarizing displacement similar to that in resting BMDM. Furthermore, activation time constants of K+ currents and the kinetics of the tail currents were different depending upon the mode of activation. Our results indicate that differential Kv beta expression modifies the electrical properties of Kv in BMDM, dependent upon proliferation and the mode of activation. This could determine physiologically appropriate surface channel complexes, allowing for greater flexibility in the precise regulation of the immune response.

Animals↗
PubMed2001

Dependence of I(Ks) biophysical properties on the expression system.

The delayed rectifier potassium current I(Ks) is important for repolarization of the cardiac action potential. In heart I(Ks) is a heteromeric channel composed of KCNQ1 (KvLQT1) and minK (KCNE1, IsK). Here we show that the KCNQ1/minK interaction is influenced by the expression system. Co-expression of KCNQ1 and minK in Xenopus oocytes resulted in potassium currents comparable to endogenous guinea pig cardiac I(Ks) in terms of temperature dependency and activation kinetics. In contrast, heterologous expression of I(Ks) in CHO cells revealed currents with a markedly different biophysical behavior. The sensitivity to the extracellular potassium concentration, temperature dependency and kinetics differ qualitatively. Potentially there is an endogenous component that affects I(Ks) which does not appear in all expression systems.

Action Potentials↗
PubMed1997

Dofetilide: first of a new generation of class III agents.

Dofetilide (Pfizer, Sandwich, Kent, UK) is a novel, highly specific class III methanesulfonanilide anti-arrhythmic drug. At nanomolar concentrations this agent prolongs both the atrial and ventricular effective refractory periods and action potential duration. Dofetilide's mechanism of action relies on potent blockade of the rapidly activating, inwardly rectifying component of the delayed rectifier potassium current (Ikr), the main current responsible for cardiac repolarisation. Dofetilide does not appear to interact with other cardiac ionic channels, and this explains its minimal effects upon conduction velocity, myocardial contractility and systemic haemodynamics. Dofetilide's mechanism of action makes it suitable for the termination of supraventricular and ventricular tachyarrhythmias. Small scale clinical trials have provided encouraging results, with preliminary data confirming its efficacy in the termination of atrial fibrillation and atrial flutter, and in increasing the electrical threshold for inducible ventricular tachycardia/fibrillation. The results of large scale, randomised, placebo-controlled trials are awaited in order to establish dofetilide's role in clinical practice. Due to its very specific mode of action, dofetilide has very few systemic side-effects. Dofetilide represents a novel and promising new class III agent.

Journal Article↗
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↗