Article
作者: Hasunuma, Tomoko ; Nakamura, Masahiko ; Sugiyama, Atsushi ; Taguchi, Isao ; Kambayashi, Ryuichi ; McCarroll, Charlotte S ; Dobi, Sara ; Kikuchi, Migaku ; Otani, Naoyuki ; Mitsuhisa, Yamano ; Matsuda, Ryuko ; Riddell, Alexandra ; Kusano, Kengo ; Smith, Godfrey ; Kaneko, Noboru ; Kayley, Scott ; Loughrey, Christopher M ; Martin, Tamara P ; Ishikawa, Tetsuya ; Inoue, Yuko ; Kumagai, Yuji ; Fujiwara, Toshihiko ; Hirano, Sayuri ; Shimamoto, Ken ; Toda, Masashi ; Da Silva Costa, Ana ; Toyoda, Shigeru ; Shinozaki, Makoto ; Mark, Patric B ; Sakai, Toshiya ; Saxena, Priyanka ; Elliott, Elspeth B ; Kitai, Takeshi ; Iwata, Kunio
BACKGROUND AND PURPOSEThe ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.EXPERIMENTAL APPROACHFollowing the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.KEY RESULTSIn rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.CONCLUSIONS AND IMPLICATIONSThe novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.