The Antiarrhythmic Activity of Novel Pyrrolidin-2-one Derivative S-75 in Adrenaline-Induced Arrhythmia.

Klaudia Lustyk,Paula Zaręba,Jacek Sapa,Kinga Sałaciak,Karolina Pytka,Agata Siwek

doi:10.3390/ph14111065

Klaudia Lustyk, Paula Zaręba + Show 4 more

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https://doi.org/10.3390/ph14111065

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Journal: Pharmaceuticals	Publication Date: Oct 20, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Jagiellonian University

Abstract

Arrhythmia is a quivering or irregular heartbeat that can often lead to blood clots, stroke, heart failure, and other heart-related complications. The limited efficacy and safety of antiarrhythmic drugs require the design of new compounds. Previous research indicated that pyrrolidin-2-one derivatives possess an affinity for α1-adrenergic receptors. The blockade of α1-adrenoceptor may play a role in restoring normal sinus rhythm; therefore, we aimed to verify the antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75. In this study, we assessed the influence on sodium, calcium, potassium channels, and β1-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β1-adrenoceptors and weak effects on ion channels decreased the role of these adrenoceptors and channels in the pharmacological activity of S-75. Next, we evaluated the influence of S-75 on normal ECG in rats and isolated rat hearts, and the tested derivative did not prolong the QTc interval, which may confirm the lack of the proarrhythmic potential. We tested antiarrhythmic activity in adrenaline-, aconitine- and calcium chloride-induced arrhythmia models in rats. The studied compound showed prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia, but no significant activity in the model of aconitine- or calcium chloride-induced arrhythmia. In addition, S-75 was not active in the model of post-reperfusion arrhythmias of the isolated rat hearts. Conversely, the compound showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia, reducing post-arrhythmogen heart rhythm disorders, and decreasing animal mortality. Thus, we suggest that the blockade of α1-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia.

Highlights

Cardiovascular diseases are the leading cause of death worldwide—around 17.9 million people die each year from coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other conditions [1]
As the antiarrhythmic effect of S-75 has never been tested, here, we examined whether this compound prevented the occurrence of an abnormal heart rhythm in adrenaline, calcium chloride, and aconitine-induced arrhythmia and reversed the adrenaline-caused irregularities of the heart rhythm
Since S-75 showed prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia, we investigated whether it demonstrates therapeutic antiarrhythmic activity

Summary

Introduction

Cardiovascular diseases are the leading cause of death worldwide—around 17.9 million people die each year from coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other conditions [1]. We distinguish several classifications of arrhythmia, considering either its origin (ventricular or supraventricular) or its effect on the heart rate (tachycardia or bradycardia) [2]. Despite the high prevalence of this heart disease, we still do not have effective and safe antiarrhythmic drugs. All available drugs lead to more or less pronounced proarrhythmic activity manifested by the occurrence of torsades de pointes, the increased number of premature beats, subsequent beats, or reentry disorders [3,4,5,6]. Any compound that increases the duration of the action potential may lead to the development of ventricular tachycardia, and any compound that changes the conduction rate or the refractory period may increase the recurrence of arrhythmias [7]. Patients with an Pharmaceuticals 2021, 14, 1065.

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