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.

Electrophysiologic effects of FPL 13210 on canine Purkinje fiber action potential duration and Vmax comparison to disopyramide

1991 ◽  
Vol 5 (1) ◽  
pp. 139-146 ◽  
Author(s):  
T. K. Knilans ◽  
A. Varró ◽  
P. P. Nánási ◽  
R. J. Murray ◽  
F. C. Kaiser ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Purkinje Fiber ◽  
Fiber Action

Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers

1989 ◽  
Vol 67 (7) ◽  
pp. 710-721 ◽  
Author(s):  
Matthew A. Flemming ◽  
Betty I. Sasyniuk
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Refractory Period ◽  
Drug Effect ◽  
Effective Refractory Period ◽  
Slow Inactivation ◽  
Purkinje Fibers ◽  
Rate Dependent

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on [Formula: see text] but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 ± 535 ms and 15.7 ± 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when [Formula: see text] depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.

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.

scholarly journals Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations

2010 ◽  
Vol 105 (3) ◽  
pp. 315-323 ◽  
Author(s):  
László Bárándi ◽  
László Virág ◽  
Norbert Jost ◽  
Zoltán Horváth ◽  
István Koncz ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Rate Dependent
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