dinoprost and Hypertrophy--Left-Ventricular

Epidemiologic studies have shown that hypercholesterolemia is associated with increased left ventricular (LV) mass. Free radicals have been shown to be increased in hyperlipidemic patients. This study sought to determine whether pravastatin administration can affect LV mass in patients with untreated total cholesterol >or=240 mg/dl by reducing 8-iso-prostaglandin F concentrations, a reliable marker of oxidant injury. Fifty patients were randomly assigned to one of two groups, one with (n = 25) and one without (n = 25) treatment with pravastatin (10 or 20 mg/d). A group of normolipidemic control subjects was used for comparison. Echocardiograms were performed at baseline and after 6 months of therapy. Hyperlipidemic patients showed significant increases in LV mass index at baseline compared with the normolipidemic control group (125 +/- 8 vs. 107 +/- 5 g/m, p < 0.0001). Pravastatin treatment significantly reduced plasma total and low-density lipoprotein cholesterol levels, as well as increased high-density lipoprotein cholesterol. After 6 months of therapy with pravastatin, the magnitude of LV mass regression correlated with the magnitude of inhibition of free radical formation assessed by 8-iso-prostaglandin F formation (r = 0.67, p = 0.002). Multivariate analysis revealed that regression of LV mass was significantly correlated only with the changes in 8-iso-prostaglandin F (p < 0.0001, adjusted R = 0.83). These findings demonstrated for the first time that in addition to its primary anti-lipidemia, pravastatin may have an additional effect of reducing LV mass-independent lipid-lowering effects, possibly through attenuation of free radical formation.

Topics: Anticholesteremic Agents; Blood Pressure; Dinoprost; Echocardiography; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Hypertrophy, Left Ventricular; Male; Middle Aged; Pravastatin

Recent studies have revealed that electrocardiographically determined left ventricular hypertrophy (ECG-LVH) is a risk factor for cardiovascular death not only in hypertensive patients but also in normotensive subjects. However, the underlying mechanisms remain to be elucidated. In this study, we tested our hypothesis that normotensive subjects with ECG-LVH have reduced nitric oxide production. A total of 840 Japanese male workers were enrolled, and 579 eligible subjects were studied. ECG-LVH was assessed according to the Sokolow-Lyon voltage criteria and the Cornell voltage-duration product. The median level of plasma NOx (nitrite plus nitrate), a marker of systemic nitric oxide production, was markedly lower in the normotensive subjects with ECG-LVH (n=73) than in those without (n=506), and the clinical characteristics were significantly different between the 2 groups (each P<0.05). Importantly, a one-to-one propensity score matching analysis showed similar markedly lower median plasma NOx level in the normotensive subjects with ECG-LVH compared with that observed in the matched normotensive subjects without ECG-LVH (P<0.05). Furthermore, the tertiles of the plasma NOx levels were inversely correlated with the prevalence and severity of ECG-LVH (both P<0.05). The lower plasma NOx levels were associated with significantly higher plasma 8-isoprostane levels, a marker of systemic lipid peroxidation (P<0.05). These results provide the first evidence that normotensive subjects with ECG-LVH exhibit defective nitric oxide production, along with increased oxidative stress. Our findings may thus explain, at least in part, a potential mechanism underlying the increased risk of cardiovascular death in normotensive individuals with ECG-LVH.

Topics: Adult; Biomarkers; Blood Pressure; Dinoprost; Electrocardiography; Humans; Hypertrophy, Left Ventricular; Japan; Lipid Peroxidation; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Oxidative Stress; Prevalence; Risk Factors; Severity of Illness Index

Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.

Topics: Acetylcysteine; Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprost; Drug Evaluation, Preclinical; Enzyme Activation; Free Radical Scavengers; Hypertrophy, Left Ventricular; Indoles; Isoprostanes; Male; Maleimides; Myocytes, Cardiac; NADPH Oxidases; Oxidative Stress; Protein Kinase C; Protein Kinase C beta; Rats; Rats, Sprague-Dawley; Superoxides; Ultrasonography

Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.

Topics: Allopurinol; Analysis of Variance; Animals; Antioxidants; Atrasentan; Biomarkers; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gout Suppressants; Hypertrophy, Left Ventricular; Hyperuricemia; Isoprostanes; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides; Time Factors; Up-Regulation; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

The study was to evaluate the effects of high-salt diet on the blood pressure and myocardium in Sprague-Dawley rats and to investigate the related mechanisms.. Rat model of high-salt diet was established by receiving standard rat chow with salt concentration of 0.3% and additional salt load via the drinking water (1% sodium chloride solution). Systolic blood pressure was measured by The indirect tail-cuff method in the rats on high-salt and normal-salt diet. The rats were placed in metabolic cages. Food intake and urine volume were recorded. The sodium and chloride in plasma and urine were measured. Transthoracic echocardiographic studies were performed at the eighth week with an echocardiographic system. The pathological variations of the myocardium were observed by the electron microscopy. The p22phox and p47phox mRNA expressions were analyzed by real time RT-PCR. The p22phox and p47phox protein expressions were analyzed by Western blot. The NADPH oxidase activity of myocardium and the serum 8-isoprostane levels were measured.. Left ventricular hypertrophy (all P < 0.05) and the decreased diastolic function of left ventricle without significantly elevated blood pressure [(128 +/- 4) mm Hg versus (125 +/- 3) mm Hg in controls, P > 0.05] were found in the rats on high-salt diet, compared to those in the rats on normal-salt diet. Furthermore, mRNA and protein expressions of the p22phox and p47phox, and the NADPH oxidase activity of myocardium were increased [(0.332 +/- 0.015) micromol x min(-1) x mg(-1) versus (0.142 +/- 0.023) micromol x min(-1) x mg(-1) in controls, P <0.05]. Serum 8-isoprostane levels [(1117 +/- 86) pg/ml versus (327 +/- 80) pg/ml in controls, P < 0.05] were also significantly increased in the rats on high-salt diet.. High-salt diet might lead to left ventricular hypertrophy and the decreased diastolic function of left ventricle through oxidative stress without significantly elevated blood pressure.

Topics: Animals; Blood Pressure; Dinoprost; Hypertrophy, Left Ventricular; Male; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary

We examined the development of cardiac hypertrophy in juvenile visceral steatosis (JVS) mice, a model of systemic carnitine deficiency, by varying the amount of lipid in the diet. Cardiac hypertrophy was markedly attenuated by decreasing soy bean oil (SBO) from 5% (w/w) to 1%. Triglyceride contents of the ventricles of JVS mice fed 1% SBO were significantly lower than in JVS mice fed 5% SBO. The addition of medium-chain triglycerides metabolically utilized by JVS mice did not affect the development of cardiac hypertrophy. On the other hand, the mRNA levels of atrial natriuretic peptide and skeletal alpha-actin, which are related to cardiac hypertrophy, were also attenuated by decreasing lipid in the diet. Adenylate energy charge and creatine phosphate in the heart of JVS mice at the early stage of hypertrophy were not significantly different from control mice given the same laboratory chow (4.6% of lipid). Although urinary prostaglandin F(2alpha) levels were found to be increased in JVS mice at 15 days of age when they developed cardiac hypertrophy, administration of aspirin was not efficacious. We, therefore, propose that the proportion of lipid in the diet is important in the development of cardiac hypertrophy in carnitine-deficient JVS mice, and that this is not related to prostaglandin formation.

Topics: Animals; Aspirin; Carnitine; Diet; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hypertrophy, Left Ventricular; Lipids; Male; Mice; Mice, Mutant Strains; Vitamin B Deficiency