Abstract 17344: Increasing Calcium-activated Potassium Current Shortens and Stabilizes Repolarization in Chronic Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ingrid M Bonilla ◽  
Victor Long ◽  
Kent Mowrey ◽  
Karsten Schober ◽  
Raul Weiss ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Canine Model ◽  
Ventricular Repolarization ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Before And After ◽  
Normal Controls

Heart failure (HF) is a chronic disease resulting in abnormal prolongation and instability of ventricular repolarization. IKCa has been suggested to stabilize repolarization in HF as IKca blockade has shown pro-arrhythmic effects in the failing ventricle. We tested the hypothesis that an SK channel (IKCa) agonist CyPPA, would shorten and stabilize ventricular repolarization in HF ventricular myocytes. Methods: A tachypacing - induced 4 month HF canine model was used (LVFS: 15.9 ± 2.5%), and LV midwall myocytes were isolated and compared to normal controls. Action potential duration at 50 (APD50), and 90% (APD90) repolarization and APD instability (beat to beat variability of repolarization, a measure of arrhythmia risk) were measured before and after the application of CyPPA (0.001nM-20uM) in control ventricular, and in 4 months HF ventricular myocytes (n=10-15 per group). Results: In control myocytes, CyPPA shortened action potential APD50 and APD90 in a concentration dependent manner (0.001nM-20uM, p<0.05 vs baseline at 20uM, Figure). In HF myocytes, CyPPA also shortened APD50 and APD90, but at lower concentrations than in controls. Notably, In addition to APD shortening, CyPPA significantly decreased repolarization instability (P<0.05 vs baseline at 1 Hz) in HF. CyPPA did not affect resting membrane potential in either group. Conclusions: HF myocytes are more sensitive to IKCa agonism than control myocytes. An IKCa agonist attenuates electrophysiologic remodeling and stabilizes repolarization in failing ventricular myocytes, suggesting a therapeutic role for this approach in HF.

Effects of extracellular ATP on ICa, [Ca2+]i, and contraction in isolated ferret ventricular myocytes

1993 ◽  
Vol 264 (3) ◽  
pp. C702-C708 ◽  
Author(s):  
Y. Qu ◽  
H. M. Himmel ◽  
D. L. Campbell ◽  
H. C. Strauss
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Ventricular Myocardium ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
The Right

The effects of extracellular ATP on the voltage-activated "L-type" Ca current (ICa), action potential, resting and transient intracellular Ca2+ levels, and cell contraction were examined in enzymatically isolated myocytes from the right ventricles of ferrets. With the use of the whole cell patch-clamp technique, extracellular ATP (10(-7) to 10(-3) M) inhibited ICa in a time- and concentration-dependent manner. ATP decreased the peak amplitude of ICa without altering the residual current at the end of 500-ms clamp steps. The concentration-response relationship for ATP inhibition of ICa was well described by a conventional Michaelis-Menten relationship with a half-maximal inhibitory concentration of 1 microM and a maximal effect of 50%. Consistent with its inhibitory effect on ICa, ATP hyperpolarized the plateau phase and shortened the action potential duration. In fura-2-loaded myocytes, extracellular ATP did not change the resting myoplasmic Ca2+ levels; however, when current was elicited under voltage-clamp conditions, ATP both decreased the myoplasmic intracellular Ca2+ transient and inhibited the degree of cell shortening. Our results suggest that ATP could be a genuine and potent extracellular modulator of cardiac function in ferret ventricular myocardium.

Electrophysiological safety of sibutramine HCl

2008 ◽  
Vol 27 (7) ◽  
pp. 553-558 ◽  
Author(s):  
KS Kim ◽  
SJ Park ◽  
HA Lee ◽  
DK Kim ◽  
EJ Kim
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Papillary Muscle ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cardiovascular Side Effects ◽  
Blocking Effects ◽  
Inward Currents ◽  
Sibutramine Hcl

Sibutramine is known to induce cardiovascular side effects such as tachycardia, vasodilation, and hypertension. The present study was aimed to examine the effects of sibutramine on action potential of guinea pig papillary muscle, recombinant hERG currents (IhERG), and inward currents (INa and ICa) of rat ventricular myocytes. Sibutramine at 30 μg/mL induced a shortening of action potential duration (APD) of guinea pig papillary muscle; on average, APD30 and APD90 were shortened by 23% and 17% at a stimulation rate of 1 Hz, respectively. Sibutramine suppressed the following currents: IhERG (IC50:2.408 ± 0.5117 μg/mL), L-type Ca current (IC50:2.709 ± 0.4701 μg/mL), and Na current (IC50:7.718 ± 1.7368 μg/mL). Sibutramine blocked IhERG, ICa, and INa in a concentration-dependent manner. In conclusion, sibutramine exerted a shortening effect on APD in guinea pig papillary muscle through its more powerful blocking effects on ICa and INa rather than IhERG.

Blockade of Myocardial ATP-sensitive Potassium Channels by Ketamine 

1997 ◽  
Vol 87 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Seong-Hoon Ko ◽  
Sang-Kyi Lee ◽  
Young-Jin Han ◽  
Huhn Choe ◽  
Yong-Geun Kwak ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Katp Channel ◽  
Ventricular Myocytes ◽  
Katp Channels ◽  
Dependent Manner ◽  
Channel Activity ◽  
Concentration Dependent Manner ◽  
Channel Currents ◽  
Inside Out

Background The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Methods Inside-out and cell-attached configurations of patch-clamp techniques and 3 M potassium chloride-filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Results Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration-dependent manner. In the inside-out patches, the concentration of ketamine for half-maximal inhibition and the Hill coefficient were 62.9 microM and 0.54, respectively. In a concentration-dependent manner, ketamine inhibited pinacidil- and 2,4-dinitrophenol-activated KATP channels in cell-attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single-channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration-dependent manner. Conclusions Ketamine inhibited KATP channel activity in a concentration-dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.

GTP-gamma-S increases the duration of backward swimming behavior and the calcium action potential in marine Paramecium

1991 ◽  
Vol 155 (1) ◽  
pp. 505-518
Author(s):  
J. Bernal ◽  
A. M. Kelsey ◽  
B. E. Ehrlich
Keyword(s):  
Action Potential ◽  
G Proteins ◽  
Swimming Behavior ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Before And After ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Gamma S ◽  
Calcium Action Potential

Behavioral and electrophysiological experiments were made to examine the hypothesis that G-proteins modulate the voltage-dependent calcium channel in the marine ciliate Paramecium calkinsi. It was found that guanosine-5′-O-(3-thiotriphosphate) (GTP-gamma-S), an analogue of GTP that binds to and activates G-proteins, increased the duration of backward swimming behavior in reversibly permeabilized Paramecium in an irreversible and concentration-dependent manner. At 1 mumol l-1 GTP-gamma-S, the duration of backward swimming behavior was increased fivefold. Other nucleotides and related compounds did not have a significant effect on the backward swimming behavior. To evaluate whether the behavioral effects were due to ion channel modulation, the calcium action potential in intact Paramecium was monitored before and after guanine nucleotide injection. Within 5 min after the injection of GTP-gamma-S or GTP into the cell, the duration of the calcium action potential was prolonged at least threefold. Like the behavioral response, the GTP-gamma-S effect on the calcium action potential duration was irreversible, whereas the effect of GTP began to decay after 6 min. GDP-beta-S, which binds to and inactivates G-proteins, markedly reduced the calcium action potential within 5 min after injection. These results support the hypothesis that the voltage-dependent calcium channels present in Paramecium are modulated by GTP-binding proteins.

Utility of the JT Peak Interval and the JT Area in Determining the Proarrhythmic Potential of QT-Shortening Agents

2018 ◽  
Vol 24 (2) ◽  
pp. 160-171 ◽  
Author(s):  
Bo Qiu ◽  
Yuhong Wang ◽  
Congxin Li ◽  
Huicai Guo ◽  
Yanfang Xu
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Potassium Channel ◽  
Early Phase ◽  
Characteristic Curve ◽  
Ventricular Tachyarrhythmia ◽  
Ventricular Repolarization ◽  
Dependent Manner ◽  
Potassium Channel Openers ◽  
Concentration Dependent Manner

Drug-induced long QT increases the risk of ventricular tachyarrhythmia known as torsades de pointes (TdP). Many biomarkers have been used to predict TdP. At present, however, there are few biomarkers for arrhythmias induced by QT-shortening drugs. The objective of the present study was to identify the best biomarkers for predicting arrhythmias caused by the 4 potassium channel openers ICA-105574, NS-1643, R-L3, and pinacidil. Our results showed that, at higher concentrations, all 4 potassium channel openers induced ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff-perfused guinea pig hearts, but not in rabbit hearts. The electrocardiography parameters were measured including QT/QTc, JT peak, Tp-e interval, JT area, short-term beat-to-beat QT interval variability (STV), and index of cardiac electrophysiological balance (iCEB). We found that the potassium channel openers at test concentrations shortened the QT/QTc and the JT peak interval and increased the JT area. Nevertheless, even at proarrhythmic concentrations, they did not always change STV, Tp-e, or iCEB. Receiver operating characteristic curve analysis showed that the JT peak interval representing the early repolarization phase and the JT area reflecting the dispersion of ventricular repolarization were the best predictors of VT/VF. Action potential recordings in guinea pig papillary muscle revealed that except for pinacidil, the potassium channel openers shortened APD30 in a concentration-dependent manner. They also evoked early or delayed afterdepolarizations at fast pacing rates. Patch-clamp recordings in guinea pig ventricular cardiomyocytes showed that the potassium channel openers enhanced the total outward currents during the early phase of action potential repolarization, especially at proarrhythmic concentrations. We concluded that the JT peak interval and the JT area are surrogate biomarkers identifying the risk of proarrhythmia associated with the administration of QT-shortening agents. The acceleration of early-phase repolarization and the increased dispersion of ventricular repolarization may contribute to the occurrence of arrhythmias.

α1-Adrenoceptor activity in arterial smooth muscle following congestive heart failure

1989 ◽  
Vol 67 (2) ◽  
pp. 110-115 ◽  
Author(s):  
Christine Forster ◽  
Susan L. Carter ◽  
Paul W. Armstrong
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Dependent Manner ◽  
Vascular Response ◽  
Peripheral Vascular ◽  
Concentration Dependent Manner ◽  
Adrenergic Agents ◽  
Before And After ◽  
High Concentrations ◽  
Peripheral Arterial

The interactions between yohimbine (selective α2-antagonist) with noradrenaline (mixed agonist) and phenylephrine (selective α1-agonist) were studied in the canine dorsal pedal artery in an attempt to characterize the peripheral vascular response to adrenergic agents before and after the development of congestive heart failure in the dog. The contractile responses of the dorsal pedal artery to potassium chloride were also examined. Both noradrenaline and phenylephrine contracted the dorsal pedal artery in a concentration-dependent manner before and at peak heart failure, the responses to the agonists being enhanced at heart failure. The responses of the artery to potassium were not modified by congestive heart failure. Yohimbine caused concentration-dependent antagonism of noradrenaline, without altering the magnitude of the maximum response, providing pA2 values ranging from 8.26 to 7.06 against low and high concentrations of noradrenaline, respectively, before heart failure development. Following heart failure, the pA2 values for yohimbine against noradrenaline remained unchanged, but slopes from the Arunlakshana–Schild plots were significantly different from unity, implying a noncompetitive antagonism. The pA2 values of yohimbine against phenylephrine were at least 10 orders of magnitude lower than those against noradrenaline. After congestive heart failure, yohimbine was even less effective against high concentrations of phenylephrine. These findings suggest that enhanced vasoconstriction during heart failure results, in part, from increased α1-adrenoceptor mechanisms in peripheral arterial smooth muscle.Key words: vascular α-adrenoceptors, congestive heart failure, dorsal pedal artery, yohimbine, noradrenaline.

Modulation of membrane potential by an acetylcholine-activated potassium current in trout atrial myocytes

2007 ◽  
Vol 292 (1) ◽  
pp. R388-R395 ◽  
Author(s):  
Cristina E. Molina ◽  
Hans Gesser ◽  
Anna Llach ◽  
Lluis Tort ◽  
Leif Hove-Madsen
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Atrial Myocytes ◽  
Atrial Tissue ◽  
Isolated Cardiac Myocytes ◽  
Inwardly Rectifying

Application of the current-clamp technique in rainbow trout atrial myocytes has yielded resting membrane potentials that are incompatible with normal atrial function. To investigate this paradox, we recorded the whole membrane current ( Im) and compared membrane potentials recorded in isolated cardiac myocytes and multicellular preparations. Atrial tissue and ventricular myocytes had stable resting potentials of −87 ± 2 mV and −83.9 ± 0.4 mV, respectively. In contrast, 50 out of 59 atrial myocytes had unstable depolarized membrane potentials that were sensitive to the holding current. We hypothesized that this is at least partly due to a small slope conductance of Im around the resting membrane potential in atrial myocytes. In accordance with this hypothesis, the slope conductance of Im was about sevenfold smaller in atrial than in ventricular myocytes. Interestingly, ACh increased Im at −120 mV from 4.3 pA/pF to 27 pA/pF with an EC50 of 45 nM in atrial myocytes. Moreover, 3 nM ACh increased the slope conductance of Im fourfold, shifted its reversal potential from −78 ± 3 to −84 ± 3 mV, and stabilized the resting membrane potential at −92 ± 4 mV. ACh also shortened the action potential in both atrial myocytes and tissue, and this effect was antagonized by atropine. When applied alone, atropine prolonged the action potential in atrial tissue but had no effect on membrane potential, action potential, or Im in isolated atrial myocytes. This suggests that ACh-mediated activation of an inwardly rectifying K+ current can modulate the membrane potential in the trout atrial myocytes and stabilize the resting membrane potential.

scholarly journals Phenanthrene impacts zebrafish cardiomyocyte excitability by inhibiting IKr and shortening action potential duration

2021 ◽  
Vol 153 (2) ◽  
Author(s):  
Shiva N. Kompella ◽  
Fabien Brette ◽  
Jules C. Hancox ◽  
Holly A. Shiels
Keyword(s):  
Air Pollution ◽  
Action Potential ◽  
Action Potential Duration ◽  
Cardiac Electrophysiology ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Polyaromatic Hydrocarbon ◽  
Premature Ventricular Contractions ◽  
Whole Cell Patch Clamp ◽  
Dose Dependent

Air pollution is an environmental hazard that is associated with cardiovascular dysfunction. Phenanthrene is a three-ringed polyaromatic hydrocarbon that is a significant component of air pollution and crude oil and has been shown to cause cardiac dysfunction in marine fishes. We investigated the cardiotoxic effects of phenanthrene in zebrafish (Danio rerio), an animal model relevant to human cardiac electrophysiology, using whole-cell patch-clamp of ventricular cardiomyocytes. First, we show that phenanthrene significantly shortened action potential duration without altering resting membrane potential or upstroke velocity (dV/dt). L-type Ca2+ current was significantly decreased by phenanthrene, consistent with the decrease in action potential duration. Phenanthrene blocked the hERG orthologue (zfERG) native current, IKr, and accelerated IKr deactivation kinetics in a dose-dependent manner. Furthermore, we show that phenanthrene significantly inhibits the protective IKr current envelope, elicited by a paired ventricular AP-like command waveform protocol. Phenanthrene had no effect on other IK. These findings demonstrate that exposure to phenanthrene shortens action potential duration, which may reduce refractoriness and increase susceptibility to certain arrhythmia triggers, such as premature ventricular contractions. These data also reveal a previously unrecognized mechanism of polyaromatic hydrocarbon cardiotoxicity on zfERG by accelerating deactivation and decreasing IKr protective current.

Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

1995 ◽  
Vol 73 (11) ◽  
pp. 1651-1660 ◽  
Author(s):  
Gwo-Jyh Chang ◽  
Ming-Jai Su ◽  
Pei-Hong Lee ◽  
Shoei-Sheng Lee ◽  
Karin Chiung-Sheue Liu
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Positive Inotropic Effect ◽  
Ventricular Myocytes ◽  
Inotropic Effect ◽  
Dependent Manner ◽  
Cardiac Tissues ◽  
Inward Current ◽  
Adrenoceptor Antagonist ◽  
Isolated Rat

The mechanisms of the positive inotropic action of a new synthetic tetrahydroisoquinoline compound, SL-1, were investigated in isolated rat cardiac tissues and ventricular myocytes. SL-1 produced a rapidly developing, concentration-dependent positive inotropic response in both atrial and ventricular muscles and a negative chronotropic effect in spontaneously beating right atria. The positive inotropic effect was not prevented by pretreatment with reserpine (3 mg/kg) or the α-adrenoceptor antagonist prazosin (1 μM), but was suppressed by either the β-adrenoceptor antagonist atenolol (3 μM) or the K+ channel blocker 4-aminopyridine (4AP, 1 mM). In the whole-cell recording study, SL-1 increased the plateau level and prolonged the action potential duration in a concentration-dependent manner and decreased the maximum upstroke velocity [Formula: see text] and amplitude of the action potential in isolated rat ventricular myocytes stimulated at 1.0 Hz. On the other hand, SL-1 had little effect on the resting membrane potential, although it caused a slight decrease at higher concentrations. Voltage clamp experiments revealed that the increase of action potential plateau and prolongation of action potential duration were associated with an increase of Ca2+ inward current (ICa) via the activation of β-adrenoceptors and a prominent inhibition of 4AP-sensitive transient outward K+ current (Ito) with an IC50 of 3.9 μM. Currents through the inward rectifier K+ channel (IKl) were also reduced. The inhibition of Ito is characterized by a reduction in peak amplitude and a marked acceleration of current decay but without changes on the voltage dependence of steady-state inactivation. In addition to the inhibition of K+ currents, SL-1 also inhibited the Na+ inward current (INa) with an IC50 of 5.4 μM, which was correlated with the decrease of [Formula: see text]. We conclude that the positive inotropic effect of SL-1 may be due to an increase in Ca2+ current mediated via partial activation of β-adrenoceptors and an inhibition of K+ outward currents and the subsequent prolongation of action potentials.Key words: SL-1, tetrahydroisoquinoline, inotropic and chronotropic action, action potential, Na+, Ca2+, and K+ currents.

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