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Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced arrhythmias without adverse effect on heart function in mice

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias. In atrial and ventricular myocytes, vidarabine inhibits adrenergic receptor stimulation-induced RyR2 phosphorylation, sarcoplasmic reticulum (SR) Ca2+ leakage, and spontaneous Ca2+ release from SR, the last of which has been considered as a potential arrhythmogenic trigger. Moreover, vidarabine also inhibits sympathetic activation-induced reactive oxygen species (ROS) production in cardiac myocytes. The pivotal role of vidarabine’s inhibitory effect on ROS production with regard to its anti-arrhythmic property has also been implied in animal studies. In addition, as expected, vidarabine exerts an inhibitory effect on AC function, which is more potent in the heart than elsewhere. Indexes of cardiac function including ejection fraction and heart rate were not affected by a dosage of vidarabine sufficient to exert an anti-arrhythmic effect. These findings suggest that vidarabine inhibits catecholamine-induced AF or ventricular arrhythmia without deteriorating cardiac function in mice.

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Abbreviations

AC:

adenylyl cyclase

AF:

atrial fibrillation

β-AR:

β-adrenergic receptor

Fsk:

forskolin

ISO:

isoproterenol

Metoprolol:

(RS)-1-(isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol

NAC:

N-acetyl-L-cysteine

NE:

norepinephrine

RyR:

ryanodine receptor

Tempol:

1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine

Vidarabine:

9-β-D-arabinofuranosyladenine

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Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (24790219, 15K18973 to K.S., 25460296, 16K08501 to T.F., 23591087 to S.O., 24390200, 25670131, 16H05300, 16K15205 to Y.I.); the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) KAKENHI Grant (22136009 to Y.I.); New Energy and Industrial Technology Development Organization (NEDO) (60890021 to Y.I.); National Cerebral and Cardiovascular Center (NCVC) (22-2-3 to Y.I.); Japan Agency for Medical Research and Development (AMED) (66890005, 66890011, 66890001, 66890023, 66890007, 66891153 to Y.I.); a Grant for Strategic Research Promotion of Yokohama City University (T.F., S.O.); the Naito Foundation (S.O.); SENSHIN Medical Research Foundation (S.O.); the Tokyo Biochemical Research Foundation (W.C., Y.I.); the Academic Contribution from Pfizer Japan (S.O.); Research Foundation for Community Medicine (S.O.) and Kitsuen Research Foundation (71890005 to Y.I.).

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  1. Kenji Suita and Takayuki Fujita contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Kenji Suita, Takayuki Fujita, Wenqian Cai, Yuko Hidaka, Huiling Jin, Rajesh Prajapati, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Satoshi Okumura & Yoshihiro Ishikawa

  2. Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan

    Kenji Suita & Satoshi Okumura

  3. Department of Physiology, Aichi Medical University, Aichi, Japan

    Motohiko Sato

  4. Vanderbilt Center for Arrhythmia Research and Therapeutics, Vanderbilt University School of Medicine, Nashville, TN, USA

    Björn C. Knollmann

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  1. Kenji Suita
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Correspondence to Takayuki Fujita or Yoshihiro Ishikawa.

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Suita, K., Fujita, T., Cai, W. et al. Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced arrhythmias without adverse effect on heart function in mice. Pflugers Arch - Eur J Physiol 470, 923–935 (2018). https://doi.org/10.1007/s00424-018-2121-4

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