1. In vivo cardiovascular profile of ryanodine receptor 2 inhibitor M201-A: Utility as an anti-atrial fibrillatory drug for patients suffering from heart failure with preserved ejection fraction.
- Author
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Kambayashi R, Goto A, Shinozaki M, Izumi-Nakaseko H, Takei Y, Iwata K, Kaneko N, and Sugiyama A
- Subjects
- Animals, Dogs, Male, Heart Atria drug effects, Heart Atria physiopathology, Dose-Response Relationship, Drug, Humans, Female, Ryanodine Receptor Calcium Release Channel metabolism, Atrial Fibrillation drug therapy, Atrial Fibrillation physiopathology, Heart Failure drug therapy, Heart Failure physiopathology, Stroke Volume drug effects, Anti-Arrhythmia Agents pharmacology
- Abstract
Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist; however, clinically available anti-AF drugs can exacerbate symptoms of HFpEF. M201-A suppressed ryanodine receptor-mediated diastolic Ca
2+ leakage, possibly inhibiting common pathological processes toward AF and HFpEF. To bridge the basic information to clinical practice, we assessed its cardiohemodynamic, anti-AF and ventricular proarrhythmic profile using halothane-anesthetized dogs (n = 4). M201-A hydrochloride in doses of 0.03, 0.3 and 3 mg/kg/10 min was intravenously administered, providing peak plasma concentrations of 0.09, 0.81 and 5.70 μg/mL, respectively. The high dose of M201-A showed various cardiovascular actions. Namely, M201-A increased mean blood pressure and tended to enhance isovolumetric ventricular relaxation without suppressing ventricular contraction or decreasing cardiac output. M201-A enhanced atrioventricular conduction, but hardy affected intra-atrial/ventricular conduction. Importantly, M201-A prolonged effective refractory period more potently in the atrium than in the ventricle, indicating that it may become an atrial-selective antiarrhythmic drug. Meanwhile, M201-A prolonged QT interval/QTcV, and showed reverse frequency-dependent delay of ventricular repolarization. M201-A prolonged J-Tpeak c without prolonging Tpeak -Tend or terminal repolarization period, indicating the risk of causing torsade de pointes is negligible. Thus, M201-A is expected to become a hopeful therapeutic strategy for patients having pathology of both AF and HFpEF., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)- Published
- 2024
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