title: Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse.
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.
authors.affiliation: Weis Center for Research, Penn State College of Medicine, Danville, Pennsylvania 17822, USA.
authors.forename: K
authors.initials: K
authors.lastname: Asai
authors.forename: G P
authors.initials: GP
authors.lastname: Yang
authors.forename: Y J
authors.initials: YJ
authors.lastname: Geng
authors.forename: G
authors.initials: G
authors.lastname: Takagi
authors.forename: S
authors.initials: S
authors.lastname: Bishop
authors.forename: Y
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: R P
authors.initials: RP
authors.lastname: Shannon
authors.forename: T E
authors.initials: TE
authors.lastname: Wagner
authors.forename: D E
authors.initials: DE
authors.lastname: Vatner
authors.forename: C J
authors.initials: CJ
authors.lastname: Homcy
authors.forename: S F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000242:Cyclic AMP / Q000096:biosynthesis; D004719:Endomyocardial Fibrosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004789:Enzyme Activation; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006339:Heart Rate; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D011433:Propranolol / Q000627:therapeutic use*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011993:Recombinant Fusion Proteins; D011433:Propranolol; D000242:Cyclic AMP; D018995:Myosin Heavy Chains; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases