Abstract
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.
MeSH terms
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Adenylyl Cyclases / metabolism
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Adrenergic beta-Antagonists / therapeutic use*
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Animals
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Blood Pressure
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Cardiomyopathy, Dilated / diagnostic imaging
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Cardiomyopathy, Dilated / genetics
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Cardiomyopathy, Dilated / pathology
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Cardiomyopathy, Dilated / prevention & control*
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Cyclic AMP / biosynthesis
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Endomyocardial Fibrosis / diagnostic imaging
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Endomyocardial Fibrosis / genetics
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Endomyocardial Fibrosis / pathology
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Endomyocardial Fibrosis / prevention & control*
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Enzyme Activation
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Female
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GTP-Binding Protein alpha Subunits, Gs / biosynthesis*
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GTP-Binding Protein alpha Subunits, Gs / genetics
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Gene Expression Regulation
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Heart Rate
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Hypertrophy
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Male
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Mice
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Mice, Transgenic
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Myocardium / pathology
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Myosin Heavy Chains / genetics
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Promoter Regions, Genetic
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Propranolol / therapeutic use*
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Receptors, Adrenergic, beta / drug effects
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Receptors, Adrenergic, beta / physiology*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Ultrasonography
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Ventricular Dysfunction, Left / diagnostic imaging
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Ventricular Dysfunction, Left / genetics
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Ventricular Dysfunction, Left / pathology
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Ventricular Dysfunction, Left / prevention & control*
Substances
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Adrenergic beta-Antagonists
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Receptors, Adrenergic, beta
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Recombinant Fusion Proteins
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Propranolol
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Cyclic AMP
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Myosin Heavy Chains
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GTP-Binding Protein alpha Subunits, Gs
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Adenylyl Cyclases