不整脈だけを抑え、心機能は守る新しい治療薬候補を開発― Ca²⁺シグナルを選択的に制御する仕組みを解明概要 ―

2026-05-13 順天堂大学

図1：本研究で明らかになったRyanozoleの作用機序
Ryanozoleは、心拡張期に不整脈の原因となる異常なCa²⁺放出のみを抑制し、収縮期には正常なCa²⁺ transientを保つことで、心機能を損なわずに不整脈を抑制する。

＜関連情報＞

• https://www.juntendo.ac.jp/news/26833.html
• https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70459

新規RyR2選択的抑制薬は心機能を損なわずにストレス誘発性不整脈を抑制する A novel selective stabilizer of the ryanodine receptor 2 prevents stress-induced ventricular arrhythmias without impairing cardiac function

Nagomi Kurebayashi, Masami Kodama, Hana Inoue, Masato Konishi, Masami Sugihara, Takashi Murayama, Ryosuke Ishida, Koichiro Ishii, Shuichi Mori, Yukari Endo, Xi Zeng, …
British Journal of Pharmacology  Published: 27 April 2026
DOI:https://doi.org/10.1111/bph.70459

Abstract

Background and Purpose

Aberrant activation of type 2 ryanodine receptors (RyR2) causes lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Developing drugs that suppress RyR2 hyperactivation may be key to novel arrhythmia treatments. This study evaluated the antiarrhythmic potential of Ryanozole, a recently developed novel RyR2 modulator with high affinity and selectivity, using CPVT mouse models harbouring mutant RyR2s.

Experimental Approach

In vitro effects of Ryanozole were evaluated by endoplasmic reticulum (ER) Ca²⁺-based assay and [³H]ryanodine-binding assay using RyR2-expressing HEK293 cells. Two lines of mice with different arrhythmia severities, RyR2-R420W and RyR2-K4750Q, were employed for in vivo and ex vivo assessments. Intracellular Ca²⁺ signals were analysed in isolated cardiomyocytes using Cal-520. Antiarrhythmic effects were evaluated by electrocardiography (ECG) under catecholaminergic challenge in anaesthetized mice and during spontaneous arrhythmias in conscious mice. ECG and echocardiographic parameters were evaluated before and after drug administration.

Key Results

Ryanozole inhibited both wild-type and mutant RyR2s with an IC₅₀ of 15–40 nM. Inhibition was more potent at lower cytosolic Ca²⁺ concentrations. Ryanozole suppressed Ca²⁺ waves and Ca²⁺ sparks without affecting action potential-evoked Ca²⁺ transients. Ryanozole effectively prevented adrenaline-induced arrhythmias and rapidly terminated ongoing spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs.

Conclusion and Implications

Ryanozole preferentially suppresses RyR2 under diastolic Ca²⁺ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca²⁺ release. This mechanism may provide potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a potential therapeutic candidate for RyR2-mediated arrhythmias, such as CPVT.