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 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.

Patch-clamp recording in myenteric neurons of guinea pig small intestine

1992 ◽  
Vol 262 (6) ◽  
pp. G1074-G1078 ◽  
Author(s):  
L. V. Baidan ◽  
A. V. Zholos ◽  
M. F. Shuba ◽  
J. D. Wood
Keyword(s):  
Small Intestine ◽  
Patch Clamp ◽  
Guinea Pig ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Myenteric Neurons ◽  
Delayed Rectifier Current ◽  
Outward Currents ◽  
Current Clamp Mode

The results of our research established the feasibility of applying patch-clamp methods in the study of the cellular neurophysiology of myenteric neurons enzymatically dissociated from adult guinea pig small intestine. Recording in current-clamp mode revealed two populations of neurons. One population discharged repetitively during depolarizing current pulses and displayed anodal-break excitation reminiscent of S/type 1 myenteric neurons. In the second population, spike discharge was limited to one or two spikes at the onset of depolarizing pulses and was similar to the behavior of AH/type 2 neurons. Recording in voltage-clamp mode revealed a complex of overlapping inward and outward whole cell currents. Fast and slow components of inward current were interpreted as sodium and calcium currents, respectively. Outward currents were blocked by cesium and consisted of components with properties of delayed rectifier current and A-type potassium current.

P703The small conductance Ca2+-activated K+-channel inhibition tool compound AP14145 protected the guinea pig heart from ventricular arrhythmia during hypokalemia whereas dofetilide was pro-arrhythmic

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B H Bentzen ◽  
L Abildgaard ◽  
N G Edvardsson ◽  
U S Soerensen ◽  
M Grunnet ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Ventricular Arrhythmia ◽  
Qt Interval ◽  
Tolerability Profile ◽  
Sk Channels ◽  
Sk Channel ◽  
Channel Inhibition ◽  
Increased Risk ◽  
Repolarization Reserve ◽  
Small Conductance

Abstract Background Hypokalemia is commonly encountered in the clinic. Hypokalemia reduces the cardiac repolarization reserve and causes increases in intracellular calcium. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that can be further exacerbated by concomitant administration of classical class 3 anti-arrhythmic agents. Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). Under physiological conditions SK channels play an insignificant role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in intracellur calcium. Purpose To study the effects of SK channel inhibition with the tool compound AP14145 or ICA under hypokalemic conditions as compared to the class 3 anti-arrhythmic agent dofetilide and time matched controls (TMC). Methods Guinea pig hearts were isolated and retrogradely perfused with normokalemic (4.5 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug for 20 min, followed by 20 min perfusion with normokalemic solution in presence of drug. A total of 24 animals were included in the study and randomly assigned to 4 groups: ICA, AP14145, dofetilide or TMC. QT-interval, ventricular effective refractory period, extra systoles and incidence of ventricular tachycardia (VT) or fibrillation (VF) were recorded for each perfusion period. Results Hypokalemia caused a small increase in QT-interval. Application of SK channel inhibitors did not cause further changes, whereas dofetilide prolonged QT compared to hypokalemia alone. During hypokalemia 3 out of 6 hearts in the TMC group developed VF (one spontaneously, two following S1S2 stimulation) whereas 4 out of 6 hearts developed VF in the dofetilide group (one spontaneously, three following S1S2 stimulation). In comparison only 1 heart out of 6 developed VF when treated with the SK channel inhibitor ICA (spontaneously) or AP14145 (following S1S2 stimulation). Conclusion Hypokalemia was associated with an increased risk of VF, an effect that was exaggerated by co-administration of dofetilide. In comparison, the structurally and functionally different SK channel inhibitors, ICA and AP14145, protected the heart from hypokalemia induced VF. These results with the tool compound AP14145 support that SK inhibition may be associated with a better safety and tolerability profile than dofetilide. Acknowledgement/Funding Innovation Fund Denmark

Temperature dependence of electrophysiological properties of guinea pig and ground squirrel myocytes

1992 ◽  
Vol 263 (1) ◽  
pp. R177-R184 ◽  
Author(s):  
J. C. Herve ◽  
K. Yamaoka ◽  
V. W. Twist ◽  
T. Powell ◽  
J. C. Ellory ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Guinea Pig ◽  
Action Potential ◽  
Ground Squirrel ◽  
Calcium Release ◽  
Maximum Amplitude ◽  
Calcium Currents ◽  
Resting Membrane Potential ◽  
Electrophysiological Properties ◽  
Time To Peak

The effects of changing temperature on the electrophysiology of isolated cardiac myocytes of the guinea pig and Richardson's ground squirrel were studied by patch-clamp techniques. In cells from both species, the resting membrane potential declined on cooling from 36 to 12 degrees C by approximately 6 mV. The duration of the plateau of the action potential in guinea pig cells increased monotonically on cooling. In contrast, the action potential of ground squirrel cells showed a biphasic response, increasing in duration from 36 to 24 degrees C and then decreasing on cooling from 24 to 12 degrees C. From voltage-clamp studies, the properties of L-type calcium currents (ICa) on cooling were compared in the two species and were found to be similar: In both cases, ICa decreased in amplitude from approximately 2 nA peak current at 36 degrees C to less than 400 pA at 12 degrees C. The Q10 of both the maximum amplitude and time to peak for ICa in both species was approximately 1.8. The time for half inactivation had a greater Q10 of 2.5-3. It is concluded that, surprisingly, factors affecting the resting membrane potential and properties of L-type calcium channels are not major contributors to cardiac dysfunction on cooling. Rather, it is sarcoplasmic reticulum calcium release and reuptake that are likely to be the most important cold-sensitive processes.

scholarly journals Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

2021 ◽  
Vol 14 (8) ◽  
pp. 748
Author(s):  
Péter P. Nánási ◽  
Balázs Horváth ◽  
Fábián Tar ◽  
János Almássy ◽  
Norbert Szentandrássy ◽  
...  
Keyword(s):  
Action Potential ◽  
Time Course ◽  
Laboratory Animals ◽  
Delayed Rectifier ◽  
Ion Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Repolarization Reserve ◽  
Electrophysiological Studies ◽  
K Current

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

Kv3.1–Kv3.2 Channels Underlie a High-Voltage–Activating Component of the Delayed Rectifier K+ Current in Projecting Neurons From the Globus Pallidus

1999 ◽  
Vol 82 (3) ◽  
pp. 1512-1528 ◽  
Author(s):  
R. Hernández-Pineda ◽  
A. Chow ◽  
Y. Amarillo ◽  
H. Moreno ◽  
M. Saganich ◽  
...  
Keyword(s):  
Heterologous Expression ◽  
Globus Pallidus ◽  
High Frequency ◽  
Calcium Binding ◽  
Repetitive Firing ◽  
Delayed Rectifier ◽  
Expression Systems ◽  
Electrophysiological Properties ◽  
Channel Proteins ◽  
Heterologous Expression Systems

The globus pallidus plays central roles in the basal ganglia circuitry involved in movement control as well as in cognitive and emotional functions. There is therefore great interest in the anatomic and electrophysiological characterization of this nucleus. Most pallidal neurons are GABAergic projecting cells, a large fraction of which express the calcium binding protein parvalbumin (PV). Here we show that PV-containing pallidal neurons coexpress Kv3.1 and Kv3.2 K+ channel proteins and that both Kv3.1 and Kv3.2 antibodies coprecipitate both channel proteins from pallidal membrane extracts solubilized with nondenaturing detergents, suggesting that the two channel subunits are forming heteromeric channels. Kv3.1 and Kv3.2 channels have several unusual electrophysiological properties when expressed in heterologous expression systems and are thought to play special roles in neuronal excitability including facilitating sustained high-frequency firing in fast-spiking neurons such as interneurons in the cortex and the hippocampus. Electrophysiological analysis of freshly dissociated pallidal neurons demonstrates that these cells have a current that is nearly identical to the currents expressed by Kv3.1 and Kv3.2 proteins in heterologous expression systems, including activation at very depolarized membrane potentials (more positive than −10 mV) and very fast deactivation rates. These results suggest that the electrophysiological properties of native channels containing Kv3.1 and Kv3.2 proteins in pallidal neurons are not significantly affected by factors such as associated subunits or postranslational modifications that result in channels having different properties in heterologous expression systems and native neurons. Most neurons in the globus pallidus have been reported to fire sustained trains of action potentials at high-frequency. Kv3.1–Kv3.2 voltage-gated K+channels may play a role in helping maintain sustained high-frequency repetitive firing as they probably do in other neurons.

scholarly journals STUDIES ON MICROPEROXISOMES II. A CYTOCHEMICAL METHOD FOR LIGHT AND ELECTRON MICROSCOPY

1972 ◽  
Vol 20 (12) ◽  
pp. 1006-1023 ◽  
Author(s):  
ALEX B. NOVIKOFF ◽  
PHYLLIS M. NOVIKOFF ◽  
CLEVELAND DAVIS ◽  
NELSON QUINTANA
Keyword(s):  
Endoplasmic Reticulum ◽  
Guinea Pig ◽  
Lipid Droplets ◽  
Smooth Endoplasmic Reticulum ◽  
Light And Electron Microscopy ◽  
Distal Tubule ◽  
Striking Difference ◽  
High Concentration ◽  
Electron Microscopic ◽  
Pig Kidney

A modification of the Novikoff-Goldfischer alkaline 3,3'-diaminobenzidine medium for visualizing peroxisomes is described. It makes possible light microscopic as well as electron microscopic studies of a recently described class of peroxisomes, the microperoxisomes. Potassium cyanide (5 x 10–3 M) is included in the medium to inhibit mitochondrial staining, the pH is 9.7 and there is a high concentration of H2O2 (0.05%). Two cell types have been chosen to illustrate the advantages of the new procedure for demonstrating the microperoxisomes: the absorptive cells in the human jejunum and the distal tubule cells in the guinea pig kidney. Suggestive relations of microperoxisomes and lipid are described in the human jejunum. The microperoxisomes are strategically located between smooth endoplasmic reticulum that radiates toward the organelles and contains lipid droplets and "central domains" of highly specialized endoplasmic reticulum which do not show the lipid droplets. The microperoxisomes are also present at the periphery of large lipid-like drops. In the guinea pig kidney tubule there is a striking difference between the thick limb of Henle and distal tubule. The distal tubule has a population of cells with large numbers of microperoxisomes readily visible by light microscopy; these cells are not present in the thick limb of Henle. Other differences between the two are also described.

scholarly journals Histamine H1 -receptor-mediated modulation of the delayed rectifier K+ current in guinea-pig atrial cells: opposite effects on IKs and IKr

1999 ◽  
Vol 128 (7) ◽  
pp. 1545-1553 ◽  
Author(s):  
Yasunori Matsumoto ◽  
Takehiko Ogura ◽  
Hiroko Uemura ◽  
Toshihiro Saito ◽  
Yoshiaki Masuda ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Delayed Rectifier ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
Atrial Cells ◽  
K Current

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

2011 ◽  
Vol 300 (5) ◽  
pp. H1806-H1813 ◽  
Author(s):  
Alberto Corrias ◽  
Wayne Giles ◽  
Blanca Rodriguez
Keyword(s):  
Purkinje Cells ◽  
Mechanisms Of Action ◽  
Delayed Rectifier ◽  
Pharmacological Interventions ◽  
Drug Induced ◽  
Current Increase ◽  
Detailed Model ◽  
Purkinje Fibers ◽  
Electrophysiological Properties ◽  
Repolarization Abnormalities

Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K+ current and rapid delayed rectifier K+ current block as well as late Na+ current increase result in significant AP changes. However, enhanced L-type Ca2+ current ( iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics.

Sign in / Sign up

Export Citation Format

Share Document