The Journal of Physiological Sciences

, Volume 69, Issue 2, pp 211–222 | Cite as

Ivabradine preserves dynamic sympathetic control of heart rate despite inducing significant bradycardia in rats

  • Toru KawadaEmail author
  • Shuji Shimizu
  • Kazunori Uemura
  • Yohsuke Hayama
  • Hiromi Yamamoto
  • Toshiaki Shishido
  • Takuya Nishikawa
  • Masaru Sugimachi
Original Paper


Ivabradine is a selective bradycardic agent that inhibits hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. HCN channels play a key role in mediating the positive chronotropic response to sympathetic nerve stimulation (SNS). We examined whether ivabradine would interfere with dynamic sympathetic control of heart rate (HR). The effect of intravenous ivabradine (2 mg/kg, n = 7) or metoprolol (10 mg/kg, n = 6) on the transfer function from SNS to HR was examined in anesthetized rats. Ivabradine preserved the asymptotic dynamic gain of the HR transfer function and nearly doubled the asymptotic dynamic gain of the transfer function from SNS to the R–R interval. In contrast, metoprolol abolished dynamic sympathetic control of HR. Preserved dynamic sympathetic control of HR, with coexisting bradycardia, may contribute to some of the beneficial effects of ivabradine previously reported in clinical application.


Metoprolol Transfer function Sympathetic stimulation 


Author contributions

TK and MS, conception and design of the study; TK performed the experiment and analyzed the data; TK, SS, KU, YH, HY, TS, TN, and MS, discussed and interpreted the results. TK and MS, drafting and revising the manuscript. All authors have read the final version of the manuscript and approved its submission to the Journal of Physiological Sciences.

Compliance with ethical standards

Research involving human participants and/or animals

Animals used in the present study were cared for in strict accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences, which has been approved by the Physiological Society of Japan. The Animal Subjects Committee at the National Cerebral and Cardiovascular Center reviewed and approved the experimental protocols.

Informed consent

Not applicable.


This study was supported in part by a Grant-in-Aid for Scientific Research (JSPS KAKENHI Grant number 18K10695).

Conflict of interest

The authors declare that there are no conflicts of interest.


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Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cardiovascular DynamicsNational Cerebral and Cardiovascular CenterOsakaJapan
  2. 2.Division of Cardiology, Department of Medicine, Faculty of MedicineKindai UniversityOsakaJapan
  3. 3.Department of Research PromotionNational Cerebral and Cardiovascular CenterOsakaJapan

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