Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice

Pooja S. Krishnaswamy, Emmanuel E. Egom, Motahareh Moghtadaei, Hailey J. Jansen, John Azer, Oleg Bogachev, Martin Mackasey, Courtney Robbins, Robert A. Rose

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that impairs autonomic regulation of heart rate (HR). This has been attributed to damage to the nerves that modulate spontaneous pacemaker activity in the sinoatrial node (SAN). Our objective was to test the hypothesis that impaired parasympathetic regulation of HR in diabetes is due to reduced responsiveness of the SAN to parasympathetic agonists. We used the Akita mouse model of type 1 diabetes to study the effects of the parasympathetic agonist carbachol (CCh) on SAN function using intracardiac programmed stimulation, high resolution optical mapping and patch-clamping of SAN myocytes. CCh decreased HR by 30% and increased corrected SAN recovery time (cSNRT) by 123% in wildtype mice. In contrast, CCh only decreased HR by 12%, and only increased cSNRT by 37% in Akita mice. These alterations were due to smaller effects of CCh on SAN electrical conduction and spontaneous action potential firing in isolated SAN myocytes. Voltage clamp experiments demonstrate that the acetylcholine-activated K+ current (IKACh) is reduced in Akita SAN myocytes due to enhanced desensitization and faster deactivation kinetics. These IKACh alterations were normalized by treating Akita SAN myocytes with PI(3,4,5)P3 or an inhibitor of regulator of G-protein signaling 4 (RGS4). There was no difference in the effects of CCh on the hyperpolarization-activated current (If) between wildtype and Akita mice. Our study demonstrates that Akita diabetic mice demonstrate impaired parasympathetic regulation of HR and SAN function due to reduced responses of the SAN to parasympathetic agonists. Our experiments demonstrate a key role for insulin-dependent phosphoinositide 3-kinase (PI3K) signaling in the parasympathetic dysfunction seen in the SAN in diabetes.

Original languageEnglish
Pages (from-to)125-135
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume82
DOIs
Publication statusPublished - May 1 2015

Bibliographical note

Funding Information:
This work was supported by operating grants from the Nova Scotia Health Research Foundation , The Canadian Institutes of Health Research (CIHR; MOP 93718 ) and the Heart and Stroke Foundation of Canada to RAR who holds New Investigator Awards from The Heart and Stroke Foundation of Canada and the CIHR. EEE is the recipient of a Heart and Stroke Foundation Fellowship award.

Publisher Copyright:
© 2015 Elsevier Ltd.

ASJC Scopus Subject Areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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