Role of Delayed Rectifier Potassium Channels in Cardiac Repolarization and Arrhythmias

Physiology ◽  
1997 ◽  
Vol 12 (4) ◽  
pp. 152-157 ◽  
Author(s):  
MC Sanguinetti ◽  
MT Keating
Keyword(s):  
Potassium Channels ◽  
Action Potentials ◽  
Ventricular Arrhythmias ◽  
Gene Mutations ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiac Action ◽  
Life Threatening ◽  
Slow Onset

Cardiac action potentials are long because the magnitude of some potassium currents is reduced at depolarized potentials. The slow onset of repolarization is initiated by the opening of delayed rectifier potassium channels. A decrease in function of these channels resulting from gene mutations or pharmacological block increases risk of life-threatening ventricular arrhythmias.

scholarly journals The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

2021 ◽  
Author(s):  
Leila Topal ◽  
Muhammad Naveed ◽  
Péter Orvos ◽  
Bence Pászti ◽  
János Prorok ◽  
...  
Keyword(s):  
Side Effects ◽  
Action Potentials ◽  
Oral Intake ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiovascular Side Effects ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

scholarly journals Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve

2002 ◽  
Vol 137 (3) ◽  
pp. 361-368 ◽  
Author(s):  
Péter Biliczki ◽  
László Virág ◽  
Norbert Iost ◽  
Julius Gy Papp ◽  
András Varró
Keyword(s):  
Potassium Channels ◽  
Cardiac Repolarization ◽  
Repolarization Reserve

Role of BK Potassium Channels Shaping Action Potentials and the Associated [Ca2+]i Oscillations in GH3 Rat Anterior Pituitary Cells

2003 ◽  
Vol 77 (3) ◽  
pp. 162-176 ◽  
Author(s):  
Pablo Miranda ◽  
Pilar de la Peña ◽  
David Gómez-Varela ◽  
Francisco Barros
Keyword(s):  
Potassium Channels ◽  
Action Potentials ◽  
Anterior Pituitary ◽  
Pituitary Cells ◽  
Anterior Pituitary Cells

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

2002 ◽  
Vol 283 (3) ◽  
pp. H1031-H1041 ◽  
Author(s):  
Gui-Rong Li ◽  
Chu-Pak Lau ◽  
Anique Ducharme ◽  
Jean-Claude Tardif ◽  
Stanley Nattel
Keyword(s):  
Left Ventricle ◽  
Action Potential ◽  
Action Potentials ◽  
Slow Component ◽  
Ionic Current ◽  
Ionic Currents ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Early Afterdepolarizations

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I K1, I to1, and I Ks increases APD and favors occurrence of EADs.

Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

2006 ◽  
Vol 291 (2) ◽  
pp. H570-H580 ◽  
Author(s):  
Ling Xiao ◽  
Liming Zhang ◽  
Wei Han ◽  
Zhiguo Wang ◽  
Stanley Nattel
Keyword(s):  
Sex Differences ◽  
Action Potentials ◽  
Ionic Current ◽  
Ionic Currents ◽  
Left Ventricular ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Qt Intervals ◽  
Whole Cell Patch Clamp ◽  
Ventricular Cells

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 ± 21 vs. 237 ± 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K+ current ( IK1) were observed. Transient outward K+ current ( Ito) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller Ito (e.g., at +30 mV, female vs. male: 2.5 ± 0.2 vs. 3.5 ± 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K+ current ( IKr) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K+ current ( IKs) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 ± 0.1 vs. 0.8 ± 0.1 pA/pF; P < 0.001; endocardium: 1.2 ± 0.1 vs. 0.7 ± 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial IKs. Female dogs had larger L-type Ca2+ current ( ICa,L) densities in all layers than male dogs (e.g., at −20 mV, female vs. male, epicardium: −4.2 ± 0.4 vs. −3.2 ± 0.2 pA/pF; midmyocardium: −4.5 ± 0.5 vs. −3.3 ± 0.3 pA/pF; endocarium: −4.5 ± 0.4 vs. −3.2 ± 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.

L-364,373 (R-L3) enantiomers have opposite modulating effects on IKs in mammalian ventricular myocytes

2013 ◽  
Vol 91 (8) ◽  
pp. 586-592 ◽  
Author(s):  
Claudia Corici ◽  
Zsófia Kohajda ◽  
Attila Kristóf ◽  
András Horváth ◽  
László Virág ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Guinea Pig ◽  
Action Potential ◽  
Right Ventricular ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Ventricular Arrhythmias ◽  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Whole Cell Patch Clamp

Activators of the slow delayed rectifier K+ current (IKs) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate IKs in myocytes from several species; however, in some studies, it failed to activate IKs. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on IKs in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch-clamp techniques at 37 °C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R-L3. In rabbit myocytes, ZS_1270B enhanced the IKs tail current by approximately 30%, whereas ZS_1271B reduced IKs tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD90 (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on IKs, which may explain why the racemic drug R-L3 previously failed to activate IKs. ZS_1270B is a potent IKs activator, therefore, this substance is appropriate to test whether IKs activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.

scholarly journals Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

2021 ◽  
Author(s):  
Brenda Gerull ◽  
Andreas Brodehl
Keyword(s):  
Ventricular Arrhythmias ◽  
Disease Onset ◽  
Therapeutic Approaches ◽  
Arrhythmogenic Cardiomyopathy ◽  
Preclinical Research ◽  
Cellular Junctions ◽  
Genes Encoding ◽  
Life Threatening ◽  
Apparently Healthy

Abstract Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

Myogenic regulation of arterial diameter: role of potassium channels with a focus on delayed rectifier potassium current

2005 ◽  
Vol 83 (8-9) ◽  
pp. 755-765 ◽  
Author(s):  
William C Cole ◽  
Tim T Chen ◽  
Odile Clément-Chomienne
Keyword(s):  
Potassium Channels ◽  
Molecular Mechanisms ◽  
Intraluminal Pressure ◽  
Delayed Rectifier ◽  
Resistance Arteries ◽  
Arterial Diameter ◽  
Resistance Vessels ◽  
Delayed Rectifier Potassium Current ◽  
Myogenic Regulation

The phenomenon of myogenic constriction of arterial resistance vessels in response to increased intraluminal pressure has been known for over 100 years, yet our understanding of the molecular mechanisms involved remains incomplete. The focus of this paper concerns the potassium (K+) channels that provide a negative feedback control of the myogenic depolarization of vascular smooth muscle cells that is provoked by elevations in intraluminal pressure, and specifically, the contribution of delayed rectifier (KDR) channels. Our knowledge of the important role played by KDR channels, as well as their molecular identity and acute modulation via changes in gating, has increased dramatically in recent years. Several lines of evidence point to a crucial contribution by heteromultimeric KV1 subunit-containing KDR channels in the control of arterial diameter and myogenic reactivity, but other members of the KV superfamily are also expressed by vascular myocytes, and less is known concerning their specific functions. The effect of pharmacological modulation of KDR channels is discussed, with particular reference to the actions of anorexinogens on KV1- and KV2-containing KDR channels. Finally, the need for a greater understanding of the mechanisms that control KDR channel gene expression is stressed in light of evidence indicating that there is a reduced expression of KDR channels in diseases associated with abnormal myogenic reactivity and vascular remodelling.Key words: resistance arteries, myogenic response, potassium channels, delayed rectifier K+ current, KV channels, KV1, KV2.

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