title: In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure.
abstract: Hearts in volume overload (VO) undergo progressive ventricular hypertrophy resulting in chronic heart failure that is unresponsive to β-adrenergic agonists. This study compared left ventricular (LV) and isolated cardiomyocyte contractility and β-adrenergic responsiveness in rats with end-stage VO heart failure (HF). Adult male Sprague-Dawley rats were studied 21 weeks after aortocaval fistula (ACF) or sham surgery. Echocardiography revealed decreased fractional shortening accompanied by increased LV chamber diameter and decreased eccentric dilatation index at end-stage ACF compared to sham. Hemodynamic measurements showed a decrease in the slope of end-systolic pressure-volume relationship, indicating systolic dysfunction. Isolated LV myocytes from ACF exhibited decreased peak sarcomere shortening and kinetics. Both Ca2+ transient amplitude and kinetics were increased in ACF myocytes, with no change under the integrated Ca2+ curves relating to contraction and relaxation phases. Increases in ryanodine receptor and phospholamban phosphorylation, along with a decrease in SERCA2 levels, were observed in ACF. These changes were associated with decreased expression of β-myosin heavy chain, cardiac troponin I and cardiac myosin binding protein-C. In vivo inotropic responses to β-adrenergic stimulation were attenuated in ACF. Interestingly, ACF myocytes exhibited a similar peak shortening to those of sham in response to a β-adrenergic agonist. The protein expression of the gap junction protein connexin-43 was decreased, although its phosphorylation at Ser-368 increased. These changes were associated with alterations in Src and ZO-1. In summary, these data suggest that the disconnect in β-adrenergic responsiveness between in vivo and in vitro conditions may be associated with altered myofilament Ca2+ sensitivity and connexin-43 degradation.
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Guggilam
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Hutchinson
authors.forename: T Aaron
authors.initials: TA
authors.lastname: West
authors.forename: Amy P
authors.initials: AP
authors.lastname: Kelly
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Galantowicz
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Davidoff
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019210:Troponin I / Q000378:metabolism; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D000318:Adrenergic beta-Agonists; D018031:Connexin 43; C580592:Gja1 protein, rat; D019210:Troponin I; D048049:Extracellular Signal-Regulated MAP Kinases; D024723:Ventricular Myosins; D007545:Isoproterenol