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.

Hypoxia-induced activation of KATP channels limits energy depletion in the guinea pig heart

1995 ◽  
Vol 269 (2) ◽  
pp. H734-H742 ◽  
Author(s):  
U. K. Decking ◽  
T. Reffelmann ◽  
J. Schrader ◽  
H. Kammermeier
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Coronary Flow ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Resonance Spectroscopy ◽  
Energy Status ◽  
Guinea Pig Heart

The functional role of ATP-dependent potassium (KATP) in hypoxic cardiac failure was investigated in isolated guinea pig hearts with glibenclamide and rimalkalim as inhibitor and activator, respectively. Monophasic action potential duration at 90% of repolarization (MAP50), left ventricular function, and cardiac energy status (31P nuclear magnetic resonance spectroscopy) were measured during normotoxic (95% O2) and hypoxic (20% O2) perfusion. In normoxic hearts, 1 microM glibenclamide did not affect MAP50, left ventricular function, and coronary flow (n = 4). In contrast, rimalkalim rapidly shortened MAP50 and left ventricular pressure (LVP) in a dose-dependent fashion (e.g., by 60.2 +/- 3.5 and 80.8 +/- 8.2%, respectively, with 0.6 microM rimalkalim). This latter effect was reversed by 1 microM (glibenclamide (n = 4). With hypoxic perfusion, a reduction in LVP was observed, along with a shortening of the action potential (MAP90; 202 +/- 13 vs. 164 +/- 9 ms) and an increase in coronary flow. Glibenclamide (1 microM) reversed the MAP90 shortening and the increase in coronary flow. In addition, glibenclamide increased LVP transiently (n = 4). When coronary flow of hypoxic hearts was kept constant, however, glibenclamide elicited a sustained positive inotropic effect (n = 7). After glibenclamide, an increase in LVP from 54 +/- 4 to 64 +/- 3 mmHg was observed, along with a reduction in the free energy change of ATP hydrolysis from -54.5 +/- 1.9 to -52.9 +/- 0.2 nJ/mol and a further increase in the coronary venous adenosine from 269 +/- 48 to 1,680 +/- 670 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization

2000 ◽  
Vol 278 (3) ◽  
pp. H806-H817 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Ventricular Repolarization ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Voltage Dependent

Although inactivation of the rapidly activating delayed rectifier current ( I Kr) limits outward current on depolarization, the role of I Kr (and recovery from inactivation) during repolarization is uncertain. To characterize I Krduring ventricular repolarization (and compare with the inward rectifier current, I K1), voltage-clamp waveforms simulating the action potential were applied to canine ventricular, atrial, and Purkinje myocytes. In ventricular myocytes, I Kr was minimal at plateau potentials but transiently increased during repolarizing ramps. The I Kr transient was unaffected by repolarization rate and maximal after 150-ms depolarizations (+25 mV). Action potential clamps revealed the I Kr transient terminating the plateau. Although peak I Kr transient density was relatively uniform among myocytes, potentials characterizing the peak transients were widely dispersed. In contrast, peak inward rectifier current ( I K1) density during repolarization was dispersed, whereas potentials characterizing I K1 defined a narrower (more negative) voltage range. In summary, rapidly activating I Kr provides a delayed voltage-dependent (and functionally time-independent) outward transient during ventricular repolarization, consistent with rapid recovery from inactivation. The heterogeneous voltage dependence of I Kr provides a novel means for modulating the contribution of this current during repolarization.

TransmembraneI Ca contributes to rate-dependent changes of action potentials in human ventricular myocytes

1999 ◽  
Vol 276 (1) ◽  
pp. H98-H106 ◽  
Author(s):  
Gui-Rong Li ◽  
Baofeng Yang ◽  
Jianlin Feng ◽  
Ralph F. Bosch ◽  
Michel Carrier ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Slow Component ◽  
Cell Voltage ◽  
High Rate ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Ventricular Cells ◽  
The Right

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at −80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model

1998 ◽  
Vol 275 (1) ◽  
pp. H301-H321 ◽  
Author(s):  
Marc Courtemanche ◽  
Rafael J. Ramirez ◽  
Stanley Nattel
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Important Determinant ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Ionic Mechanisms

The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

scholarly journals Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species

2012 ◽  
Vol 302 (5) ◽  
pp. H1023-H1030 ◽  
Author(s):  
Thomas O'Hara ◽  
Yoram Rudy
Keyword(s):  
Guinea Pig ◽  
Drug Response ◽  
Cellular Level ◽  
Quantitative Comparison ◽  
Rate Dependence ◽  
Delayed Rectifier ◽  
Adrenergic Stimulation ◽  
Early Afterdepolarizations ◽  
Rate Dependent ◽  
Delayed Rectifier Current

Explanations for arrhythmia mechanisms at the cellular level are usually based on experiments in nonhuman myocytes. However, subtle electrophysiological differences between species may lead to different rhythmic or arrhythmic cellular behaviors and drug response given the nonlinear and highly interactive cellular system. Using detailed and quantitatively accurate mathematical models for human, dog, and guinea pig ventricular action potentials (APs), we simulated and compared cell electrophysiology mechanisms and response to drugs. Under basal conditions (absence of β-adrenergic stimulation), Na+/K+-ATPase changes secondary to Na+ accumulation determined AP rate dependence for human and dog but not for guinea pig where slow delayed rectifier current ( IKs) was the major rate-dependent current. AP prolongation with reduction of rapid delayed rectifier current ( IKr) and IKs (due to mutations or drugs) showed strong species dependence in simulations, as in experiments. For humans, AP prolongation was 80% following IKr block. It was 30% for dog and 20% for guinea pig. Under basal conditions, IKs block was of no consequence for human and dog, but for guinea pig, AP prolongation after IKs block was severe. However, with β-adrenergic stimulation, IKs played an important role in all species, particularly in AP shortening at fast rate. Quantitative comparison of AP repolarization, rate-dependence mechanisms, and drug response in human, dog, and guinea pig revealed major species differences (e.g., susceptibility to arrhythmogenic early afterdepolarizations). Extrapolation from animal to human electrophysiology and drug response requires great caution.

Contribution of frequency-augmented inward Ca2+ current to myocardial contractility

2009 ◽  
Vol 87 (1) ◽  
pp. 69-75 ◽  
Author(s):  
Leonard D. Parilak ◽  
David G. Taylor ◽  
Yejia Song ◽  
Thomas Burkart ◽  
John C. Shryock ◽  
...  
Keyword(s):  
Heart Rate ◽  
Action Potential ◽  
Myocardial Contractility ◽  
Human Action ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Force Frequency ◽  
Rate Dependent ◽  
Frequency Relationship

The sarcoplasmic reticular Ca2+ pump (SERCA) is thought to be the primary determinant of heart rate-dependent increases in myocardial contractile [Ca2+]i and force (force–frequency relationship (FFR)), an important mechanism to increase cardiac output. This report demonstrates a rate-dependent role for inward Ca2+ current (ICa) in the human and rat FFR. Human action potential plateau height increased linearly with contractility when heart rate increased in vivo, as measured by monophasic action potential catheter and echocardiography. Rat rate-dependent developed force and cytosolic [Ca2+]i transients were quantified in isolated left ventricular papillary muscles, and ICa and action potential duration in cardiomyocytes. ICa and SERCA measurements better reflected [Ca2+]i and force transients than SERCA activity alone. These data support a direct and (or) indirect contribution to myocardial contractility by ICa at heart rates from approximately 1 to 3–4 Hz (60 to 180–240 bpm) in tandem with SERCA to sustain the typical ‘bell shape’ of the FFR across species.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

2011 ◽  
Vol 300 (2) ◽  
pp. H565-H573 ◽  
Author(s):  
Masahide Harada ◽  
Yukiomi Tsuji ◽  
Yuko S. Ishiguro ◽  
Hiroki Takanari ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Action Potential ◽  
High Frequency ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
High Frequency Stimulation ◽  
Electrophysiological Properties ◽  
Rate Dependent ◽  
Frequency Stimulation ◽  
And Control

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF ( n = 18) and control ( n = 17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs) >1,000 ms but significantly shorter at BCLs <400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17–81%), and conduction velocity was significantly decreased in CHF (by 6–20%). In both groups, high-frequency stimulation (BCLs <150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs <150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

scholarly journals Contribution of L-type Ca2+current to electrical activity in sinoatrial nodal myocytes of rabbits

1999 ◽  
Vol 276 (3) ◽  
pp. H1064-H1077 ◽  
Author(s):  
E. Etienne Verheijck ◽  
Antoni C. G. van Ginneken ◽  
Ronald Wilders ◽  
Lennart N. Bouman
Keyword(s):  
Action Potential ◽  
Calcium Current ◽  
Sodium Current ◽  
Delayed Rectifier ◽  
Current Clamp ◽  
Patch Clamp Technique ◽  
Inward Current ◽  
Delayed Rectifier Current ◽  
Diastolic Depolarization ◽  
Recovery From Inactivation

The role of L-type calcium current ( I Ca,L) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit, with the use of the amphotericin-perforated patch-clamp technique. Nifedipine, at a concentration of 5 μM, was used to block I Ca,L. At this concentration, nifedipine selectively blocked I Ca,L for 81% without affecting the T-type calcium current ( I Ca,T), the fast sodium current, the delayed rectifier current ( I K), and the hyperpolarization-activated inward current. Furthermore, we did not observe the sustained inward current. The selective action of nifedipine on I Ca,L enabled us to determine the activation threshold of I Ca,L, which was around −60 mV. As nifedipine (5 μM) abolished spontaneous activity, we used a combined voltage- and current-clamp protocol to study the effects of I Ca,L blockade on repolarization and diastolic depolarization. This protocol mimics the action potential such that the repolarization and subsequent diastolic depolarization are studied in current-clamp conditions. Nifedipine significantly decreased action potential duration at 50% repolarization and reduced diastolic depolarization rate over the entire diastole. Evidence was found that recovery from inactivation of I Ca,L occurs during repolarization, which makes I Ca,L available already early in diastole. We conclude that I Ca,L contributes significantly to the net inward current during diastole and can modulate the entire diastolic depolarization.

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