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Parasympathetic Dysfunction and Cardiac Arrhythmias in Diabetic Mice
Author(s) -
Park HoJin,
Du Chuang,
Georgescu Serban P,
Madias Christopher,
Zhang Yali,
Aronovitz Mark J,
Dunlap Kathleen,
Galper Jonas B
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1164.7
Subject(s) - medicine , endocrinology , insulin , diabetes mellitus , myocyte , myocardial infarction , ventricular tachycardia , receptor
Aim: to establish a molecular mechanism for diabetic autonomic neuropathy and the increased incidence of arrhythmia and sudden death in a mouse model for type I diabetes. In the heart acetylcholine binding to M 2 receptors releases Gα i2 and inhibits β‐adrenergic stimulated cAMP levels and L‐type Ca currents (I Ca, L ). Isoproterenol (Iso) stimulated I Ca, L equally in both ventricular myocytes from WT and type I diabetic Akita mice, 2.8±0.13 (N=13) and 2.71±0.27 (N=10) fold, respectively. However, carbamylcholine (Cab) inhibition of I so‐stimulated I Ca, L was markedly reduced in Akita myocytes compared to that in WT, 30.4±2.8% vs 55.2±3.6% (p<0.01). Furthermore, Gα i2 expression in Akita ventricles was decreased to 39±12% of WT (p=0.02). In insulin treated euglycemic Akita mice, Iso stimulated ICa, L 3.23±0.3 (N=11) fold while carb inhibited I Ca, L by 64.3±3.3% consistent with insulin reversal of parasympathetic dysfunction. Insulin stimulated Gα i2 expression in cardiomyocytes. Following myocardial infarction Akita mice developed 8,000 PVCs/hour and 4000 runs of ventricular tachycardia (VT) (N=15), peak 18h, compared to 50 PVCs/hour and no VT in WT mice (N=15). These data supported the conclusion that hypoinsulinemia in the type I diabetic mouse results in decreased expression of Gα i2 , which leads to a relatively unopposed sympathetic input to the heart and predisposes the heart to life‐threatening arrhythmias.