Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model: Influence of non-cardiac alpha(1)-adrenergic receptors

作者：Mow Tomas; Frederiksen Kristen; Thomsen Morten B^*

来源：European Journal of Pharmacology, 2015, 748: 10-17.

DOI：10.1016/j.ejphar.2014.12.012

• Cardiac arrhythmia
• Action potentials
• Adrenergic receptors
• Animal model

Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (I-Kr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs with comparable I-Kr-blocking characteristics. The reduced pro-arrhythmic properties of antipsychotic drugs has been attributed to a variety of different causes e.g., effects on alpha(1)-adrenergic receptors, beta-adrenergic receptors, muscarinic receptors or cardiac ion channels like Ca2+- and Na+ -channels. Since only limited experimental information exists about the effects of alpha(1)-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this In this study we show that four antipsychotic drugs all have high affinity for alpha(1)-adrenergic receptor (sertindole > risperidone > haloperidol > olanzapine) and all block I-Kr (sertindole > haloperidol > risperidone > olanzapine). In canine Purkinje fibres, alpha(1)-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed for the first time in an in vivo pro-arrhythmic rabbit model that several antipsychotic drugs in accordance with their known alpha(1)-adrenergic receptor blocking properties reduced the incidence of drug induced TdP and that the overall ability of the antipsychotic drugs to prevent TdP was associated with prevention of methoxamine induced increase in blood pressure. Further investigations are required to clarify the relative importance of alpha(1)-adrenergic receptor antagonism in conjunction with the additional effects of antipsychotic drugs on various receptors and ion channels.

• 出版日期2015-2-5