temocapril-hydrochloride and Ventricular-Dysfunction--Left

Promoted myocardial stiffening has a crucial role in the transition to overt diastolic heart failure (DHF) in hypertensive hearts and is attributed to progressive ventricular fibrosis. Previous studies revealed the effects of an angiotensin II type 1 receptor blocker (ARB) and an angiotensin-converting enzyme inhibitor (ACEI) on the synthesis and degradation of collagens in the other phenotype of heart failure, systolic heart failure, which has a different pathophysiology; however, little is known about their effects in DHF.. To investigate effects of an ACEI and an ARB on the regulatory system of ventricular fibrosis in hypertensive DHF.. Dahl salt-sensitive rats fed a diet containing 8% NaCl from age 7 weeks (DHF model) were divided into three groups: six untreated rats, six rats treated with a subdepressor dose of an ARB, candesartan cilexetil (1 mg/kg per day), from age 8 weeks, and six rats treated with a subdepress or dose of an ACEI, temocapril hydrochloride (0.2 mg/kg per day), from age 8 weeks. Six Dahl salt-sensitive rats fed on normal chow served as controls. Data were collected when animals were aged 20 weeks.. The administration of an ARB or an ACEI inhibited ventricular fibrosis to the same degree. The ACEI decreased the level of type I collagen mRNA, but the decrease was less than that induced by the ARB. The difference in collagen synthesis was probably cancelled out by that in degradation: both in-vitro and in-situ zymography showed that gelatinase activity was greater in the rats treated with the ACEI than in those treated with the ARB.. An ARB and an ACEI inhibited ventricular fibrosis through different mechanisms in hypertensive DHF.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Collagen Type I; Echocardiography; Fibrosis; Gene Expression; Heart Failure; Heart Ventricles; Hemodynamics; Hypertension; Male; Rats; Rats, Inbred Dahl; Tetrazoles; Thiazepines; Ventricular Dysfunction, Left

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.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium-Binding Proteins; Calcium-Transporting ATPases; Diastole; Disease Progression; Drug Therapy, Combination; Extracellular Matrix; Heart Failure; Heart Ventricles; Hemodynamics; Hypertension; Imidazoles; Inflammation; Male; Olmesartan Medoxomil; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tetrazoles; Thiazepines; Ventricular Dysfunction, Left

Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI.. Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks.. Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy.. After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Bradykinin; Collagen Type I; Collagen Type III; Drug Administration Schedule; Drug Therapy, Combination; Glyceraldehyde-3-Phosphate Dehydrogenases; Imidazoles; Male; Models, Animal; Myocardial Infarction; Myocardium; Norepinephrine; Olmesartan Medoxomil; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Tetrazoles; Thiazepines; Transforming Growth Factor beta; Ventricular Dysfunction, Left

Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload.. Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans.. We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group.. After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction.. Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Evaluation Studies as Topic; Insulin-Like Growth Factor I; Male; Myocardium; Myosin Heavy Chains; Random Allocation; Rats; Rats, Inbred Strains; Thiazepines; Ventricular Dysfunction, Left