title: AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure.
abstract: Diastolic heart failure (DHF) has become a social burden; however, evidences leading to its therapeutic strategy are lacking. This study investigated effects of addition of angiotensin II type 1 receptor blocker (ARB) to angiotensin-converting enzyme inhibitor (ACEI) at advanced stage of DHF in hypertensive rats. Dahl salt-sensitive rats fed 8% NaCl diet from age 7 weeks served as DHF model, and those fed a normal chow served as control. The DHF model rats were arbitrarily assigned to 3 treatment regimens at age 17 weeks: ACEI (temocapril 0.4 mg/kg per day), combination of ACEI (temocapril 0.2 mg/kg per day) with ARB (olmesartan 0.3 mg/kg per day), or placebo. At age 17 weeks, this model represents progressive ventricular hypertrophy and fibrosis, relaxation abnormality, and myocardial stiffening. Data were collected at age 20 weeks. As compared with the monotherapy with ACEI, the addition of ARB induced more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening, improvement of relaxation, and inhibition of hemodynamic deterioration. Such benefits were associated with greater decreases in reactive oxygen species (ROS) generation, macrophage infiltration, and gene expression of transforming growth factor (TGF)-beta(1) and interleukin (IL)-1beta, but not with changes in gene expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha. Thus, ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at an advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-alpha.
authors.affiliation: Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. kazuhiro@medone.med.osaka-u.ac.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshida
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Mayu
authors.initials: M
authors.lastname: Nishio
authors.forename: Tomohito
authors.initials: T
authors.lastname: Ohtani
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003971:Diastole; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005109:Extracellular Matrix / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000150:complications*; D007093:Imidazoles / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology; D008297:Male; D000068557:Olmesartan Medoxomil; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013777:Tetrazoles / Q000627:therapeutic use*; D013841:Thiazepines / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000099211:Phospholamban
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007093:Imidazoles; D000068557:Olmesartan Medoxomil; D017382:Reactive Oxygen Species; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013777:Tetrazoles; D013841:Thiazepines; D000099211:Phospholamban; C055603:temocapril hydrochloride