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Delayed Rectifier Current (delayed + rectifier_current)
Selected AbstractsEffects of female steroid hormones on A-type K+ currents in murine colonTHE JOURNAL OF PHYSIOLOGY, Issue 2 2006Elizabeth A. H. Beckett 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 Kv4.3 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. Kv4.3 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. [source] Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramideJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003Erika Hanada ABSTRACT Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10,100 ,m) and erythromycin (100 ,m) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 ,m) and Ito (IC50 = 20.9 + 0.13 ,m) while erythromycin reduced IK (IC50 = 60.1 + 0.29 ,m) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration. [source] Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for IKsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010J Ducroq Introduction:, Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods:, The effects of moxifloxacin (100 µM) and doxorubicin (30 µM), with or without dexrazoxane (from 3 to 30 µM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results:, Moxifloxacin (100 µM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 µM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 µM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications:, Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 [source] Modeling hERG and its Interactions with Drugs: Recent Advances in Light of Current Potassium Channel SimulationsCHEMMEDCHEM, Issue 4 2008Maurizio Recanatini Prof. Abstract The hERG K+ channel is responsible for the rapid delayed rectifier current in cardiac myocytes, and a block of its functioning may be related with the (inherited or drug-induced) long QT syndrome. For this reason, in recent times, some interest has arisen around computational studies aimed at developing hERG/drug models for the prediction of drug binding (docking) modes, in view of the assessment of the hERG blocking potential. On the other hand, voltage-gated K+ channels have been the subject of molecular simulations for several years, and rigorous protocols for studying the main aspects of their functions (permeation, gating, voltage sensing) have been published. In this article, we briefly introduce these classical computational works on K+ channels, and then review in depth the reports on the latest advanced modeling studies on hERG. The aim is to put the hERG modeling work in the more general context of the ion channel simulations field, to show the peculiarity of hERG on the one side, and also to indicate some possible new avenues in the use of modeling techniques to increase our knowledge of this important channel. [source] Endothelin-1 Modulates the Arrhythmogenic Activity of Pulmonary VeinsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 3 2008AMEYA R. UDYAVAR M.D. Objective: Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity. Methods: Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps. Results: In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 ± 1.0 Hz to 0.8 ± 0.5 Hz (n = 16). BQ-485 (100 ,M, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium,calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity. Conclusion: Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents. [source] | ||||||||||