Lustyk Klaudia, Sałaciak Kinga, Zaręba Paula, Siwek Agata, Sapa Jacek, Pytka Karolina
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Department of Physiochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Pharmaceuticals (Basel). 2021 Oct 20;14(11):1065. doi: 10.3390/ph14111065.
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 α-adrenergic receptors. The blockade of α-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 β-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β-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 QT 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 α-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia.
心律失常是一种心跳颤动或不规则的情况，常常会导致血液凝块、中风、心力衰竭以及其他与心脏相关的并发症。抗心律失常药物有限的疗效和安全性需要设计新的化合物。先前的研究表明，吡咯烷-2-酮衍生物对α-肾上腺素能受体具有亲和力。α-肾上腺素能受体的阻断可能在恢复正常窦性心律中发挥作用；因此，我们旨在验证新型吡咯烷-2-酮衍生物S-75的抗心律失常活性。在本研究中，我们评估了其对钠、钙、钾通道以及β-肾上腺素能受体的影响，以研究S-75的作用机制。对β-肾上腺素能受体缺乏亲和力以及对离子通道的微弱作用降低了这些肾上腺素能受体和通道在S-75药理活性中的作用。接下来，我们评估了S-75对大鼠正常心电图和离体大鼠心脏的影响，测试的衍生物并未延长QT间期，这可能证实其缺乏促心律失常的潜力。我们在大鼠肾上腺素、乌头碱和氯化钙诱导的心律失常模型中测试了抗心律失常活性。所研究的化合物在肾上腺素诱导的心律失常中显示出预防性抗心律失常活性，但在乌头碱或氯化钙诱导的心律失常模型中无显著活性。此外，S-75在离体大鼠心脏再灌注后心律失常模型中无活性。相反，该化合物在肾上腺素诱导的心律失常中显示出治疗性抗心律失常特性，减少心律失常后心脏节律紊乱，并降低动物死亡率。因此，我们认为α-肾上腺素能受体的阻断可能有助于恢复肾上腺素诱导的心律失常中的正常心律。
