title: Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation.
abstract: There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.
authors.affiliation: Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, Johannesburg, Parktown, 2193, Johannesburg, South Africa.
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Osadchii
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Norton
authors.forename: Richard
authors.initials: R
authors.lastname: McKechnie
authors.forename: Dawn
authors.initials: D
authors.lastname: Deftereos
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Woodiwiss
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D004280:Dobutamine / Q000494:pharmacology; D015536:Down-Regulation; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013599:Systole / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D004280:Dobutamine; D000420:Albuterol; D009638:Norepinephrine