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.

Guinea pig visceral C-fiber neurons are diverse with respect to the K+ currents involved in action-potential repolarization

1994 ◽  
Vol 71 (2) ◽  
pp. 561-574 ◽  
Author(s):  
E. P. Christian ◽  
J. Togo ◽  
K. E. Naper
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Outward Current ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Whole Cell ◽  
C Fiber ◽  
K Current ◽  
Action Potential Repolarization

1. Intracellular recordings were made from C-fiber neurons identified by antidromic conduction velocity in intact guinea pig nodose ganglia maintained in vitro, and whole-cell patch clamp recordings were made from dissociated guinea pig nodose neurons to investigate the contribution of various K+ conductances to action-potential repolarization. 2. The repolarizing phase of the intracellularly recorded action potential was prolonged in a concentration-dependent manner by charybdotoxin (Chtx; EC50 = 39 nM) or iberiatoxin (Ibtx; EC50 = 48 nM) in a subpopulation of 16/36 C-fiber neurons. In a subset of these experiments, removal of extracellular Ca2+ reversibly prolonged action-potential duration (APD) in the same 4/9 intracellularly recorded C-fiber neurons affected by Chtx (> or = 100 nM). These convergent results support that a Ca(2+)-activated K+ current (IC) contributes to action-potential repolarization in a restricted subpopulation of C-fiber neurons. 3. Tetraethylammonium (TEA; 1-10 mM) increased APD considerably further in the presence of 100-250 nM Chtx or Ibtx, or in nominally Ca(2+)-free superfusate in 14/14 intracellularly recorded C-fiber neurons. TEA affected APD similarly in subpopulations of neurons with and without IC, suggesting that a voltage-dependent K+ current (IK) contributes significantly to action-potential repolarization in most nodose C-fiber neurons. 4. Substitution of Mn2+ for Ca2+ reduced outward whole-cell currents elicited by voltage command steps positive to -30 mV (2-25 ms) in a subpopulation of 21/36 dissociated nodose neurons, supporting the heterogeneous expression of IC. The kinetics of outward tail current relaxations (tau s of 1.5-2 ms) measured at the return of 2-3 ms depolarizing steps to -40 mV were indistinguishable in neurons with and without IC, precluding a separation of the nodose IC and IK by a difference in deactivation rates. 5. Chtx (10-250 nM) reduced in a subpopulation of 3/8 C-fiber neurons the total outward current elicited by voltage steps depolarized to -30 mV in single microelectrode voltage-clamp recordings. TEA (5-10 mM) further reduced outward current in the presence of 100-250 nM Chtx in all eight experiments. The Chtx-sensitive current was taken to represent IC, and the TEA-sensitive current, the IK component contributing to action-potential repolarization. 6. Rapidly inactivating current (IA) was implicated in action-potential repolarization in a subpopulation of intracellularly recorded C-fiber neurons. In 4/7 neurons, incremented hyperpolarizing prepulses negative to -50 mV progressively shortened APD.(ABSTRACT TRUNCATED AT 400 WORDS)

Molecular mechanism of doxorubicin-induced anticholinergic effect in guinea-pig atria

2000 ◽  
Vol 78 (6) ◽  
pp. 483-489 ◽  
Author(s):  
Yukio Hara ◽  
Kyosuke Temma ◽  
Zin Sekiya ◽  
Akihito Chugun ◽  
Hiroshi Kondo
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Acetylcholine Receptor ◽  
Action Potential Duration ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Anticholinergic Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Muscarinic Acetylcholine

The molecular mechanisms of anticholinergic actions of doxorubicin were examined by electrophysiological methods in atria and myocytes isolated from guinea-pig heart. A direct anticholinergic action of doxorubicin was confirmed with antagonistic action on carbachol-induced negative inotropic effect in atria. Both carbachol and adenosine produced shortening of action potential duration in atria measured by a microelectrode method. Doxorubicin (10-100 µM) inhibited the carbachol-induced action potential shortening in a concentration-dependent manner. However, doxorubicin did not antagonize the shortening elicited by adenosine. The whole-cell voltage clamp technique was performed to induce the muscarinic acetylcholine-receptor-operated K+ current (IK.ACh) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 µM) suppressed carbachol-induced IK.ACh in a concentration-dependent manner (IC50 = 5.6 µM). In contrast, doxorubicin (10 and 100 µM) suppressed neither adenosine-induced IK.ACh nor GTPgammaS-induced IK.ACh. These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.Key words: action potential duration, anticholinergic action, atrial cell, doxorubicin, the muscarinic acetylcholine-receptor-operated K+ current.

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.

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.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig

2013 ◽  
Vol 91 (4) ◽  
pp. 306-315 ◽  
Author(s):  
Oleg E. Osadchii
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Left Ventricular ◽  
Ventricular Repolarization ◽  
Monophasic Action Potential ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Left Ventricular Chamber ◽  
The Right

Quinidine is a class Ia Na+ channel blocker that prolongs cardiac repolarization owing to the inhibition of IKr, the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

Vasodilation induced by substance P in guinea pig carotid arteries

1994 ◽  
Vol 266 (3) ◽  
pp. H1132-H1137
Author(s):  
G. Zhang ◽  
Y. Yamamoto ◽  
K. Miwa ◽  
H. Suzuki
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Carotid Arteries ◽  
Smooth Muscles ◽  
Peak Amplitude ◽  
Resting Potential ◽  
Dependent Manner ◽  
Similar Form ◽  
Concentration Dependent Manner ◽  
High K

In the guinea pig carotid artery with an intact endothelium, substance P (SP, 10(-10)-10(-7) M) relaxed the norepinephrine- (NE) contracted smooth muscles transiently, in a concentration-dependent manner. Acetylcholine (ACh, 10(-6) M) produced a sustained relaxation. SP and ACh also relaxed muscles contracted with high-K (29.6 mM) solution, with a similar form but with a reduced amplitude compared with findings in NE-contracted muscles. In the presence of nitroarginine (10(-5) M) and NE, the ACh-induced relaxation was transient, with a reduced amplitude, whereas the SP-induced relaxation was not significantly changed. In muscles contracted with high-K solution containing nitroarginine, neither SP nor ACh produced relaxation. SP (> 10(-11) M) transiently hyperpolarized the membrane, but only when this peptide was applied from the intimal side of the intact vessel, and the peak amplitude reached approximately 20 mV from the resting potential at 10(-8) M. ACh transiently hyperpolarized the membrane (the peak amplitude being approximately 10 mV), in both the adventitial and intimal applications. In high-K solution, neither SP nor ACh produced hyperpolarization. The amplitude of hyperpolarizations produced by SP did not significantly change in the presence of nitroarginine, oxyhemoglobin, or indomethacin. Thus, SP-induced relaxation seems to be produced mainly by endothelium-derived hyperpolarizing factor-induced hyperpolarization.

Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes

1989 ◽  
Vol 414 (6) ◽  
pp. 669-675 ◽  
Author(s):  
D. Escande ◽  
D. Thuringer ◽  
S. Le Guern ◽  
J. Courteix ◽  
M. Laville ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Potassium Channel ◽  
Cardiac Myocytes ◽  
Potassium Channel Openers ◽  
K Channels

Differential sensitivity to ATP-sensitive potassium channel openers of norepinephrine-induced contraction of guinea pig and rat aorta

Life Sciences ◽  
1998 ◽  
Vol 62 (24) ◽  
pp. 2171-2179 ◽  
Author(s):  
Wataru Saito ◽  
Miwako Aida ◽  
Minoru Sasaki ◽  
Yayoi Saito ◽  
Yoshio Tanaka ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Potassium Channel ◽  
Rat Aorta ◽  
Differential Sensitivity ◽  
Potassium Channel Openers
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