title: Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice.
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.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Pooja S
authors.initials: PS
authors.lastname: Krishnaswamy
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Emmanuel E
authors.initials: EE
authors.lastname: Egom
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Motahareh
authors.initials: M
authors.lastname: Moghtadaei
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Hailey J
authors.initials: HJ
authors.lastname: Jansen
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Azer
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Oleg
authors.initials: O
authors.lastname: Bogachev
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Mackasey
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Courtney
authors.initials: C
authors.lastname: Robbins
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada; School of Biomedical Engineering, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: robert.rose@dal.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rose
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000503:physiopathology*; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects / Q000294:innervation*
chemical_list: D002316:Cardiotonic Agents; D007328:Insulin; D020710:RGS Proteins; C098799:RGS4 protein; D002217:Carbachol; D000109:Acetylcholine
keywords: Diabetes mellitus; Insulin signaling; Ion channels; Parasympathetic nervous system; Sinoatrial node