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 The electrophysiological effect of cannabidiol on hERG current and in guinea-pig and rabbit cardiac preparations

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Péter Orvos ◽  
Bence Pászti ◽  
Leila Topal ◽  
Péter Gazdag ◽  
János Prorok ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Guinea Pig ◽  
Oral Intake ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
High Concentration ◽  
Electrophysiological Properties ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Herg Current

Abstract Cannabis use is associated with cardiovascular adverse effects ranging from arrhythmias to sudden cardiac death. The exact mechanism of action behind these activities is unknown. The aim of our work was to study the effect of cannabidiol (CBD), tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol on cellular cardiac electrophysiological properties including ECG parameters, action potentials, hERG and IKr ion channels in HEK cell line and in rabbit and guinea pig cardiac preparations. CBD increased action potential duration in rabbit and guinea pig right ventricular papillary muscle at lower concentrations (1 µM, 2.5 µM and 5 µM) but did not significantly change it at 10 µM. CBD at high concentration (10 µM) decreased inward late sodium and L-type calcium currents as well. CBD inhibited hERG potassium channels with an IC50 value of 2.07 µM at room temperature and delayed rectifier potassium current with 6.5 µM at 37 °C, respectively. The frequency corrected QT interval (QTc) was significantly lengthened in anaesthetized guinea pig without significantly changing other ECG parameters. Although the IC50 value of CBD was higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that hERG and potassium channel inhibition might have a role in the possible proarrhythmic adverse effects of cannabinoids in situations where metabolism of CBD impaired and/or the repolarization reserve is weakened.

scholarly journals Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

2008 ◽  
Vol 295 (6) ◽  
pp. H2264-H2272 ◽  
Author(s):  
Katja E. Odening ◽  
Omar Hyder ◽  
Leonard Chaves ◽  
Lorraine Schofield ◽  
Michael Brunner ◽  
...  
Keyword(s):  
Heart Rate ◽  
Polymorphic Ventricular Tachycardia ◽  
In Vivo Model ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Drug Induced ◽  
Littermate Control ◽  
Anesthetic Agents ◽  
Anesthetic Drugs ◽  
Repolarization Reserve

Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents ( IKs) or rapidly activating K+ currents ( IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current ( IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

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.

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.

Potassium Currents in Precursor Cells Isolated From the Anterior Subventricular Zone of the Neonatal Rat Forebrain

1999 ◽  
Vol 81 (1) ◽  
pp. 95-102 ◽  
Author(s):  
R. R. Stewart ◽  
T. Zigova ◽  
M. B. Luskin
Keyword(s):  
Subventricular Zone ◽  
Action Potentials ◽  
Potassium Current ◽  
Potassium Currents ◽  
Precursor Cells ◽  
Neonatal Rat ◽  
Delayed Rectifier ◽  
Activation Time ◽  
Rat Forebrain ◽  
Anterior Subventricular Zone

Stewart, R. R., T. Zigova, and M. B. Luskin. Potassium currents in precursor cells isolated from the anterior subventricular zone of the neonatal rat forebrain. J. Neurophysiol. 81: 95–102, 1999. The progenitor cells from the anterior part of the neonatal subventricular zone, the SVZa, are unusual in that, although they undergo division, they have a neuronal phenotype. To characterize the electrophysiological properties of the SVZa precursor cells, recordings were made of potassium and sodium currents from SVZa cells that were removed from postnatal day 0–1 rats and cultured for 1 day. The properties of the delayed rectifier and A-type potassium currents were described by classical Hodgkin and Huxley analyses of activation and inactivation. In addition, cells were assessed under current clamp for their ability to generate action potentials. The A-type potassium current ( I K(A)) was completely inactivated at a holding potential of −50 mV. The remaining potassium current resembled the delayed rectifier current ( I K(DR)) in that it was blocked by tetraethylammonium (TEA; IC50 4.1 mM) and activated and inactivated slowly compared with I K(A). The conductance-voltage ( G- V) curve revealed that G increased continuously from 0.2 nS at −40 mV to a peak of 2.6 nS at +10 or +20 mV, and then decreased for voltages above +30 mV. Activation time constants were largest at −40 mV (∼11 ms) and smallest at 100 mV (∼1.5 ms). The properties of I K(A) were studied in the presence of 20 mM TEA, to block I K(DR), and from a holding potential of −15 mV, to inactivate both I K(DR) and I K(A). I K(A) was then allowed to recover from inactivation to negative potentials during 200- to 800-ms pulses. Recovery from inactivation was fastest at −130 mV (∼21 ms) and slowest at −90 mV (∼135 ms). Inactivation was voltage independent from −60 to +60 mV with a time constant of ∼15 ms. At steady state, I K(A) was half inactivated at −90 mV. G K(A) increased from 0.2 nS at −60 mV to a peak of 2.4 nS at +40 mV. Finally, the activation time constants ranged from ∼1.9 ms at −50 mV to 0.7 ms at +60 mV. The properties of I K(A) resembled those of I K(A) found in differentiating cerebellar granule neurons. Most SVZa cells had sodium currents (28/32 cells). However, in current clamp 11 of 12 cells were incapable of generating action potentials from voltages of −30 to −100 mV, suggesting that the available current densities were too low to support excitability.

Combined inhibition of key potassium currents has different effects on cardiac repolarization reserve and arrhythmia susceptibility in dogs and rabbits

2015 ◽  
Vol 93 (7) ◽  
pp. 535-544 ◽  
Author(s):  
Zoltán Husti ◽  
Katalin Tábori ◽  
Viktor Juhász ◽  
Tibor Hornyik ◽  
András Varró ◽  
...  
Keyword(s):  
Qt Interval ◽  
Potassium Currents ◽  
Torsades De Pointes ◽  
Cardiac Repolarization ◽  
Development Phase ◽  
Short Term ◽  
Drug Induced ◽  
Reliable Assessment ◽  
Repolarization Reserve ◽  
High Incidence

A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STVQT) following combined pharmacological inhibition of IK1+IKs and IK1+IKr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of IK1+IKs in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of IK1+IKr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STVQT in both models. The relatively different roles of IK1 and IKs in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger IK1 and IKs), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects.

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