Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Yingjie Liu, Hailey J. Jansen, Pooja S. Krishnaswamy, Oleg Bogachev, Robert A. Rose

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.

Original languageEnglish
Article number12465
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
We acknowledge Megan McRae, Erin Seto, Adam Kirkby, and Sara Rafferty for technical support and experimental assistance. This work was supported by the Canadian Institutes of Health Research to R.A.R. (MOP 142486 and PJT 166105). Y.L. holds a Canadian Institutes of Health Research Fellowship. H.J.J. was supported by a Killam Postdoctoral Fellowship and a Libin Cardiovascular Institute Postdoctoral Fellowship.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus Subject Areas

  • General

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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