Generating and influencing Torsades de Pointes--like polymorphic ventricular tachycardia in isolated guinea pig hearts.
Torsades de Pointes (TdP) is a polymorphic ventricular arrhythmia which can degenerate into ventricular fibrillation. The most typical symptom of TdP is the ECG morphology where QRS complexes seem to rotate around the isoelectric baseline. Bradycardia and delayed repolarization are regarded as pathophysiologic predispositions. For better understanding of the pathophysiology and the evaluation of therapeutic or proarrhythmic potential of drugs, a functional experimental model is needed. In the present study, an experimental model of polymorphic tachyarrhythmias taken as TdP equivalents in isolated guinea pig hearts was developed. The hearts were perfused by the Langendorff technique. Bradycardia was induced by dissection of the sinus node, and prolongation of the QT interval by infusion of two inhibitors of the sodium channel inactivation, veratridine and DPI 201-106. TdP equivalents were triggered reproducibly by application of electrical single stimuli at the end of the T wave. Experiments with different concentrations of the channel active substances alone and in combination, with different perfusion times and mode of electrical stimulation (single pulse versus train stimulation), showed the highest incidence for TdP equivalents by means of an initial 30 min long infusion of 0.5 microM each veratridine and DPI 201-106 in combination with electrical single stimuli. After finishing the infusion with the channel active substances but still with lasting effects from them. TdP equivalents were triggered repeatedly in five of six experiments. The reasons for this increased TdP susceptibility after finishing the infusion are not known. In a separate series of six similarly arranged experiments, the incidence for TdP equivalents could be decreased from 83% to 12.5% (p < 0.001) by increasing the concentration of magnesium in the perfusate from 1.17 to 5.0 mM. With these experiments, the clinically known therapeutic effect of magnesium suppressing TdP could be demonstrated in an in vitro model for the first time. The results suggest that this model could be used as a base for further studies of clinical relevant drugs, especially antiarrhythmic agents, to obtain hints of possible risks of proarrhythmic effects or of suitability for therapeutic use at TdP attacks.
Department of Veterinary Pharmacology, Bern, Switzerland.
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Gerhardy
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Scholtysik
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Schaad
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Haltiner
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Hess
D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D016171:Torsades de Pointes / Q000503:physiopathology*; D014701:Veratridine / Q000627:therapeutic use
D002316:Cardiotonic Agents; D010879:Piperazines; D014701:Veratridine; C046261:DPI 201-106; D008274:Magnesium