title: Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic beta-adrenoreceptor activation in rats.
abstract: We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic beta-adrenoreceptor activation (isoproterenol [ISO], 0.1 mg/kg/day for 1 month or 6 months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6 months, but not after 1 month of beta-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure-volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6 months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1 month of ISO administration, reduced beta1- and beta2-adrenoreceptor-mediated and sustained alpha-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of beta-adrenoreceptor agonists and upregulation of alpha-adrenoreceptor-mediated contractile responses were noted after 6 months of ISO administration. Increased adrenergic-inotropic responsiveness after 6 months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.
authors.affiliation: Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, 2193 Johannesburg, South Africa.
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Osadchii
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Woodiwiss
authors.forename: Dawn
authors.initials: D
authors.lastname: Deftereos
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Norton
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D009638:Norepinephrine