Zacopride Exerts an Antiarrhythmic Effect by Specifically Stimulating the Cardiac Inward Rectifier Potassium Current in Rabbits: Exploration of a New Antiarrhythmic Strategy

2020 ◽  
Vol 26 (44) ◽  
pp. 5746-5754
Author(s):  
Yuanyuan Lin ◽  
Junhu Li ◽  
Baozhong Zhu ◽  
Qinghua Liu ◽  
Xiaojie Bai ◽  
...  
Keyword(s):  
Potassium Current ◽  
Inward Rectifier ◽  
Antiarrhythmic Effect ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Inward Rectifier Potassium Current ◽  
Antiarrhythmic Effects

Background: Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats. Objective: Our aims were to confirm that the antiarrhythmic effects of zacopride are mediated by selectively enhancing IK1 in rabbits. Methods: The effects of zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro. Results: Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 μmol/L zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by zacopride (0.1-10 μmol/L) in a concentration- dependent manner. Furthermore, zacopride at 1 μmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes. Conclusion: Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.

scholarly journals Ginsenoside Rb1 exerts antiarrhythmic effects by inhibiting INa and ICaL in rabbit ventricular myocytes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhipei Liu ◽  
Lv Song ◽  
Peipei Zhang ◽  
Zhenzhen Cao ◽  
Jie Hao ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Potassium Current ◽  
Ischemia Reperfusion ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Ginsenoside Rb1 ◽  
Patch Clamp Technique ◽  
High Calcium

AbstractGinsenoside Rb1 exerts its pharmacological action by regulating sodium, potassium and calcium ion channels in the membranes of nerve cells. These ion channels are also present in cardiomyocytes, but no studies have been reported to date regarding the effects of Rb1 on cardiac sodium currents (INa), L-type calcium currents (ICaL) and action potentials (APs). Additionally, the antiarrhythmic potential of Rb1 has not been assessed. In this study, we used a whole-cell patch clamp technique to assess the effect of Rb1 on these ion channels. The results showed that Rb1 inhibited INa and ICaL, reduced the action potential amplitude (APA) and maximum upstroke velocity (Vmax), and shortened the action potential duration (APD) in a concentration-dependent manner but had no effect on the inward rectifier potassium current (IK1), delayed rectifier potassium current (IK) or resting membrane potential (RMP). We also designed a pathological model at the cellular and organ level to verify the role of Rb1. The results showed that Rb1 abolished high calcium-induced delayed afterdepolarizations (DADs), depressed the increase in intracellular calcium ([Ca2+]i), relieved calcium overload and protected cardiomyocytes. Rb1 can also reduce the occurrence of ventricular premature beats (VPBs) and ventricular tachycardia (VT) in ischemia-reperfusion (I-R) injury.

Ionic Mechanisms Mediating the Differential Effects of Methohexital and Thiopental on Action Potential Duration in Guinea Pig and Rabbit Isolated Ventricular Myocytes 

1999 ◽  
Vol 90 (1) ◽  
pp. 156-164 ◽  
Author(s):  
Anatoly E. Martynyuk ◽  
Timothy E. Morey ◽  
Pekka M.J. Raatikainen ◽  
Christoph N. Seubert ◽  
Donn M. Dennis
Keyword(s):  
Guinea Pig ◽  
Potassium Current ◽  
Ventricular Myocytes ◽  
Inward Rectifier ◽  
Delayed Rectifier ◽  
Delayed Rectifier Potassium Current ◽  
Ionic Mechanisms ◽  
Inward Rectifier Potassium Current ◽  
Calcium Inward Current ◽  
Outward Potassium Current

Background Commonly used barbiturate anesthetics may significantly influence cardiac electrophysiologic characteristics. The authors evaluated thiopental (a thiobarbiturate) and methohexital (an oxybarbiturate), two compounds with similar physicochemical properties but different structures, to determine whether they have distinct effects on the major ionic currents that determine action potential duration (APD) in ventricular myocytes. Methods The effects of thiopental and methohexital (50 microM) on APD at 50% (APD50) and 90% (APD90) repolarization were studied in guinea pig and rabbit single ventricular myocytes using the patch-clamp technique in a whole-cell configuration. The ionic mechanisms underlying the APD changes were evaluated by measuring the anesthetics' effects on the L-type calcium inward current, the inward rectifier potassium current, and the delayed rectifier potassium current in guinea pig cells and on the transient outward potassium current in rabbit cells. Results Thiopental and methohexital caused opposite effects on APD. Whereas thiopental prolonged APD50 and APD90 in guinea pig and rabbit ventricular myocytes, methohexital shortened them. Thiopental markedly depressed both the inward and outward components of the inward rectifier potassium current, whereas methohexital caused minimal inhibition of the inward component and no change in the outward component. The delayed rectifier potassium current was inhibited by thiopental but significantly potentiated by methohexital. Neither thiopental nor methohexital significantly affected the transient outward potassium current or the L-type calcium inward current. Conclusions Despite their similar lipid solubilities, molecular weights, and pKa values, thiopental increased and methohexital decreased the APD in ventricular myocytes by predominantly inhibiting the inward rectifier potassium current and the delayed rectifier potassium current and by increasing the delayed rectifier potassium current, respectively. These characteristics suggest distinct structure-specific actions of barbiturates on the function of myocardial ionic channels.

Effects of relaxin on rat atrial myocytes. I. Inhibition of I(to) via PKA-dependent phosphorylation

1997 ◽  
Vol 272 (4) ◽  
pp. H1791-H1797 ◽  
Author(s):  
E. S. Piedras-Renteria ◽  
O. D. Sherwood ◽  
P. M. Best
Keyword(s):  
Potassium Current ◽  
Peptide Hormone ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Electrophysiological Properties ◽  
Whole Cell Patch Clamp ◽  
Rat Hearts ◽  
Voltage Dependent

The peptide hormone relaxin has direct, positive inotropic and chronotropic effects on rat hearts in vivo and in vitro. Relaxin's effects on the electrophysiological properties of single quiescent atrial cells from normal rats were investigated with a whole cell patch clamp. Relaxin had a significant inhibitory effect on outward potassium currents. The outward potassium current consisted of a transient component (I(to)) and a sustained component (I(S)). The addition of 100 ng/ml of relaxin inhibited the peak I(to) in a voltage-dependent manner (74% inhibition at a membrane potential of -10 mV to 30% inhibition at +70 mV). The time to reach peak I(to) and the apparent time constant of inactivation of I(to) were increased by relaxin. Dialysis with the protein kinase A inhibitor 5-24 amide (2 microM) prevented relaxin's effects, suggesting an obligatory role for this kinase in the relaxin-dependent regulation of the potassium current.

Characterization of a delayed rectifier potassium current in chicken growth plate chondrocytes

1992 ◽  
Vol 262 (5) ◽  
pp. C1335-C1340 ◽  
Author(s):  
K. B. Walsh ◽  
S. D. Cannon ◽  
R. E. Wuthier
Keyword(s):  
Growth Plate ◽  
Potassium Current ◽  
Reversal Potential ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Growth Plate Chondrocytes ◽  
Patch Clamp Technique ◽  
Delayed Rectifier Potassium Current ◽  
Current Activation ◽  
External K

With the use of the whole cell arrangement of the patch-clamp technique, an outward-directed time-dependent potassium current was identified in cultured chicken growth plate chondrocytes. This delayed rectifier potassium current (IK) activated with a sigmoidal time course during voltage steps to potentials positive to -40 mV. The half-maximal voltage required for current activation was determined to be -8 mV. The reversal potential (Erev) for IK, measured using deactivating tail currents, was -72 mV in the presence of 140 mM internal and 5 mM external [K+] solutions. Changes in external [K+] caused Erev to shift in a manner expected for a potassium-selective channel. In addition, increasing external [K+] from 5 to 50 mM caused the slope conductance of the tail currents to increase twofold. The chondrocyte IK was inhibited by the potassium-channel blocker 4-aminopyridine (4-AP) at concentrations of 0.5-4 mM and by the scorpion venom toxin charybdotoxin (CTX; 10 nM) but was unaffected by 10 mM tetraethylammonium (TEA). Addition of 20 microM ZnCl2 reduced IK in a voltage-dependent manner with the greatest inhibition found to occur at potentials near the threshold for current activation. Reduction of IK by ZnCl2 was accompanied by a slowing in the kinetics of IK activation. On the basis of the gating and pharmacological properties of this current, it is suggested that the chondrocyte channel belongs to a superfamily of K+ channels found in bone and immune system cells. The chondrocyte K+ channel may contribute to the unusually high [K+] found in the extracellular fluid of growth plate cartilage.

Dendritic excitability and a voltage-gated calcium current in locust nonspiking local interneurons

1993 ◽  
Vol 69 (5) ◽  
pp. 1484-1498 ◽  
Author(s):  
G. Laurent ◽  
K. J. Seymour-Laurent ◽  
K. Johnson
Keyword(s):  
Patch Clamp ◽  
Resting Potential ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Inward Current ◽  
Time To Peak ◽  
Clamp Technique ◽  
Voltage Dependent

1. The active properties of axonless nonspiking interneurons in the thoracic nervous system of the locust Schistocerca americana were studied in vivo with the switched current-clamp technique from dendritic impalements, and in vitro with the whole-cell variation of the patch-clamp technique. 2. In 20% of in vivo recordings, depolarization of a dendrite to potentials more positive than about -40 mV evoked resonant behaviour and/or regenerative potentials. The latter were slow (half width: 20-30 ms), small (base-to-peak amplitude: 25-35 mV), and were often followed by a pronounced after hyperpolarization (AHP). 3. The slow regenerative potentials sometimes had multiple peaks separated by incomplete repolarizations. The voltage envelope of such potentials was always broader than that of spikes with single peaks. In other recordings, a same depolarizing pulse could evoke several regenerative potentials with different waveforms. These results suggested the presence of multiple dendritic initiation sites separated by regions of inexcitable membrane, allowing decremental conduction and the passive fusion of spike envelopes. 4. Graded active responses could also be evoked on rebound from short hyperpolarizations such as inhibitory postsynaptic potentials (IPSPs) provided that the membrane was already depolarized to about -40 mV. IPSPs evoked by several presynaptic interneurons differed in their ability to evoke rebound potentials suggesting that some synaptic sites were electrically closer than others to regions of active membrane. 5. Patch-clamp recordings from somata of nonspiking neurons isolated from 75% embryos and grown in culture medium for 1-2 days revealed the presence of an inactivating inward current resistant to 0.5-1 microM tetrodotoxin (TTX). The inward current was carried equally well by Ba2+, and sensitive to blockade by Cd2+ (0.5 mM), Ni2+ (0.75 mM), or Co2+ (2.5 mM). 6. The current activated around -40 mV, with voltage-dependent activation (time-to-peak approximately 20 ms at -35 mV and 1-2 ms at 0 mV). Tail currents evoked upon repolarization were well fitted by a single exponential (tau = 1-2 ms). Deactivation time constants shorter than 300 microseconds, however, could not be measured. 7. The current inactivated rapidly in a voltage-dependent manner, following two-exponential kinetics. A very small persistent component could be explained by the overlap between activation and inactivation curves, greatest at approximately -20 mV. The voltage of half-inactivation was about -25 mV. At a resting potential of -58 mV, 90% of the current was available for activation. Recovery from steady-state inactivation followed the sum of two or more exponential processes.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Aminophylline affects the cardiac rat inward rectifier potassium current in a dual way

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
NJD Ramalho ◽  
O Svecova ◽  
R Kula ◽  
M Simurdova ◽  
J Simurda ◽  
...  
Keyword(s):  
Steady State ◽  
Potassium Current ◽  
Ventricular Myocytes ◽  
Inward Rectifier ◽  
Public Institution ◽  
Patch Clamp Technique ◽  
Rat Ventricular Myocytes ◽  
Funding Sources ◽  
Inward Rectifier Potassium Current ◽  
Isolated Rat

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education, Youth and Sports of the Czech Republic Introduction Aminophylline, a bronchodilator used in clinical practice to treat namely severe astma attacks, often induces atrial fibrillation in patients. Modifications of the inward rectifier potassium current IK1 are known to play a role in the genesis of fibrillation. Purpose We aimed to investigate the effect of aminophylline at clinically-relevant concentrations between 3 and 100 µM on IK1 in isolated rat ventricular myocytes. Methods Experiments were performed by the whole cell patch clamp technique on enzymatically isolated rat right ventricular myocytes at room temperature. IK1 was measured as the current sensitive to 100 µM Ba2+. Results We observed a dual steady-state effect of aminophylline at most of the applied concentrations. Either inhibition or activation was apparent in individual cells during application of aminophylline at a given concentration. The smaller was magnitude of the control IK1, the more likely was activation of the current in the presence of aminophylline and vice versa (tested at 10 and 30 µM). The effect was voltage-independent and fully reversible during the subsequent wash-out. The mean aminophylline effect was inhibitory at all concentrations (10, 15, 4, and 23%-inhibition at -50 mV at 3, 10, 30, and 100 µM, respectively). Using a modified version of the population model of IK1 channels that we published before, the dual effect can be explained by interaction of aminophylline with two channel populations in a different way, the first one being inhibited and the second one being activated by the drug. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells can be simulated. Conclusions Aminophylline at clinically-relevant concentrations affects IK1 in rat ventricular myocytes in a dual way, showing both the steady-state activation and inhibition in various cells, even at the same concentration. It may be related to a different effect of the drug on various Kir2.x subunits forming the heterotetrameric IK1 channels present at the cell membrane of a single cell.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

scholarly journals Exploration of in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic potentials with phytochemical screening of flowers of Brassica nigra

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Mohammad Sarowar Uddin ◽  
Md. Shalahuddin Millat ◽  
Mohammad Safiqul Islam ◽  
Md. Saddam Hussain ◽  
Md. Giash Uddin ◽  
...  
Keyword(s):  
Brassica Nigra ◽  
Anxiolytic Activity ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Standard Drug ◽  
Lead Compounds ◽  
Lysis Activity ◽  
Test Models

Abstract Background Brassica nigra is a plant of Brassicaceae family, which possesses numerous medicinal values. Our present study is intended to assess the potential in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic properties of MCE of B. nigra flowers. MCE was fractioned for separating the compound on the basis of polarity by using chloroform, n-hexane and ethyl acetate solvent. Thrombolytic and anthelminthic activities were explained by collecting human erythrocytes and earthworms as test models, respectively. Anxiolytic activity was evaluated by elevated plus maze and hole board models while cytotoxic test was conducted through brine shrimp lethality bioassay. Results MCE revealed the presence of alkaloids, flavonoids, tannin, diterpenes, glycosides, carbohydrates, phenols, fixed oils and fat. In case of thrombolytic test, the MCE, CSF, ASF and n-HSF had produced maximum clot lysis activity at 5 and 10 mg/ml dose conditions. Two different concentrations (10 and 20 mg/ml) of MCE and its fractions showed significant (p < 0.05) anthelminthic activities in a dose-dependent manner. Significant anxiolytic activity was observed for all fractions which was comparable to the standard drug diazepam (p < 0.05). Again, the cytotoxic screening also presented good potentials for all fractions. Conclusion From the findings of present study, we can conclude that MCE of B. nigra flowers and its fraction possess significant anxiolytic, anthelmintic, anticancer and thrombolytic properties which may be a good candidate for treating these diseases through the determination of bio-active lead compounds.

scholarly journals Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuxing Shen ◽  
Chao Wu ◽  
Meng Lei ◽  
Qing Yan ◽  
Haoyang Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Serum Enzyme ◽  
Herg Channels ◽  
Anti Tumor Activity ◽  
Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

scholarly journals Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Zhang ◽  
Guoyu Yin ◽  
Heping Zhao ◽  
Hanzhi Ling ◽  
Zhen Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Intracellular Degradation ◽  
Main Pathway ◽  
First Time

AbstractIn inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

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