phkineticaФармакокинетика и ФармакодинамикаPharmacokinetics and Pharmacodynamics2587-78362686-8830ООО «Издательство ОКИ»10.37489/2587-7836-2023-3-56-67phkinetica-382Research ArticleДОКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ ФАРМАКОДИНАМИКИPRECLINICAL PHARMACODYNAMICS STUDIESОсобенности антиаритмического действия соединения АЛМ-802Features of the compound ALM-802 antiarrhythmic actionhttps://orcid.org/0000-0003-4229-3107БарчуковВ. В.BarchukovV. V.

Барчуков Владимир Валерьевич - н. с. лаборатории фармакологического скрининга

Москва

Vladimir V. Barchukov - Research scientist of laboratory of pharmacological screening

Moscow

barchukov.pharm@yandex.ruhttps://orcid.org/0000-0002-1990-3803ЗинченкоВ. П.ZinchenkoV. P.

Зинченко Валерий Петрович - д. б. н., зав. лабораторией внутриклеточной сигнализации

Пущино

Valery P. Zinchenko - Dr. Sci. (Biol.), Head of laboratory of intracellular signaling

Pushchino

vpz@mail.ruhttps://orcid.org/0000-0002-3988-7724ЦоринИ. Б.TsorinI. B.

Цорин Иосиф Борисович - д. б. н., в. н. с. лаборатории фармакологического скрининга

Москва

Iosif B. Tsorin - Dr. Sci. (Biology), Leading researcher of laboratory of pharmacological screening

Moscow

tsorinib@yandex.ruhttps://orcid.org/0000-0001-8333-2294ТепловИ. Ю.TeplovI. Yu.

Теплов Илья Юрьевич - к. б. н., н. с. лаборатории внутриклеточной сигнализации

Пущино

Ilya Yu. Teplov - PhD, Cand. Sci. (Biology), Researcher of laboratory of intracellular signaling

Pushchino

t.i.y@mail.ruhttps://orcid.org/0000-0002-4779-427XСтолярукВ. Н.StolyarukV. N.

Столярук Валерий Николаевич - к. м. н., с. н. с. лаборатории фармакологического скрининга

Москва

Valeriy N. Stolyaruk - PhD, Cand. Sci. (Med.), Senior researcher scientist of laboratory of pharmacological screening

Moscow

vns539@yandex.ruhttps://orcid.org/0000-0002-7407-7516ВититноваМ. Б.VititnovaM. B.

Вититнова Марина Борисовна - к. б. н., с. н. с. лаборатории фармакологического скрининга

Москва

Marina B. Vititnova - PhD, Cand. Sci. (Biology), Senior researcher scientist of laboratory of pharmacological screening

Moscow

MB-Vit@yandex.ruhttps://orcid.org/0000-0003-2617-0334МокровГ. В.MokrovG. V.

Мокров Григорий Владимирович - к. х. н., в. н. с. лаборатории тонкого органического синтеза отдела химии лекарственных средств

Москва

Grigory V. Mokrov - PhD, Cand. Chemical Sci., Leading researcher of the fine organic synthesis laboratory at the drug chemistry department

Moscow

g.mokrov@gmail.comhttps://orcid.org/0000-0003-2832-4739КрыжановскийС. АKryzhanovskiiS. A.

Крыжановский Сергей Александрович - д. м. н., зав. лабораторией фармакологического скрининга

Москва

Sergey A. Kryzhanovskii - Dr. Sci (Med.), Head of laboratory of pharmacological screening

Moscow

SAK-538@yandex.ruФГБНУ «НИИ фармакологии имени В.В. Закусова»РоссияFSBI “Research Zakusov Institue of Pharmacology”Russian FederationФГБУН «Институт биофизики клетки Российской академии наук» (ИБК РАН)РоссияInstitute of Cell Biophysics of the Russian Academy of Sciences (ICB RAS)Russian Federation202303112023035667Copyright © Барчуков В.В., Зинченко В.П., Цорин И.Б., Теплов И.Ю., Столярук В.Н., Вититнова М.Б., Мокров Г.В., Крыжановский С.А., 20232023Барчуков В.В., Зинченко В.П., Цорин И.Б., Теплов И.Ю., Столярук В.Н., Вититнова М.Б., Мокров Г.В., Крыжановский С.А.Barchukov V.V., Zinchenko V.P., Tsorin I.B., Teplov I.Y., Stolyaruk V.N., Vititnova M.B., Mokrov G.V., Kryzhanovskii S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacokinetica.ru/jour/article/view/382Введение

Введение. Сердечно-сосудистые заболевания (ССЗ) остаются одной из главных причин смерти во всем мире, ежегодно унося более 17 млн жизней. В связи с этим возникает актуальная задача — создание инновационных лекарств для борьбы с ССЗ. Одной из потенциальных мишеней для таких препаратов являются рианодиновые рецепторы 2 типа (RyR2), так как известно, что они играют важную роль в поддержании гомеостаза ионов Ca2+ в кардиомиоцитах, а их аномальная активность играет одну из ключевых ролей в генезе нарушений сердечного ритма.

Цель исследования — изучить механизмы, лежащие в основе антиаритмического действия АЛМ-802.

Методы

Методы. На первом этапе были проведены эксперименты in vivo с использованием моделей аконитиновой, хлоридкальциевой, хлоридбариевой и реперфузионных аритмий для оценки антиаритмического эффекта соединения АЛМ-802. На втором этапе исследования в электрофизиологических экспериментах, выполненных на клетках гиппокампа новорождённых крыс, оценивали влияние соединения AЛM-802 на потенциалзависимые трансмембранные ионные Na+–, К+– и Ca2+–каналы, а также его влияние на внутриклеточную концентрацию ионов Ca2+. В экспериментах, выполненных на изолированной полоске миокарда, оценивали влияние соединения АЛМ-802 на активность RyR2.

Результаты

Результаты. В экспериментах in vivo соединение АЛМ-802 (2 мг/кг, в/в) на вышеприведённых моделях проявляет выраженную антиаритмическую активность, сопоставимую/превосходящую таковую, показанную для эталонных препаратов прокаинамид, верапамил и амиодарон. В экспериментах in vitro показано, что АЛМ-802 (69,8 µM) инициирует инактивацию ионных K+- и Na+-каналов и не влияет на активность ионных каналов Ca2+. Соединение АЛМ-802 эффективно предотвращает увеличение концентрации ионов Ca2+ в цитозоле во время деполяризации. Кроме того, в экспериментах на изолированной полоске миокарда показано, что соединение АЛМ-802 (5×10–5 М) блокирует RyR2.

Заключение

Заключение. Таким образом, по спектру антиаритмической активности соединение АЛМ-802 сочетает в себе свойства антиаритмических лекарственных средств IA или IC и III классов по классификации Е.М. Vaughan Williams. Помимо этого, соединение АЛМ-802 проявляет антагонистическую активность в отношении RyR2. Последнее представляется также достаточно важным, поскольку известно, что в условиях патологии миокарда аномальная активность RyR2 инициирует диастолическую утечку ионов Са2+ из цистерн СПР, что влечёт за собой снижение инотропной функции левого желудочка сердца и значительно повышает риск развития злокачественных нарушений сердечного ритма.

Introduction

Introduction. Cardiovascular diseases (CVD) remain one of the leading causes of death worldwide, claiming over 17 million lives annually. This highlights the urgent need to develop innovative drugs to combat CVD. One potential target for such drugs is type 2 ryanodine receptors (RyR2), as they play an important role in maintaining ion homeostasis in cardiomyocytes, and their abnormal activity plays a key role in the genesis of cardiac arrhythmias.

Research objective is to study the mechanisms underlying the antiarrhythmic action of ALM-802.

Methods

Methods. In the first stage, in vivo experiments were performed using models of aconitine, calcium chloride, barium chloride arrhythmia, and reperfusion arrhythmias to evaluate the antiarrhythmic effect of the compound ALM-802. The second stage of the study involved electrophysiological experiments performed on hippocampal cells of newborn rats to evaluate the effect of the compound on voltage-gated transmembrane Na+, K+, and Ca2+ ion channels, as well as its effect on intracellular ion concentration of Ca2+. Experiments performed on an isolated myocardial strip evaluated the effect of the compound ALM-802 on the activity of RyR2.

Results

Results. In in vivo experiments, the compound ALM-802 (2 mg/kg, iv) exhibits significant antiarrhythmic activity comparable/superior to that shown by the reference drugs procainamide, verapamil, and amiodarone on the models mentioned above. In in vitro experiments, it was shown that ALM-802 (69.8 µM) initiates the inactivation of K+ and Na+ ion channels and does not affect the activity of Ca2+ ion channels. The compound ALM-802 effectively prevents the increase of Ca2+ ion concentration in the cytosol during depolarization of contraction. In addition, experiments on isolated myocardial strips showed that the compound ALM-802 (5x10-5 M) blocks RyR2.

Conclusion

Conclusion. Thus, based on the spectrum of its antiarrhythmic activity, the compound ALM-802 combines the properties of antiarrhythmic drugs of class IA or IC and class III according to the E.M. Vaughan Williams classification. In addition, the ALM-802 compound exhibits antagonistic activity towards RyR2. The latter is also considered significant, as it is known that under conditions of myocardial pathology, abnormal activity of RyR2 initiates diastolic leakage of Ca2+ ions from the sarcoplasmic reticulum cysterns, which leads to a decrease in the inotropic function of the left ventricle of the heart and significantly increases the risk of developing malignant cardiac arrhythmias.

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The authors declare that there are no conflicts of interest present.