A novel selective stabilizer of the ryanodine receptor 2 prevents stress‐induced ventricular arrhythmias without impairing cardiac function
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: 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: 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: 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.
Authors
- Yukari Endo (ORCID: https://orcid.org/0000-0002-6059-3245)
- Utako Yokoyama (ORCID: https://orcid.org/0000-0003-1803-0155)
- Yukiko Inoue (ORCID: https://orcid.org/0000-0002-4105-9127)
- Takayuki Oka (ORCID: https://orcid.org/0009-0000-1677-4586)
- S. Noguchi (ORCID: https://orcid.org/0000-0001-6165-3716)
- Hiroyuki Kagechika (ORCID: https://orcid.org/0000-0002-6747-1013)
- Ryosuke Ishida (ORCID: https://orcid.org/0000-0003-2840-7905)
- N Suzuki
- Nagomi Kurebayashi (ORCID: https://orcid.org/0000-0002-5005-9698)
- Takashi Murayama (ORCID: https://orcid.org/0000-0002-3845-2980)
- Xi Zeng (ORCID: https://orcid.org/0000-0001-7379-8410)
- Hiroyuki Kusuhara (ORCID: https://orcid.org/0000-0002-3641-8746)
- Junko Kurokawa (ORCID: https://orcid.org/0000-0002-9098-0908)
- Haruo Ogawa (ORCID: https://orcid.org/0000-0001-5515-1533)
- Kayoko Kanamitsu (ORCID: https://orcid.org/0000-0002-7576-9389)
- Masato Konishi (ORCID: https://orcid.org/0000-0003-3405-3357)
- Eri Nakashima
- Hajime Nishio
- Masami Kodama (ORCID: https://orcid.org/0000-0002-4615-3534)
- Masami Sugihara (ORCID: https://orcid.org/0000-0002-8014-4850)
- Y. Otori
- Koichiro Ishii (ORCID: https://orcid.org/0009-0005-6604-027X)
- Mirei Takahashi
- Hana Inoue (ORCID: https://orcid.org/0000-0002-2278-5617)
- Ayuna Tsutsumi
- Noriko Nakaya
- Ryushi Sato
- Shuichi Mori
- Takayoshi Inoue
- Takashi Sakurai
Institutions
- Hyogo Medical University (JP)
- University of Shizuoka (JP)
- Tokyo Medical University (JP)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- Juntendo University (JP)
- Joyson Safety Systems (Japan) (JP)
- National Center of Neurology and Psychiatry (JP)
- The University of Tokyo (JP)
- Hyogo University (JP)
Publication Details
- Journal
- British Journal of Pharmacology
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1111/bph.70459
- Primary Topic
- Cardiac electrophysiology and arrhythmias
- Type
- article
- Field-Weighted Citation Impact
- 0.00