Development of new antiarrhythmic drugs alternative to beta blocker therapy

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K18973
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Tsurumi University (2016-2018); Yokohama City University (2015)
• Principal Investigator: Suita Kenji 鶴見大学, 歯学部, 学部助手 (90569542)
• Research Collaborator: ISHIKAWA Yoshihiro ; OKUMURA Satoshi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 不整脈 / 分子標的薬 / ベータアドレナリン受容体 / アデニル酸シクラーゼ / cAMP / Epac

Outline of Final Research Achievements

Excessive and chronic activation of sympathetic beta-adrenergic receptor (β-AR) signal are known to be a trigger of arrhythmias. In this study, we focus on the cardiac subtype of adenylate cyclase (AC) and exchanged protein directly activated by cAMP (Epac), a cAMP target protein, that mediates the β-AR signaling. We used the gene knockout mice to determine the role of both factors in arrhythmogenesis. Further, antiarrhythmic effect and adverse effects on cardiac function of inhibitors selective for cardiac AC and Epac1 subtypes were compared with a β-blocker. As a result, arrhythmia onset was significantly suppressed in AC5 and Epac1 knockout mice as compared to control mice. In addition, it has been clarified that inhibitors of both molecules prevented arrhythmias without deteriorating heart function as observed in β-blocker-treated mice.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

β遮断薬は交感神経の過剰亢進による不整脈の治療に使用されてきたが、心機能を低下させる副作用は特に高齢者にとって問題である。超高齢社会をむかえたわが国において、副作用が少なく高齢者に安心して処方できる不整脈治療法の開発は重要な課題である。本研究の結果から、β受容体シグナル伝達経路を仲介する細胞内因子である心臓型AC5やEpac1をターゲットとした治療薬が、上記の要求を満たす有望な候補であることが明らかとなった。