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Cardiac Action Potential (cardiac + action_potential)
Selected AbstractsZebrafish as a model for long QT syndrome: the evidence and the means of manipulating zebrafish gene expressionACTA PHYSIOLOGICA, Issue 3 2010I. U. S. Leong Abstract Congenital long QT syndrome (LQT) is a group of cardiac disorders associated with the dysfunction of cardiac ion channels. It is characterized by prolongation of the QT-interval, episodes of syncope and even sudden death. Individuals may remain asymptomatic for most of their lives while others present with severe symptoms. This heterogeneity in phenotype makes diagnosis difficult with a greater emphasis on more targeted therapy. As a means of understanding the molecular mechanisms underlying LQT syndrome, evaluating the effect of modifier genes on disease severity as well as to test new therapies, the development of model systems remains an important research tool. Mice have predominantly been the animal model of choice for cardiac arrhythmia research, but there have been varying degrees of success in recapitulating the human symptoms; the mouse cardiac action potential (AP) and surface electrocardiograms exhibit major differences from those of the human heart. Against this background, the zebrafish is an emerging vertebrate disease modelling species that offers advantages in analysing LQT syndrome, not least because its cardiac AP much more closely resembles that of the human. This article highlights the use and potential of this species in LQT syndrome modelling, and as a platform for the in vivo assessment of putative disease-causing mutations in LQT genes, and of therapeutic interventions. [source] Repolarization of the cardiac action potential.ACTA PHYSIOLOGICA, Issue 2010Does an increase in repolarization capacity constitute a new anti-arrhythmic principle? Abstract The cardiac action potential can be divided into five distinct phases designated phases 0,4. The exact shape of the action potential comes about primarily as an orchestrated function of ion channels. The present review will give an overview of ion channels involved in generating the cardiac action potential with special emphasis on potassium channels involved in phase 3 repolarization. In humans, these channels are primarily Kv11.1 (hERG1), Kv7.1 (KCNQ1) and Kir2.1 (KCNJ2) being the responsible ,-subunits for conducting IKr, IKs and IK1. An account will be given about molecular components, biophysical properties, regulation, interaction with other proteins and involvement in diseases. Both loss and gain of function of these currents are associated with different arrhythmogenic diseases. The second part of this review will therefore elucidate arrhythmias and subsequently focus on newly developed chemical entities having the ability to increase the activity of IKr, IKs and IK1. An evaluation will be given addressing the possibility that this novel class of compounds have the ability to constitute a new anti-arrhythmic principle. Experimental evidence from in vitro, ex vivo and in vivo settings will be included. Furthermore, conceptual differences between the short QT syndrome and IKr activation will be accounted for. [source] Functions of erg K+ channels in excitable cellsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2004Jürgen R. Schwarz Abstract Ether-ą-go-go -related gene (erg) channels are voltage-dependent K+ channels mediating inward-rectifying K+ currents because of their peculiar gating kinetics. These characteristics are essential for repolarization of the cardiac action potential. Inherited and acquired malfunctioning of erg channels may lead to the long QT-syndrome. However, erg currents have also been recorded in many other excitable cells, like smooth muscle fibres of the gastrointestinal tract, neuroblastoma cells or neuroendocrine cells. In these cells erg currents contribute to the maintenance of the resting potential. Changes in the resting potential are related to cell-specific functions like increase in hormone secretion, frequency adaptation or increase in contractility. [source] Ageing to arrhythmias: conundrums of connections in the ageing heartJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2006Sandra A. Jones The proportion of the population that is elderly continues to increase, leading to an increasing need to address problems chiefly associated with old age. Progressive ageing of the heart is associated with an increasing incidence of arrhythmias and disorders of the normal origin of the heartbeat, the sinoatrial node. This intrinsic pacemaker of the heart has an increasing tendency with age to lose its dominant role in pacing the heart, and regulation of heart rate becomes erratic. This ,sick sinus syndrome' is associated with fainting, palpitations, shortness of breath and sudden death. Current treatment of this condition is by implantation of an artificial pacemaker, an intervention increasingly required with age. The current evidence suggests that the normal heartbeat fails due to changes in the expression of critical proteins that ensure the correct production and conduction of the cardiac action potential. Depletion of a protein directly responsible for providing electrical connections between the cells of the heart, connexin 43, appears to leave the normal cardiac pacemaker disconnected and unable to drive the heart. This process may be associated with age-dependent changes in stress-related signalling. Simple interventions such as exercise could impact on the processes hypothesized to be involved and may offer a means to preserve the stability of the electrical activity of the heart into old age without pharmacological manipulation. [source] KATP channel openers: Structure-activity relationships and therapeutic potentialMEDICINAL RESEARCH REVIEWS, Issue 2 2004Raimund Mannhold Abstract ATP-sensitive potassium channels (KATP channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. KATP channels were identified in a variety of tissues including muscle cells, pancreatic ,-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, KATP channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via KATP channels. Given their many physiological functions, KATP channels represent promising drug targets. Sulfonylureas like glibenclamide block KATP channels; they are used in the therapy of type 2 diabetes. Openers of KATP channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. © 2003 Wiley Periodicals, Inc. Med Res Rev, 24, No. 2, 213,266, 2004 [source] The evolutionarily conserved residue A653 plays a key role in HERG channel closingTHE JOURNAL OF PHYSIOLOGY, Issue 11 2009Svetlana Z. Stepanovic Human ether-a-go-go- related gene (HERG) encodes the rapid, outwardly rectifying K+ current IKr that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of IKr can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K+ channels. HERG-A653 is close to the ,glycine hinge' implicated in K+ channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V1/2 of activation ranging from ,23.6 (A653S) to ,62.5 (A653V) compared to ,11.2 mV for wild-type (WT). Deactivation was also drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and prolonged holding potentials at ,130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the IKr inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the channel activation threshold. [source] Heterogeneity Of The Properties Of INa in Epicardial And Endocardial Cells Of Rat VentricleCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2002Bonny N Honen SUMMARY 1. Ventricular INa heterogeneity was investigated in adult rat hearts. Differences in transient outward potassium current (Ito) were used to confirm isolation of subepicardial and subendocardial cells. Mean peak Ito was 6.0 ± 0.7 and 1.6 ± 0.45 pA/pF in epicardial and endocardial cells, respectively (P < < 0.01). 2. Maximum sodium conductance was smaller in subendocardial cells compared with subepicardial cells (2.39 ± 0.11 vs 2.78 ± 0.12 nS/pF, respectively; n = 17 for both; 0.01 < P < 0.05) and 50% activation occurred at a slightly more negative potential (,47.6 ± 0.8 vs,44.9 ± 0.9 mV, respectively; n = 10 for both; 0.01 < P < 0.05). 3. The potential for 50% inactivation was not significantly different in subepicardial compared with subendocardial cells (72.2 ± 1.0 vs 72.8 ± 2.2 mV, respectively; n = 17 for both; NS). 4. Persistent sodium current density appeared smaller in subendocardial (n = 19) compared with subepicardial (n = 11) cells (at a test potential of ,25 mV current, density was 0.118 ± 0.041 vs 0.144 ± 0.085 pA/pF, respectively), although this was not statistically significant due to large variability between cells. 5. Mathematical modelling of the cardiac action potential indicated that the combined effects of differences in current density and voltage dependence of sodium currents are unlikely to contribute to ventricular action potential heterogeneity between epicardial and endocardial cells. [source] Blockade of HERG K+ channel by an antihistamine drug brompheniramine requires the channel binding within the S6 residue Y652 and F656JOURNAL OF APPLIED TOXICOLOGY, Issue 2 2008Sang-Joon Park Abstract A number of clinically used drugs block delayed rectifier K+ channels and prolong the duration of cardiac action potentials associated with long QT syndrome. This study investigated the molecular mechanisms of voltage-dependent inhibition of human ether- a-go-go -related gene (HERG) delayed rectifier K+ channels expressed in HEK-293 cells by brompheniramine, an antihistamine. Brompheniramine inhibited HERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC50) value of 1.7 µm at 0 mV. A block of HERG current by brompheniramine was enhanced by progressive membrane depolarization and showed significantly negative shift in voltage-dependence of channel activation. Inhibition of HERG current by brompheniramine showed time-dependence. The S6 residue HERG mutant Y652A and F656C largely reduced the blocking potency of HERG current. These results indicate that brompheniramine mainly inhibited the HERG potassium channel through the residue Y652 and F656 and these residues may be an obligatory determinant in inhibition of HERG current for brompheniramine. Copyright © 2007 John Wiley & Sons, Ltd. [source] Transmural Action Potential Repolarization Heterogeneity Develops Postnatally in the RabbitJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2004Ph.D., SALIM F. IDRISS M.D. Introduction: In the hereditary long QT syndrome, arrhythmia risk changes with age despite the presence of an ion channel mutation throughout development. Age-dependent changes in the transmural dispersion of repolarization may modulate this vulnerability. We recorded cardiac action potentials in infant, periadolescent, and adult rabbit myocardium to determine if transmural heterogeneities in repolarization are developmentally determined. Methods and Results: Arterially perfused ventricular preparations were studied from 2-week (n = 7), 7-week (n = 7), and adult (n = 6) NZW rabbits. Action potentials were recorded with microelectrodes in five regions: epicardium (epi), subepicardium (subepi), midwall (mid), subendocardium (subendo), and endocardium (endo) during endocardial S1 pacing at cycle lengths of 2,000, 1,000, and 500 ms. At 2 weeks, the transmural APD90 profile was flat. With age, APD prolongation from subepi to endo created a transmural repolarization gradient. At 7 weeks, APD90 was significantly longer at subendo [204 ± 2 ms (mean ± SE) 2,000-ms cycle length, P < 0.05] vs both endo (193 ± 2 ms) and epi (172 ± 2 ms), causing a heterogeneous transmural APD90 gradient. In adults, the transmural gradient was a smooth continuum such that APD was shortest in epicardium and longest in endocardium. Conclusion: The transmural distribution of APD is developmentally determined. Tissue-specific age-dependent changes in APD can result in transmural repolarization heterogeneity. These age-related effects may modulate arrhythmia vulnerability during development. (J Cardiovasc Electrophysiol, Vol. 15, pp. 795-801, July 2004) [source] | ||||||||||||||||