Modulation of the effects of sotalol on Purkinje strand electromechanical characteristics

1989 ◽  
Vol 67 (11) ◽  
pp. 1463-1467 ◽  
Author(s):  
David A. Lathrop ◽  
András Varró
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Potassium Conductance ◽  
Channel Blockers ◽  
Early Afterdepolarizations ◽  
Force Development ◽  
Transmembrane Action Potential ◽  
Potassium Channel Activator ◽  
Cardiac Sodium Channels ◽  
Arrhythmogenic Effects

The modulation of the effects of sotalol (30 μM) by two sodium channel blockers, tetrodotoxin (0.07 μM) and lidocaine (50 μM), and by a potassium channel activator, nicorandil (30 μM), were examined. Sotalol alone greatly increased Purkinje fiber transmembrane action potential duration and, in some preparations, induced early afterdepolarizations. Concurrent with the changes in action potential duration, sotalol also increased isolated Purkinje strand developed force paced at slow rates (0.33 Hz). These sotalol-induced alterations of Purkinje strand electromechanical characteristics were similar to those produced by either veratrine (0.6 or 1.0 μg/mL) or by tetraethylammonium (10 mM). The effects of sotalol on action potential duration and force development were reversed by exposure to either tetrodotoxin or nicorandil. Lidocaine also reversed the effects of sotalol on action potential duration and developed force. The sotalol-induced increase in action potential duration and development of early afterdepolarizations may, therefore, be abated by combination with drugs that either block cardiac sodium channels or that increase membrane potassium conductance. Combination with such drugs may help prevent the adverse arrhythmogenic effects of sotalol.Key words: sotalol, lidocaine, action potential duration, nicorandil, force development, tetrodotoxin.

Termination of Action Potential Due to Site Selective Ion Channel Blockers

2019 ◽  
Vol 19 (02) ◽  
pp. 2050015
Author(s):  
Krishnendu Pal ◽  
Gautam Gangopadhyay
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Ionic Current ◽  
Channel Blockers ◽  
Quiescent State ◽  
Ion Channel Blockers ◽  
Different Types ◽  
Site Selective

Here, we have provided a qualitative theoretical description about how the action potential generation and its associated intrinsic properties such as ionic current, spiking frequency, action potential duration, gating dynamics, etc. are affected due to site selective ion channel blockers, by suitably adapting Gillespie’s stochastic simulation technique to an extended Hodgkin–Huxley Markov model, representing a very basic type of neuron. Considering different types and degrees of blocking potency of channel blockers to channel proteins, we have found that the nature of action potential termination process and corresponding ionic current profiles are very distinct from each other. With the increasing blocking affinity, the frequency of action potential spiking falls off exponentially in presence of sodium channel only blockers and dual type blockers having more sodium binding potency than potassium blockers, whereas in contrast, for potassium channel only blockers, dual type blockers having equal or higher potassium blocking affinity with respect to sodium blocking, the spiking frequency initially is enhanced followed by a gradual decrease due to the competition between channel number fluctuation and overall sodium and potassium conductances. Sodium channel blockers tend to shorten the action potential duration while the potassium channel blockers broaden it. The channel gating dynamics are also found to be changed drastically for different types of blockers. The final quiescent state arrival time and the quiescent state membrane voltage profiles show distinct features for different types of channel blockers with different applied external stimulus. Finally, we showed how consistent our results are with the existing literature of experimentally observed channel blocking effects in diverse systems and compared the similarities, dissimilarities and advantages of our model with an existing theoretical drug binding model with Langevin description. Our approach provides a qualitative pathway to investigate the effects of many other types of blocking mechanisms such as closed state, inactivated state blocking with desired level of structural and functional details.

scholarly journals Oxidative shift in tissue redox potential increases beat-to-beat variability of action potential duration

2015 ◽  
Vol 93 (7) ◽  
pp. 563-568 ◽  
Author(s):  
Kornél Kistamás ◽  
Bence Hegyi ◽  
Krisztina Váczi ◽  
Balázs Horváth ◽  
Tamás Bányász ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Action Potential ◽  
Redox Potential ◽  
Cardiac Arrhythmias ◽  
Action Potential Duration ◽  
Detectable Effect ◽  
Short Term ◽  
Early Afterdepolarizations ◽  
Short Term Variability ◽  
Reduced State

Profound changes in tissue redox potential occur in the heart under conditions of oxidative stress frequently associated with cardiac arrhythmias. Since beat-to-beat variability (short term variability, SV) of action potential duration (APD) is a good indicator of arrhythmia incidence, the aim of this work was to study the influence of redox changes on SV in isolated canine ventricular cardiomyocytes using a conventional microelectrode technique. The redox potential was shifted toward a reduced state using a reductive cocktail (containing dithiothreitol, glutathione, and ascorbic acid) while oxidative changes were initiated by superfusion with H2O2. Redox effects were evaluated as changes in “relative SV” determined by comparing SV changes with the concomitant APD changes. Exposure of myocytes to the reductive cocktail decreased SV significantly without any detectable effect on APD. Application of H2O2 increased both SV and APD, but the enhancement of SV was the greater, so relative SV increased. Longer exposure to H2O2 resulted in the development of early afterdepolarizations accompanied by tremendously increased SV. Pretreatment with the reductive cocktail prevented both elevation in relative SV and the development of afterdepolarizations. The results suggest that the increased beat-to-beat variability during an oxidative stress contributes to the generation of cardiac arrhythmias.

Stretch-induced changes in arrhythmogenesis and excitability in experimentally based heart cell models

1998 ◽  
Vol 275 (2) ◽  
pp. H431-H442 ◽  
Author(s):  
Tara L. Riemer ◽  
Eric A. Sobie ◽  
Leslie Tung
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Linear Time ◽  
Reversal Potential ◽  
Resting Potential ◽  
Heart Cell ◽  
Excitation Threshold ◽  
Early Afterdepolarizations ◽  
Increased Risk ◽  
Induced Changes

Mechanoelectric coupling in the heart is well documented and has been suggested as a cause of arrhythmia. One hypothesized mechanism for the stretch sensitivity of cardiac muscle is the presence of stretch-activated channels (SACs). This study uses modeling to explore the influence of SACs on cardiac resting potential, excitation threshold, and action potential in the context of arrhythmia. We added a putative SAC, modeled as a linear, time-independent conductance with reversal potential of −20 or −50 mV, to guinea pig and frog ventricular membrane models. Increased stretch conductance led to resting potential depolarization, a decreased excitation threshold, altered action potential duration, and, under certain conditions, early afterdepolarizations. We conclude that stretch increases cellular excitability, making the heart prone to ectopic activity. Regional effects of stretch on action potential duration can vary and are influenced by factors such as the SAC reversal potential, ionic conditions, and baseline currents, all of which may lead to an increased dispersion of refractoriness throughout the heart and therefore an increased risk of arrhythmia.

Effects of Morphine and Meperidine on Action Potential Production in Frog's Skeletal Muscle Fibers

1975 ◽  
Vol 53 (1) ◽  
pp. 92-96 ◽  
Author(s):  
G. B. Frank ◽  
H. S. Buttar
Keyword(s):  
Skeletal Muscle ◽  
Action Potential ◽  
Action Potential Duration ◽  
Muscle Fibers ◽  
Potassium Conductance ◽  
Potential Production ◽  
Skeletal Muscle Fibers ◽  
Adequate Stimulus ◽  
Specific Increase ◽  
Secondary Rise

Morphine (3.3 × 10−4–33 × 10−4 M) and meperidine (8.8 × 10−5–35 × 10−5 M) inhibited action potential production in frog's skeletal muscle fibers. Over these concentration ranges, neither the resting membrane potentials nor the resting membrane electric properties of the fibers appeared to be modified. Both drugs depressed excitability and the rising phase of the action potential by inhibiting the specific increase in sodium conductance which normally follows an adequate stimulus. Both drugs also seemed to inhibit the secondary rise in potassium conductance which normally occurs during an action potential, causing a prolongation of the action potential duration.

Electromechanical characterization of the effects of racemic sotalol and its optical isomers on isolated canine ventricular trabecular muscles and Purkinje strands

1985 ◽  
Vol 63 (12) ◽  
pp. 1506-1512 ◽  
Author(s):  
David A. Lathrop
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Torsade De Pointes ◽  
Optical Isomers ◽  
Maximal Increase ◽  
Beta Adrenergic ◽  
Force Development ◽  
Rate Dependent ◽  
Adrenergic Blockers ◽  
Fiber Action

In both isolated canine ventricular trabecular muscle and Purkinje strand preparations, dl-sotalol and its two optical isomers d- and l-sotalol produced a concentration-dependent increase in action potential duration while other transmembrane electrical characteristics were not significantly affected. The magnitude of the increase in action potential durations was greater in Purkinje strand preparations. In Purkinje strand preparations, the effect was rate dependent (i.e., the increase in duration was proportionately greater when stimulation frequency was slowed). From the concentration of each compound calculated to produce a 50% maximal increase in Purkinje fiber action potential durations, d-sotalol appeared to be one to three times more potent than either l-sotalol or the racemate. Each compound appeared to increase force development in ventricular trabecular muscle preparations stimulated at a frequency of 2 Hz. Increased force development was only observed in Purkinje strand preparations stimulated at slower rates (0.5–0.33 Hz). These results are unlike those produced by other beta-adrenergic blockers and suggest that the antiarrhythmic effects of sotalol are related primarily to its effect of action potential duration. The estimated potency ratios established for the effect of dl-sotalol and its optical isomers on both trabeculae and Purkinkje fiber action potential durations (d > dl − l) may indicate that these effects are unrelated to the beta-adrenergic blocking properties of these compounds. The differential effect of sotalol on isolated trabeculae and Purkinje strand preparations may help to explain the clinically reported phenomenon of sotalol-induced torsade de pointes.

Sodium- and Calcium-Dependent Mechanisms in the Action Potential of the Secretory Epithelium of a Clam Mantle

1989 ◽  
Vol 145 (1) ◽  
pp. 395-402
Author(s):  
PAULO S. BEIRÃO ◽  
JOSÉ HAMILTON M. NASCIMENTO
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Calcium Channel Blockers ◽  
Local Anesthetics ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Basolateral Membrane ◽  
Channel Blockers ◽  
Calcium Dependent ◽  
Repolarization Phase

The secretory epithehum of the mantle of the clam Anomalocardia brasiliana is excitable. The ionic dependence of its action potentials was investigated. Two distinct phases could be recognized by their ionic dependences. The early spike phase, that appeared in all action potentials, was dependent on the Na+ concentration of the solution in the interstitial space and was insensitive to tetrodotoxin (TTX) at concentrations as high as 36μmol l−1. It was inhibited by local anesthetics, and its repolarization was inhibited by veratrine. The data show this electrogenesis is caused by TTX-insensitive sodium channels located at the basolateral membrane of this epithelium. Cardiac-like action potentials were recorded in several specimens: the rapid Na+-dependent spike was followed by a slower repolarization phase that formed a plateau and increased the action potential duration. The plateau amplitude was markedly increased when the external Ca2+ concentration was increased to (60 mmol l−1 and it was inhibited by the addition of inorganic calcium channel blockers such as Mn2+ and Cd2+. These observations suggest that inward Ca2+ currents cause the sustained depolarization during the plateau.

scholarly journals Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias

2018 ◽  
Author(s):  
Kazuharu Furutani ◽  
Kunichika Tsumoto ◽  
I-Shan Chen ◽  
Kenichiro Handa ◽  
Yuko Yamakawa ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Arrhythmias ◽  
Action Potential Duration ◽  
Potassium Current ◽  
Low Voltage ◽  
Sodium Current ◽  
Ionic Current ◽  
Delayed Rectifier ◽  
Early Afterdepolarizations ◽  
Herg Channels

AbstractFatal cardiac arrhythmias are caused by some, but not all, drugs that inhibit the cardiac rapid delayed-rectifier current (IKr) by blocking hERG channels. Here, we propose a novel mechanism that could make certain hERG blockers less proarrhythmic. Several drugs that block hERG channels, yet have favorable cardiac safety profiles, also evoke another effect; they increase the current amplitude upon low-voltage depolarization (facilitation). Voltage-clamp recordings of hERG block and facilitation by nifekalant, a Class III antiarrhythmic agent, constrained a model of human cardiac IKr. In human ventricular action potential simulations, nifekalant showed its therapeutic ability to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evoked early afterdepolarizations, which cause lethal arrhythmias. Facilitation prevented early afterdepolarizations at the same degree of block by increasing IKr during repolarization phase of action potentials. Thus, facilitation is proposed to reduce the arrhythmogenic risk of hERG blockers.AbbreviationsAP: action potential; APD: action potential duration; APD90: action potential duration measured at 90% repolarization; EAD: early afterdepolarization; hERG: human ether-ago-go-related gene; ICaL: L-type Ca2+ channel current; Inet: net ionic current; IK1: inward-rectifier potassium current; IKr: rapid component of the delayed-rectifier potassium current; INa: sodium current; ORd: O’Hara-Rudy dynamic

scholarly journals Influence of Glucose on the Transmembrane Action Potential of Anoxic Papillary Muscle

1965 ◽  
Vol 48 (5) ◽  
pp. 887-899 ◽  
Author(s):  
Don P. MacLeod ◽  
E. E. Daniel
Keyword(s):  
Action Potential ◽  
Papillary Muscle ◽  
Glucose Concentration ◽  
Action Potential Duration ◽  
Marked Reduction ◽  
Force Of Contraction ◽  
Reduction In Force ◽  
Transmembrane Action Potential ◽  
Induced Changes ◽  
Effect Of Glucose

The response of the cat papillary muscle to anoxia has been found to alter depending on the glucose concentration in the medium. At a glucose concentration of 5 mM anoxia caused a marked reduction in force of contraction and action potential duration within 20 minutes. At a glucose concentration of 50 mM anoxia induced similar changes in the force of contraction but little or no change in action potential duration. Elevation of glucose concentration during an anoxic interval reversed the anoxia-induced changes in action potential but had little effect on force of contraction. This effect of glucose could be partially duplicated by xylose and 2-deoxyglucose and in addition, 2-deoxyglucose has been found to prevent the effect of subsequently added glucose. These sugars appear to be transported by a system responsible for glucose transport but are not metabolized to any extent. It would appear therefore that transport of glucose is in some way related to transport of potassium as increased potassium permeability is thought by many to be responsible for anoxia-induced changes in action potential duration.

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