scholarly journals Cardiac electrophysiological effects of ibuprofen in dog and rabbit ventricular preparations: Possible implication to enhanced proarrhythmic risk

2020 ◽  
Author(s):  
Bence József Pászti ◽  
Janos Prorok ◽  
Tibor Magyar ◽  
Tamás Árpádffy-Lovas ◽  
Balázs Györe ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Dependent Manner ◽  
Maximal Rate ◽  
Patch Clamp Technique ◽  
Repolarization Reserve ◽  
Proarrhythmic Risk ◽  
Electrophysiological Effects ◽  
Dog Myocytes ◽  
Isolated Ventricular Myocytes

Ibuprofen is a widely used non-steroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n=6) and rabbit (100 µM; n=7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated, and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n=7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60 mV) and 15.2% (20 mV) respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%. We conclude that ibuprofen seems to be free from effects on AP parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Abstract 15280: Comparisons of Action Potentials and Ionic Currents Between Neonatal Rat Ventricular Myocytes and Adult Zebrafish Ventricular Myocytes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Adonis Z Wu ◽  
Shien-Fong Lin ◽  
Sheng-Nan Wu
Keyword(s):  
Electrical Properties ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Firing Frequency ◽  
Neonatal Rat ◽  
Adult Zebrafish ◽  
Patch Clamp Technique ◽  
Action Current ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes

Introduction: Zebrafish heart is established as a model to investigate cardiac electrical abnormalities. However, electrical properties of adult zebrafish cardiomyocytes are not sufficiently characterized. Hypothesis: In this study, by comparing the electrical properties between neonatal rat ventricular myocytes (NRVMs) and adult zebrafish ventricular myocytes (AZVMs), we intended to characterize the action potential (AP), action current (AC) and the properties of Na + current ( I Na ) in AZVMs. Methods: We used patch-clamp technique to characterize the electrical properties, including AP, AC and I Na , in cultured NRVMs and freshly isolated AZVMs. Results: NVRMs showed larger AP amplitude (119±6 vs. 79±4mV, p<.05) but shorter AP duration (APD 90 , 136±11 vs. 213±19 ms, p<.05) than those of AZVMs. The AP duration exhibited marked frequency-dependent alterations in AZVMs. Under the slow pacing rate, early after-depolarizations (EAD) emerged under slow pacing rate with 0.05 Hz. In cell-attached voltage-clamp recordings made from AZVMs, ACs could be elicited by +10 mV steps. As the depolarization step increased to +70 mV, the latency for appearance of ACs was progressively reduced from >123 ms to 9.8 ms. The presence of spontaneous ACs was monitored in spontaneously beating NRVMs and AZVMs. The AC amplitude in NRVMs was larger compared to that in AZVMs (17.3±2.1 vs. 11.6±1.1 pA, p<.05), although firing frequency of AC in NRVMs is higher than in AZVMs (1.13±0.09 vs. 0.38±0.03 Hz, p<.05). The lowering effect of ranolazine, a I Na antagonist, on firing frequency was significantly larger in NRVMs (1.13±0.09 to 0.31±0.02 Hz, p<.05) than in AZVMs (0.38±0.03 to 0.27±0.02 Hz). There was a hyperpolarizing shift of peak I Na in AZVM compared to NRVM. Conclusions: Our results demonstrated major differences in the cellular electrical behavior between AZVMs and NRVMs.

Effects of estrogen on action potential and membrane currents in guinea pig ventricular myocytes

1999 ◽  
Vol 277 (2) ◽  
pp. H826-H833 ◽  
Author(s):  
Seiko Tanabe ◽  
Toshio Hata ◽  
Masayasu Hiraoka
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Action Potentials ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Membrane Currents ◽  
Patch Clamp Technique ◽  
17Β Estradiol ◽  
Electrophysiological Effects ◽  
Ionic Basis

To explore a possible ionic basis for the prolonged Q-T interval in women compared with that in men, we investigated the electrophysiological effects of estrogen in isolated guinea pig ventricular myocytes. Action potentials and membrane currents were recorded using the whole cell configuration of the patch-clamp technique. Application of 17β-estradiol (10–30 μM) significantly prolonged the action potential duration (APD) at 20% (APD20) and 90% repolarization (APD90) at stimulation rates of 0.1–2.0 Hz. In the presence of 30 μM 17β-estradiol, APD20 and APD90 at 0.1 Hz were prolonged by 46.2 ± 17.1 and 63.4 ± 11.7% of the control ( n = 5), respectively. In the presence of 30 μM 17β-estradiol the peak inward Ca2+ current ( I CaL) was decreased to 80.1 ± 2.5% of the control ( n = 4) without a shift in its voltage dependence. Application of 30 μM 17β-estradiol decreased the rapidly activating component of the delayed outward K+ current ( I Kr) to 63.4 ± 8% and the slowly activating component ( I Ks) to 65.8 ± 8.7% with respect to the control; the inward rectifier K+ current was barely affected. The results suggest that 17β-estradiol prolonged APD mainly by inhibiting the I Kcomponents I Krand I Ks.

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.

Depression of delayed outward K+ current by Co2+ in guinea pig ventricular myocytes

1991 ◽  
Vol 261 (1) ◽  
pp. C23-C31 ◽  
Author(s):  
Z. Fan ◽  
M. Hiraoka
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Hill Coefficient ◽  
Maximal Response ◽  
Fluctuation Analysis ◽  
Dependent Manner ◽  
Surface Charges ◽  
Patch Clamp Technique ◽  
Voltage Range ◽  
K Current

Effects of Co2+ on the delayed outward K+ current (IK) in guinea pig ventricular myocytes were studied using the whole cell patch-clamp technique. IK was activated by depolarizing voltage pulses positive to -30 mV and reached half-maximal activation at +24 mV. Co2+ shifted the activation curve to a more depolarized voltage range in a concentration-dependent manner, with a Co2+ concentration at which half-maximal response occurs (IC50) of 8 mM and a saturation value of +38 mV. The voltage dependency of IK gatings showed a shift similar to that of activation. In both cases the shift could be explained by screening of surface potential. The density of total negative surface charges sensed by Co2+ was estimated to be 1 e/225 A2. Co2+ also reduced the fully activated IK [IK(full)], and the dose-response curve had a Hill coefficient of 0.5 and an IC50 of 1 mM at 0 mV. Depression of IK(full) was mainly voltage independent. The single-channel unitary current estimated by fluctuation analysis was approximately 0.1 pA at -30 mV either in the absence or presence of Co2+. Therefore, the depression of IK(full) is due to an equivalent reduction in the number of functional channels. It is concluded that Co2+ depressed IK through multiple mechanisms.

Transforming growth factor-β1 decreases cardiac muscle L-type Ca2+ current and charge movement by acting on the Cav1.2 mRNA

2007 ◽  
Vol 292 (1) ◽  
pp. H622-H631 ◽  
Author(s):  
Guillermo Avila ◽  
Irma M. Medina ◽  
Esperanza Jiménez ◽  
Guillermo Elizondo ◽  
Citlalli I. Aguilar
Keyword(s):  
Transforming Growth Factor ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Charge Movement ◽  
Type I ◽  
Mrna Levels ◽  
Patch Clamp Technique ◽  
Rat Cardiomyocytes ◽  
Electrophysiological Effects ◽  
Tgf Β1

Transforming growth factors-β (TGF-βs) are essential to the structural remodeling seen in cardiac disease and development; however, little is known about potential electrophysiological effects. We hypothesized that chronic exposure (6–48 h) of primary cultured neonatal rat cardiomyocytes to the type 1 TGF-β (TGF-β1, 5 ng/ml) may affect voltage-dependent Ca2+ channels. Thus we investigated T- ( ICaT) and L-type ( ICaL) Ca2+ currents, as well as dihydropyridine-sensitive charge movement using the whole cell patch-clamp technique and quantified CaV1.2 mRNA levels by real-time PCR assay. In ventricular myocytes, TGF-β1 did not exert significant electrophysiological effects. However, in atrial myocytes, TGF-β1 reduced both ICaL and charge movement (55% at 24–48 h) without significantly altering ICaT, cell membrane capacitance, or channel kinetics (voltage dependence of activation and inactivation, as well as the activation and inactivation rates). Reductions of ICaL and charge movement were explained by concomitant effects on the maximal values of L-channels conductance ( Gmax) and charge movement (Qmax). Thus TGF-β1 selectively reduces the number of functional L-channels on the surface of the plasma membrane in atrial but not ventricular myocytes. The TGF-β1-induced ICaL reduction was unaffected by supplementing intracellular recording solutions with okadaic acid (2 μM) or cAMP (100 μM), two compounds that promote L-channel phosphorylation. This suggests that the decreased number of functional L-channels cannot be explained by a possible regulation in the L-channels phosphorylation state. Instead, we found that TGF-β1 decreases the expression levels of atrial CaV1.2 mRNA (70%). Thus TGF-β1 downregulates atrial L-channel expression and may be therefore contributing to the in vivo cardiac electrical remodeling.

Sera from patients with idiopathic dilated cardiomyopathy decrease ICa in cardiomyocytes isolated from rabbits

2004 ◽  
Vol 287 (5) ◽  
pp. H1928-H1936 ◽  
Author(s):  
Cristiane del Corsso ◽  
Antônio Carlos Campos de Carvalho ◽  
Helena Furtado Martino ◽  
Wamberto Antonio Varanda
Keyword(s):  
Dilated Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Blood Donors ◽  
Ventricular Myocytes ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Patch Clamp Technique ◽  
Cardiac Functions ◽  
Rabbit Ventricular Myocytes ◽  
Electrophysiological Effects ◽  
Do So

Autoantibodies against muscarinic and adrenergic receptors have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDC) and Chagas disease, but it is still unclear whether they can functionally interact with their respective receptors to modulate cardiac functions. In this study, our goal was to detect the presence of those antibodies in the sera of patients with IDC and characterize their electrophysiological effects on cardiomyocytes from rabbits. By using ELISA immunoassays, we detected high titers of antibodies against muscarinic M2 receptors in the sera of all IDC patients, whereas the detection of antibodies against the β1-receptor occurred in 50% of them. Electrophysiological experiments using the whole cell configuration of the patch-clamp technique showed that sera from 43% of IDC patients induced a significant decrease (∼26%) in isoproterenol-stimulated L-type Ca2+ currents in rabbit ventricular myocytes, whereas the sera from healthy blood donors failed to do so. As expected, IDC sera also decreased the action potential duration (by 10.5%) due to a shortening of the plateau phase. Sera that reduced isoproterenol-stimulated L-type Ca2+ currents did not cause any effect on K+ currents. We conclude that sera from IDC patients have autoantibodies, which interact with muscarinic M2 receptors of rabbit cardiomyocytes, acting in an agonist-like fashion. This action results in changes in electrogenesis, which, as often observed in patients with IDC, could initiate ventricular arrhythmias that lead to sudden death.

scholarly journals Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes

2000 ◽  
Vol 130 (8) ◽  
pp. 1753-1766 ◽  
Author(s):  
K H Yuill ◽  
M K Convery ◽  
P C Dooley ◽  
S A Doggrell ◽  
J C Hancox
Keyword(s):  
Guinea Pig ◽  
Action Potentials ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Isolated Ventricular Myocytes

Depression of excitability by sphingosine 1-phosphate in rat ventricular myocytes

1998 ◽  
Vol 275 (6) ◽  
pp. H2291-H2299 ◽  
Author(s):  
Karen L. MacDonell ◽  
David L. Severson ◽  
Wayne R. Giles
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Potassium Conductance ◽  
Ionic Currents ◽  
Stimulus Current ◽  
Muscle Action Potential ◽  
Action Potential Waveform ◽  
Sphingosine 1 Phosphate ◽  
Electrophysiological Effects

Sphingosine 1-phosphate (S-1- P) is a bioactive sphingolipid that is released from activated platelets. Extracellular S-1- P augments an inwardly rectifying potassium conductance in cultured atrial preparations, but the electrophysiological effects of this compound in the ventricle are unknown. The electrophysiological effects of S-1- P were examined in single myocytes from rat ventricular muscle. Action potential waveforms and underlying ionic currents in the presence and absence of 3 μM S-1- P (1–6 min) were recorded. S-1- P increased the minimum stimulus current needed to elicit an action potential by ∼100 pA. Pertussis toxin or preexposure to S-1- P did not alter this effect. The action potential waveform was unchanged by S-1- P. The inward sodium current ( I Na) was examined in a range of membrane potentials just negative to the potential for firing an action potential. S-1- P reversibly inhibited peak I Na by ∼50 pA, whereas the inward rectifier potassium current was not significantly changed. The results of this study suggest that S-1- P inhibits rat ventricular excitability by reducing I Na.

scholarly journals Inhibitory Effect of Cinobufagin on L-Type Ca2+Currents, Contractility, and Ca2+Homeostasis of Isolated Adult Rat Ventricular Myocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Pinya Li ◽  
Qiongtao Song ◽  
Tao Liu ◽  
Zhonglin Wu ◽  
Xi Chu ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Cell Contractility ◽  
Rat Ventricular Myocytes ◽  
Adult Rat ◽  
Time To Peak ◽  
Whole Cell Patch Clamp

Cinobufagin (CBG), a major bioactive ingredient of the bufanolide steroid compounds of Chan Su, has been widely used to treat coronary heart disease. At present, the effect of CBG on the L-type Ca2+current (ICa-L) of ventricular myocytes remains undefined. The aim of the present study was to characterize the effect of CBG on intracellular Ca2+([Ca2+]i) handling and cell contractility in rat ventricular myocytes. CBG was investigated by determining its influence onICa-L, Ca2+transient, and contractility in rat ventricular myocytes using the whole-cell patch-clamp technique and video-based edge-detection and dual-excitation fluorescence photomultiplier systems. The dose of CBG (10−8 M) decreased the maximal inhibition of CBG by 47.93%. CBG reducedICa-Lin a concentration-dependent manner with an IC50of 4 × 10−10 M, upshifted the current-voltage curve ofICa-L, and shifted the activation and inactivation curves ofICa-Lleftward. Moreover, CBG diminished the amplitude of the cell shortening and Ca2+transients with a decrease in the time to peak (Tp) and the time to 50% of the baseline (Tr). CBG inhibited L-type Ca2+channels, and reduced[Ca2+]iand contractility in adult rat ventricular myocytes. These findings contribute to the understanding of the cardioprotective efficacy of CBG.

scholarly journals Methadone block of K+ current in squid giant fiber lobe neurons.

1996 ◽  
Vol 107 (2) ◽  
pp. 243-260 ◽  
Author(s):  
F T Horrigan ◽  
W F Gilly
Keyword(s):  
Time Course ◽  
Strong Dependence ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
K Channel ◽  
Bathing Solution ◽  
Dependent Manner ◽  
Giant Fiber ◽  
Patch Clamp Technique ◽  
Pipette Solution

Voltage-dependent ionic currents were recorded from squid giant fiber lobe neurons using the whole-cell patch-clamp technique. When applied to the bathing solution, methadone was found to block IK, I Na and I Ca. Both I Na and I Ca were reduced without apparent change in kinetics and exhibited IC(50)'s of 50-100 and 250-500 mu M, respectively, at +10 mV. In contrast, IK was reduced in a time-dependent manner that is well fit by a simple model of open channel block (K(D)= 32+/- or 2 mu M, +60 mV, 10 degrees Celsius). The mechanism of I(K) block was examined in detail and involves a direct action of methadone, a tertiary amine, on K channels rather than an opioid receptor-mediated pathway. The kinetics of I(K) block resemble those reported for internally applied long chain quaternary ammonium (QA) compounds; and recovery from I(K) block is QA-like in its slow time course and strong dependence on holding potential. A quaternary derivative of methadone (N-methyl-methadone) only reproduced the effects of methadone on I(K) when included in the pipette solution; this compound was without effect when applied externally. I(K) block thus appears to involve diffusion of methadone into the cytoplasm and occlusion of the open K channel at the internal QA blocking site by the protonated form of the drug. This proposed mode of action is supported by the pH and voltage dependence of block as well as by the observation that high external K+ speeds the rate of drug dissociation. In addition, the effect of methadone on I(K) evoked during prolonged (300 ms) depolarizations suggests that methadone block may interfere with endogenous K+ channel inactivation. The effects of temperature, methadone stereoisomers, and the methadone-like drugs propoxyphene and nor-propoxyphene on IK block were examined. Methadone was also found to block I(K) in GH3 cells and in chick myoblasts.

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