Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse

Transgenic (TG) mice with cardiac G(salpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with G(salpha) overexpression could be averted with chronic beta-a...

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Bibliographic Details
Published in:The Journal of clinical investigation 1999-09, Vol.104 (5), p.551-558
Main Authors: Asai, K, Yang, G P, Geng, Y J, Takagi, G, Bishop, S, Ishikawa, Y, Shannon, R P, Wagner, T E, Vatner, D E, Homcy, C J, Vatner, S F
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - metabolism
Adrenergic beta-Antagonists - therapeutic use
Animals
Blood Pressure
Cardiomyopathy, Dilated - diagnostic imaging
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - pathology
Cardiomyopathy, Dilated - prevention & control
Cyclic AMP - biosynthesis
Endomyocardial Fibrosis - diagnostic imaging
Endomyocardial Fibrosis - genetics
Endomyocardial Fibrosis - pathology
Endomyocardial Fibrosis - prevention & control
Enzyme Activation
Female
Gene Expression Regulation
GTP-Binding Protein alpha Subunits, Gs - biosynthesis
GTP-Binding Protein alpha Subunits, Gs - genetics
Heart Rate
Hypertrophy
Male
Mice
Mice, Transgenic
Myocardium - pathology
Myosin Heavy Chains - genetics
Promoter Regions, Genetic
Propranolol - therapeutic use
Receptors, Adrenergic, beta - drug effects
Receptors, Adrenergic, beta - physiology
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - genetics
Signal Transduction - drug effects
Signal Transduction - genetics
Space life sciences
Ultrasonography
Ventricular Dysfunction, Left - diagnostic imaging
Ventricular Dysfunction, Left - genetics
Ventricular Dysfunction, Left - pathology
Ventricular Dysfunction, Left - prevention & control
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Summary:Transgenic (TG) mice with cardiac G(salpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with G(salpha) overexpression could be averted with chronic beta-adrenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type littermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of older TG mice, and abolished premature mortality. Propranolol also prevented the increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 9-month-old TG mice, was actually eliminated by chronic propranolol. This study indicates that chronic sympathetic stimulation over an extended period is deleterious and results in cardiomyopathy. Conversely, beta-AR blockade is salutary in this situation and can prevent the development of cardiomyopathy.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI7418