Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice
| Autor: | Robert A. Rose, Martin Mackasey, Oleg Bogachev, Hailey J. Jansen, Motahareh Moghtadaei, Pooja S. Krishnaswamy, Courtney Robbins, John Azer, Emmanuel E. Egom |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty Cardiotonic Agents Carbachol medicine.drug_class Voltage clamp Action Potentials Diabetes Mellitus Experimental Mice Parasympathetic nervous system Parasympathetic Nervous System Internal medicine Diabetes mellitus Heart rate medicine Animals Insulin Myocyte Myocytes Cardiac Molecular Biology Sinoatrial Node Sinoatrial node business.industry Myocardium Heart medicine.disease Acetylcholine Disease Models Animal Diabetes Mellitus Type 1 medicine.anatomical_structure Endocrinology Cardiology and Cardiovascular Medicine business RGS Proteins medicine.drug |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 82:125-135 |
| ISSN: | 0022-2828 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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