title: Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction.
abstract: In order to examine the reversibility of heart failure due to myocardial infarction (MI) by β-adrenoceptor blockade, 12 weeks infarcted rats were treated with or without metoprolol (50 mg/kg/day) for 8 weeks. The depressed left ventricular (LV) systolic pressure, positive and negative rates of changes in pressure development, ejection fraction, fractional shortening and cardiac output, as well as increased LV end-diastolic pressure in 20 weeks MI animals were partially reversed by metoprolol. MI-induced decreases in septum (systolic) thickness as well as increase in LV posterior wall thickness and LV internal diameter were partially or fully reversible by metoprolol. Treatment of MI animals with metoprolol partially reversed the elevated levels of plasma norepinephrine and dopamine without affecting the elevated levels of epinephrine. Although sarcoplasmic reticular (SR) Ca(2+)-uptake, as well as protein content for SR Ca(2+)-pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca(2+)-stimulated ATPase activity, as well as mRNA levels for SR Ca(2+)-pump, phospholamban and α-myosin heavy chain, were unaffected whereas increased mRNA level for β-myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by β-adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca(2+)-pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines.
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Hospital Research, Department of Physiology and Division of Cardiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Babick
authors.forename: Vijayan
authors.initials: V
authors.lastname: Elimban
authors.forename: Shelley
authors.initials: S
authors.lastname: Zieroth
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D004298:Dopamine / Q000097:blood / Q000378:metabolism; D004837:Epinephrine / Q000097:blood / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D000099211:Phospholamban
chemical_list: D000251:Adenosine Triphosphatases; D002118:Calcium; D002135:Calcium-Binding Proteins; D004298:Dopamine; D004837:Epinephrine; D008790:Metoprolol; D018995:Myosin Heavy Chains; D009638:Norepinephrine; D010455:Peptides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000099211:Phospholamban; C445259:beta-adrenergic receptor kinase inhibitory peptide