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.

Dual effects of external magnesium on action potential duration in guinea pig ventricular myocytes

1995 ◽  
Vol 268 (6) ◽  
pp. H2321-H2328 ◽  
Author(s):  
S. Zhang ◽  
T. Sawanobori ◽  
H. Adaniya ◽  
Y. Hirano ◽  
M. Hiraoka
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Decay Time ◽  
Action Potential Duration ◽  
Time Course ◽  
Ventricular Myocytes ◽  
Membrane Surface ◽  
Surface Charges ◽  
Whole Cell Patch Clamp ◽  
K Current

Effects of extracellular magnesium (Mg2+) on action potential duration (APD) and underlying membrane currents in guinea pig ventricular myocytes were studied by using the whole cell patch-clamp method. Increasing external Mg2+ concentration [Mg2+]o) from 0.5 to 3 mM produced a prolongation of APD at 90% repolarization (APD90), whereas 5 and 10 mM Mg2+ shortened it. [Mg2+]o, at 3 mM or higher, suppressed the delayed outward K+ current and the inward rectifier K+ current. Increases in [Mg2+]o depressed the peak amplitude and delayed the decay time course of the Ca2+ current (ICa), the latter effect is probably due to the decrease in Ca(2+)-induced inactivation. Thus 3 mM Mg2+ suppressed the peak ICa but increased the late ICa amplitude at the end of a 200-ms depolarization pulse, whereas 10 mM Mg2+ suppressed both components. Application of 10 mM Mg2+ shifted the voltage-dependent activation and inactivation by approximately 10 mV to more positive voltage due to screening the membrane surface charges. Application of manganese (1-5 mM) also caused dual effects on APD90, similar to those of Mg2+, and suppressed the peak ICa with slowed decay. These results suggest that the dual effects of Mg2+ on APD in guinea pig ventricular myocytes can be, at least in part, explained by its action on ICa with slowed decay time course in addition to suppressive effects on K+ currents.

Effect of aminophylline on the contraction threshold of rat diaphragm fibers

1991 ◽  
Vol 71 (4) ◽  
pp. 1409-1414 ◽  
Author(s):  
A. S. Losavio ◽  
B. A. Kotsias
Keyword(s):  
Membrane Potential ◽  
Sarcoplasmic Reticulum ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Direct Visualization ◽  
Rat Diaphragm ◽  
Current Clamp ◽  
Cyclic Monophosphate ◽  
Dose Dependent

We studied the effect of aminophylline (0.1–1 mM) on the contraction threshold (CT) of rat diaphragm fibers (25 degrees C). The CT was measured by direct visualization (x200) of the fiber under current-clamp conditions. The main findings are the following: 1) Aminophylline lowers the CT, in a dose-dependent manner, toward more negative values of the resting membrane potential (Vm). 2) Dibutyryl adenosine 3′,5′-cyclic monophosphate (2 mM) shifts the CT, although this change is smaller than in the presence of xanthine. 3) Tetracaine (1 mM), a drug that diminishes Ca release from the sarcoplasmic reticulum, reduces the shift induced by 1 mM aminophylline; this is partially overcome by increasing aminophylline concentration to 5 mM. 4) Hyperpolarization of the fibers shifts the CT to more negative Vm. We suggest that the displacement in the CT to more negative Vm plays an important role in the potentiating effect of aminophylline. This could be the result of an enhancement of Ca release from the sarcoplasmic reticulum.

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.

Hypertensive-diabetic cardiomyopathy in rats

1990 ◽  
Vol 258 (3) ◽  
pp. H793-H805 ◽  
Author(s):  
F. S. Fein ◽  
B. E. Zola ◽  
A. Malhotra ◽  
S. Cho ◽  
S. M. Factor ◽  
...  
Keyword(s):  
Action Potential ◽  
Right Ventricular ◽  
Action Potential Duration ◽  
Stimulus Frequency ◽  
Negative Inotropic Effect ◽  
Left Ventricular ◽  
Resting Membrane Potential ◽  
Contraction And Relaxation ◽  
And Control ◽  
Myocardial Pathology

Left ventricular papillary muscle function, transmembrane action potentials, myosin adenosinetriphosphatase (ATPase) and isoenzyme distribution, and myocardial pathology were studied in hypertensive (H), diabetic (D), hypertensive-diabetic (HD), and control (C) rats. There was approximately 50% relative left ventricular hypertrophy in H and HD rats. Relative lung and liver weights were greater in HD rats. Peak velocity of shortening tended to decrease progressively in H, D, and HD rats. The duration of contraction and relaxation was markedly prolonged in Ds and HDs. The length-developed tension relation was blunted in HDs. The negative inotropic effect of verapamil was similar in all groups. Resting membrane potential and amplitude were decreased in D and HD rats. Action potential duration was increased in H, D, and especially HD rats. The shortening of action potential duration with increased stimulus frequency was greater in H, D, and especially HD rats than in Cs. Left ventricular myosin ATPase and V1 isoenzyme content decreased progressively in H, D, and HD rats. Right ventricular V1 isoenzyme content was not affected in H rats but was markedly decreased in D and HD rats. Left (and right) ventricular pathology was unchanged in rats with diabetes but was increased in rats with hypertension. These data suggest that the combination of myocardial pathology (due to hypertension) and cellular dysfunction (caused mainly by diabetes) may result in cardiomyopathy and congestive heart failure in the HD rat.

Hyperpolarizing effect of aminophylline, theophylline, and cAMP on rat diaphragm fibers

1988 ◽  
Vol 64 (5) ◽  
pp. 1893-1899 ◽  
Author(s):  
O. Delbono ◽  
B. A. Kotsias
Keyword(s):  
Normal Values ◽  
Bath Temperature ◽  
Resting Membrane Potential ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Rat Diaphragm ◽  
K Concentration ◽  
Dose Dependent ◽  
K Permeability

We studied the effect of aminophylline and theophylline (0.1–2 mM) on the resting membrane potential (Vm) of rat diaphragm fibers in vitro (25 degrees C). The main findings are the following. 1) Aminophylline and theophylline hyperpolarize the fibers in a dose-dependent manner. This effect is present with 0.1 and 0.25 mM of aminophylline and theophylline, respectively, and the maximum effect is reached with 1 mM of the drug (approximately 5–8 mV in comparison to the normal values). This effect is reversible by washing out the preparation with normal solution. 2) Dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP, 2 mM) produces a similar increment in the Vm. 3) The hyperpolarizing action observed in the presence of aminophylline, theophylline, and DBcAMP is suppressed by 5 X 10(-4) M ouabain or by lowering the bath temperature to 5 degrees C. These results suggest that the xanthines may directly or indirectly stimulate a Na-K pump. Two possibilities may be considered: 1) an electrogenic effect of the Na-K pump and 2) a reduction in the extracellular K+ concentration in the solution contacting the external side of the cell as a consequence of the activity of the Na-K pump. Alternative mechanisms such as a reduction in Na permeability or an increment in K permeability might collaborate in the hyperpolarizing effect of the drugs tested.

Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes

2000 ◽  
Vol 278 (2) ◽  
pp. E302-E307 ◽  
Author(s):  
Zhuo-Qian Sun ◽  
Kaie Ojamaa ◽  
William A. Coetzee ◽  
Michael Artman ◽  
Irwin Klein
Keyword(s):  
Action Potential ◽  
Cardiac Electrophysiology ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Mechanisms Of Action ◽  
Transient Outward Current ◽  
Prolonged Action ◽  
Electrophysiological Properties ◽  
Whole Cell Patch Clamp ◽  
Prolonged Action Potential Duration

Thyroid hormones play an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action. The effects of triiodothyronine (T3) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats were studied using whole cell patch clamp techniques. Hypothyroid ventricular myocytes showed significantly prolonged action potential duration (APD90) compared with euthyroid myocytes, APD90 of 151 ± 5 vs. 51 ± 8 ms, respectively. Treatment of hypothyroid ventricular myocytes with T3 (0.1 μM) for 5 min significantly shortened APD by 24% to 115 ± 10 ms. T3 similarly shortened APD in euthyroid ventricular myocytes, but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient outward current ( I to), which prolonged the APD by threefold. Transient outward current ( I to) was not affected by the acute application of T3 to either euthyroid or hypothyroid myocytes; however, I to density was significantly reduced in hypothyroid compared with euthyroid ventricular myocytes.

Effects of relaxin on rat atrial myocytes. II. Increased calcium influx derived from action potential prolongation

1997 ◽  
Vol 272 (4) ◽  
pp. H1798-H1803 ◽  
Author(s):  
E. S. Piedras-Renteria ◽  
O. D. Sherwood ◽  
P. M. Best
Keyword(s):  
Action Potential ◽  
Calcium Influx ◽  
Calcium Currents ◽  
Atrial Myocytes ◽  
Inotropic Effects ◽  
Whole Cell Patch Clamp ◽  
Rat Hearts ◽  
Action Potential Prolongation ◽  
Dose Dependent ◽  
Rat Atrial Cells

Relaxin produces positive inotropic and chronotropic effects in rat hearts. The effect of relaxin on the action potential duration (APD) of single quiescent rat atrial cells was investigated with a whole cell patch clamp. Relaxin induced a significant, dose-dependent prolongation of the APD. This effect was maximal at 200 ng/ml (nominal concentration of 33.6 nM), which caused, on average, a 57% increase in the time taken to reach 90% repolarization. The effect of relaxin was blocked by the protein kinase A inhibitor 5-24 amide, indicating that its effect is mediated by an adenosine 3',5'-cyclic monophosphate-dependent mechanism. The increased APD induced by relaxin caused an enhanced entrance of calcium, with the charge carried through voltage-activated calcium channels increased by approximately 25%. This increase was not due to a direct modulation of calcium currents (20); rather, it was a consequence of the longer period of cellular depolarization. Our findings that relaxin increased the APD and therefore increased the calcium influx in atrial myocytes could explain the positive inotropic effects induced by relaxin in atrial preparations.

Sprint training shortens prolonged action potential duration in postinfarction rat myocyte: mechanisms

2001 ◽  
Vol 90 (5) ◽  
pp. 1720-1728 ◽  
Author(s):  
Xue-Qian Zhang ◽  
Lian-Qin Zhang ◽  
Bradley M. Palmer ◽  
Yuk-Chow Ng ◽  
Timothy I. Musch ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Outward Current ◽  
Activation Parameters ◽  
Resting Membrane Potential ◽  
Transient Outward Current ◽  
Sprint Training ◽  
Myocyte Hypertrophy ◽  
Dependent Inactivation ◽  
Prolongation Of Action Potential

Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current ( I to) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca2+ homeostasis and contractility after MI, the present study evaluated whether 6–8 wk of HIST would shorten the prolonged APD and improve the depressed I to in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly ( P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I towere significantly ( P < 0.0001) reduced in MI-Sed myocytes. HIST significantly ( P < 0.001) enhanced the fast and slow components of I to in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I toinactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I to toward normal levels.

Activation of Phosphatidylinositol-Linked Novel D1 Dopamine Receptors Inhibits High-Voltage-Activated Ca2+ Currents in Primary Cultured Striatal Neurons

2009 ◽  
Vol 101 (5) ◽  
pp. 2230-2238 ◽  
Author(s):  
Li-Qun Ma ◽  
Chao Liu ◽  
Fang Wang ◽  
Na Xie ◽  
Jun Gu ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
High Voltage ◽  
Dependent Manner ◽  
Striatal Neurons ◽  
Inhibitory Effects ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Intracellular Ca ◽  
Dose Dependent

Recent evidences indicate the existence of a putative novel phosphatidylinositol (PI)-linked D1 dopamine receptor that mediates excellent anti-Parkinsonian but less severe dyskinesia action. To further understand the basic physiological function of this receptor in brain, the effects of a PI-linked D1 dopamine receptor-selective agonist 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) on high-voltage activated (HVA) Ca2+ currents in primary cultured striatal neurons were investigated by whole cell patch-clamp technique. The results indicated that stimulation by SKF83959 induced an inhibition of HVA Ca2+ currents in a dose-dependent manner in substance-P (SP)-immunoreactive striatal neurons. Application of D1 receptor, but not D2, α1 adrenergic, 5-HT receptor, or cholinoceptor antagonist prevented SKF83959-induced reduction, indicating that a D1 receptor-mediated event assumed via PI-linked D1 receptor. SKF83959-induced inhibitory modulation was mediated by activation of phospholipase C (PLC), mobilization of intracellular Ca2+ stores and activation of calcineurin. Furthermore, the inhibitory effects were attenuated significantly by the L-type calcium channel antagonist nifedipine, suggesting that L-type calcium channels involved in the regulation induced by SKF83959. These findings may help to further understand the functional role of the PI-linked dopamine receptor in brain.

Influence of age and run training on cardiac Na+/Ca2+ exchange

2003 ◽  
Vol 95 (5) ◽  
pp. 1994-2003 ◽  
Author(s):  
Lisa C. Mace ◽  
Bradley M. Palmer ◽  
David A. Brown ◽  
Korinne N. Jew ◽  
Joshua M. Lynch ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Left Ventricular ◽  
Brown Norway ◽  
Resting Membrane Potential ◽  
Whole Cell Patch Clamp ◽  
Age Related ◽  
Intracellular Ca ◽  
Whole Heart ◽  
Exchange Activity

Effects of age and training on myocardial Na+/Ca2+ exchange were examined in young sedentary (YS; 14-15 mo), aged sedentary (AS; 27-31 mo), and aged trained (AT; 8- to 11-wk treadmill run training) male Fischer Brown Norway rats. Whole heart performance and isolated cardiocyte Na+/Ca2+ exchange characteristics were measured. At the whole heart level, a small but significant slowing of late isovolumic left ventricular (LV) relaxation, which may be indicative of altered Na+/Ca2+ exchange activity, was seen in hearts from AS rats. This subtle impairment in relaxation was not observed in hearts from AT rats. At the single-cardiocyte level, late action potential duration was prolonged, resting membrane potential was more positive, and overshoot potential was greater in cardiocytes from AS rats than from YS rats ( P < 0.05). Training did not influence any of these age-related action potential characteristics. In electrically paced cardiocytes, neither shortening nor intracellular Ca2+ concentration ([Ca2+]i) dynamics was influenced by age or training. Similarly, neither age nor training influenced the rate of [Ca2+]i clearance via forward (Nain+ /Caout2+) Na+/Ca2+ exchange after caffeine-induced Ca2+ release from the sarcoplasmic reticulum or cardiac Na+/Ca2+ exchanger protein (NCX1) expression. However, when whole cell patch-clamp techniques combined with fluorescence microscopy were used to evaluate the ability of Na+/Ca2+ exchange to alter cytosolic [Ca2+] ([Ca2+]c) under conditions where membrane potential ( Vm) and internal and external [Na+] and [Ca2+] could be controlled, we observed age-associated increases in forward Na+/Ca2+ exchange-mediated [Ca2+]c clearance ( P < 0.05) that were not influenced by training. The age-related increase in forward Na+/Ca2+ exchange activity provides a hypothetical explanation for the late action potential prolongation observed in this study.

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