title: Reversal of subcellular remodelling by losartan in heart failure due to myocardial infarction.
abstract: This study tested the reversal of subcellular remodelling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve weeks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 weeks and assessed for cardiac function, cardiac remodelling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 weeks MI-induced heart failure were associated with increases in plasma catecholamine levels. Haemodynamic examination revealed depressed cardiac function, whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 weeks of inducing MI. These changes in cardiac function, cardiac remodelling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca(2+)-pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca(2+)-stimulated ATPase activity and α-myosin heavy chain mRNA levels were depressed, whereas β-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca(2+)-release activity and mRNA levels for SR Ca(2+)-pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca(2+)-release channels were observed in untreated or treated heart failure. These results suggest that the partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodelling as well as partial recovery of SR and MF functions.
authors.affiliation: Department of Physiology, Institute of Cardiovascular Sciences, St Boniface Hospital Research, Winnipeg, Manitoba, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Babick
authors.forename: Donald
authors.initials: D
authors.lastname: Chapman
authors.forename: Shelley
authors.initials: S
authors.lastname: Zieroth
authors.forename: Vijayan
authors.initials: V
authors.lastname: Elimban
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D006332:Cardiomegaly / Q000188:drug therapy; D002395:Catecholamines / Q000097:blood; D003331:Coronary Vessels / Q000601:surgery; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology; D006334:Heart Function Tests / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000150:complications*; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D000099211:Phospholamban
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002135:Calcium-Binding Proteins; D002395:Catecholamines; D019808:Losartan; D018995:Myosin Heavy Chains; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C000594638:MYH7 protein, rat