Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1.

To elucidate the ionic mechanism of endothelin-1 (ET-1)-induced focal ventricular tachyarrhythmias, the regulation of I(K1) and its main molecular correlates, Kir2.1, Kir2.2 and Kir2.

Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation.

Flavonoids are naturally occurring food ingredients that have been associated with reduced cardiovascular mortality in epidemiological studies. In a previous study, we demonstrated for the first time that flavonoids are inhibitors of cardiac human ether-à-go-go-related gene (HERG) channels. Furthermore, we observed that grapefruit juice induced mild QTc prolongation in healthy subjects.

QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.

Background: A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date.

Methods And Results: We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes.

Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action.

Ajmaline is a class Ia anti-arrhythmic drug used in several European countries and Japan as first-line treatment for ventricular tachyarrhythmia. Ajmaline has been reported to induce cardiac output (QT) prolongation and to inhibit cardiac potassium currents in guinea pig cardiomyocytes. In order to elucidate the molecular basis of these effects, we examined effects of ajmaline on human ether a-go-go related gene HERG potassium channels.

Identification and characterisation of a novel KCNQ1 mutation in a family with Romano-Ward syndrome.

Romano-Ward syndrome (RWS), the autosomal dominant form of the congenital long QT syndrome, is characterised by prolongation of the cardiac repolarisation process associated with ventricular tachyarrhythmias of the torsades de pointes type. Genetic studies have identified mutations in six ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and the accessory protein Ankyrin-B gene, to be responsible for this disorder. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequence analysis have identified a KCNQ1 mutation in a family that were clinically conspicuous due to several syncopes and prolonged QTc intervals in the ECG.

Activation of cardiac human ether-a-go-go related gene potassium currents is regulated by alpha(1A)-adrenoceptors.

Patients with cardiac disease typically develop life-threatening ventricular arrhythmias during physical or emotional stress, suggesting a link between adrenergic stimulation and regulation of the cardiac action potential. Human ether-a-go-go related gene (hERG) potassium channels conduct the rapid component of the repolarizing delayed rectifier potassium current, I(Kr). Previous studies have revealed that hERG channel activation is modulated by activation of the beta-adrenergic system.

Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone.

Trazodone is an atypical antidepressant that is commonly used in the treatment of affective disorders. There have repeatedly been reports of cardiac arrhythmia associated with this drug and concerns have been raised regarding the cardiac safety of trazodone. However, interaction with HERG channels as a main factor of cardiac side effects has not been studied to date.

Human cardiac inwardly rectifying current IKir2.2 is upregulated by activation of protein kinase A.

Objective: The cardiac inwardly rectifying potassium current IK1 and its molecular correlates Kir2.1 and Kir2.2 play an important role in cardiac repolarisation and in the pathogenesis of hereditary long-QT syndrome (LQTS-7).

Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action.

1 The topoisomerase II inhibitor amsacrine is used in the treatment of acute myelogenous leukemia. Although most anticancer drugs are believed not to cause acquired long QT syndrome (LQTS), concerns have been raised by reports of QT interval prolongation, ventricular fibrillation and death associated with amsacrine treatment. Since blockade of cardiac human ether-a-go-go-related gene (HERG) potassium currents is an important cause of acquired LQTS, we investigated the acute effects of amsacrine on cloned HERG channels to determine the electrophysiological basis for its proarrhythmic potential.

Hypoxia-induced inhibition of whole cell membrane currents and ion transport of A549 cells.

In excitable cells, hypoxia inhibits K channels, causes membrane depolarization, and initiates complex adaptive mechanisms. It is unclear whether K channels of alveolar epithelial cells reveal a similar response to hypoxia. A549 cells were exposed to hypoxia during whole cell patch-clamp measurements.

Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.

Budipine is a non-dopaminergic antiparkinsonian drug causing acquired forms of Long QT syndrome (aLQTS). As a consequence, the manufacturer has restricted the use of budipine in patients who exhibit additional risk factors for the development of "Torsades-de-Pointes" tachycardias (TdP). The molecular basis of this serious side effect has not been elucidated yet.

Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels.

Dronedarone is a noniodinated benzofuran derivative that has been synthesized to overcome the limiting iodine-associated adverse effects of the potent antiarrhythmic drug amiodarone. In this study, the acute electrophysiological effects of dronedarone on repolarizing potassium channels were investigated to determine the class III antiarrhythmic action of this compound. HERG and KvLQT1/minK potassium channels conduct the delayed rectifier potassium current IK in human heart, being a primary target for class III antiarrhythmic therapy.

Human beta(3)-adrenoreceptors couple to KvLQT1/MinK potassium channels in Xenopus oocytes via protein kinase C phosphorylation of the KvLQT1 protein.

Modulation of the slow component of the delayed rectifier potassium current (IKs) in heart critically affects cardiac arrhythmogenesis. Its current amplitude is regulated by the sympathetic nervous system. However, the signal transduction from the beta-adrenergic system to the KvLQT1/MinK (KCNQ1/KCNE1) potassium channel, which is the molecular correlate of the IKs current in human cardiomyocytes, is not sufficiently understood.

Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein.

Objective: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood.

Protein kinase A-mediated phosphorylation of HERG potassium channels in a human cell line.

Objective: To investigate the molecular mechanism of human ether-a-go-go-related gene (HERG) potassium channels regulated by protein kinase A (PKA) in a human cell line.

Methods: HERG channels were stably expressed in human embryonic kidney (HEK) 293 cells, and currents were measured with the patch clamp technique. The direct phosphorylation of HERG channel proteins expressed heterologously in Xenopus laevis oocytes was examined by (32)P labeling and immunoprecipitation with an anti-HERG antibody.

Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel.

Chromanol 293B and dofetilide are inhibitors of IKs and IKr, i.e., of the slow and the rapid component of the delayed rectifier potassium current.

Antiarrhythmic drug carvedilol inhibits HERG potassium channels.

Objective: The aryloxypropanolamine carvedilol is a multiple action cardiovascular drug with blocking effects on alpha-receptors, beta-receptors, Ca(2+)-channels, Na(+)-channels and various native cardiac K(+) channels, thereby prolonging the cardiac action potential. In a number of clinical trials with patients suffering from congestive heart failure, carvedilol appeared to be superior to other beta-blocking agents in reducing total mortality. Given the multiple pharmacological actions of carvedilol, this may be due to specific channel blockade rather than beta-antagonistic activity.

A K+ single channel and whole-cell clamp study on the effects of levocromakalim in guinea pig portal vein cells.

Single channel cell-attached patch and whole-cell clamp experiments on the mode of action of the K+ channel opener (KCO), levcromakalim, were performed in guinea pig isolated portal vein cells. At +20 mV (135/23 mM K+ in bath/pipette), 10 microM levcromakalim activated K+ channels with a chord conductance of 23.2 pS (K(KCO)), which were sensitive to the blocker of ATP-dependent K+ channels (K(ATP)), glibenclamide.

Intracellular ADP activates ATP-sensitive K+ channels in vascular smooth muscle cells of the guinea pig portal vein.

Vasodilatation following tissue ischemia is assumed to partially result from activation of ATP-dependent K+ channels (KATP). To assess the effect of cytosolic adenosine nucleotides, the balance of which depends on tissue pO2, on KATP, we have measured steady state outward currents (SSC) by the whole-cell clamp technique in smooth muscle cells of the guinea pig portal vein at different concentrations of ATP and ADP in the pipette solution. Glibenclamide, a selective inhibitor of KATP, was used as a pharmacological tool.

Tedisamil inhibits the delayed rectifier K+ current in single smooth muscle cells of the guinea-pig portal vein.

Tedisamil is a new bradycardic agent with an inhibitory action on K+ channels in cardiac muscle, and secondary beneficial effects in experimentally induced cardiac ischemia. In whole-cell clamp studies in enzymatically dispersed, single smooth muscle cells from the guinea-pig portal vein, tedisamil inhibited the delayed rectifier K+ current (determined as the charge transferred through the cell membrane), the mean concentration for half-maximal inhibition being 2.9 microM.

Effects of the K+ channel blocker tedisamil on 86Rb efflux induced by cromakalim, high potassium and noradrenaline, and on mechanical tension in rabbit isolated vascular smooth muscle.

Tedisamil, a new bradycardic agent with an inhibitory action on K+ channels in cardiac muscle, was found to inhibit in a non-competitive manner the relaxation induced by the K+ channel opener cromakalim in noradrenaline-stimulated helical strips from rabbit aortae. Tedisamil tended to be more potent in this respect than glibenclamide; the latter however competitively antagonized the cromakalim-induced relaxation. In rabbit aorta preloaded with 86Rb as a marker of K+, 10 mumol/l tedisamil inhibited the 86Rb efflux induced by 10 mumol/l cromakalim.

Pharmacological characterization of nicorandil by 86Rb efflux and isometric vasorelaxation studies in vascular smooth muscle.

Nicorandil and cromakalim were found to stimulate 86Rb efflux (a marker of K+ ions) from resting preparations of rabbit aorta. This action was suppressed by 10(-5) M glibenclamide, an antagonist of K(+)-channel openers in vascular smooth muscle. Through intracellular production of cyclic GMP, and subsequent suppression of cellular Ca2+ activation, nitrovasodilators interfere indirectly with the activation of Ca(2+)-dependent ion channels.

Tedisamil blocks single large-conductance Ca(2+)-activated K+ channels in membrane patches from smooth muscle cells of the guinea-pig portal vein.

Enzymatically dispersed smooth muscle cells of the guinea-pig portal vein were studied by the patch-clamp technique. They were found to have Ca(2+)-dependent K+ channels with the typical properties of the "BK" channel, i.e.