4-hydroxy-2-nonenal and olmesartan

As hypertension (HT) is one of the risk factors for lower urinary tract symptoms, we investigated the effect of an angiotensin II type I receptor blocker, olmesartan, on bladder dysfunction in the spontaneously hypertensive rat (SHR).. Twelve-week-old male SHRs were administered perorally with olmesartan (0, 1, or 3 mg/kg/day) or nifedipine (30 mg/kg/day) for 6 weeks. Wistar rats were used as normotensive controls. The effects of olmesartan or nifedipine on blood pressure (BP), bladder blood flow (BBF), urodynamic parameters, tissue levels of malondialdehyde (MDA), nuclear factor erythroid 2-related factor 2 (Nrf2), and nerve growth factor (NGF) were measured in the bladder. Localization of 4-hydroxy-2-nonenal (4-HNE), Nrf2, and NGF in the bladder was shown by immunohistochemistry.. The SHRs showed significant increase in BP, micturition frequency, and expression of MDA, 4-HNE, Nrf2, and NGF when compared to the control Wistar rats. Conversely, there was a decrease in BBF and single voided volume in SHRs when compared to Wistar rats. Treatment with olmesartan and nifedipine significantly improved BP. However, only olmesartan significantly ameliorated urodynamic parameters and oxidative damage compared to the non-treated SHR. The immunoreactivities of 4-HNE, Nrf2, and NGF in SHR urothelium and blood vessels were increased compared to the control. Treatment with a high dose of olmesartan decreased the expressions of 4-HNE, Nrf2, and NGF in the bladder.. Our data suggest that BP, BBF, and oxidative stress may be responsible for the functional changes in HT-related bladder dysfunction. Olmesartan significantly ameliorated this bladder dysfunction.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Disease Models, Animal; Hypertension; Imidazoles; Male; Malondialdehyde; Nerve Growth Factor; NF-E2-Related Factor 2; Nifedipine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Wistar; Regional Blood Flow; Tetrazoles; Urinary Bladder; Urinary Bladder Diseases; Urodynamics

Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H₂O₂-producing Nox4 increased 40-100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50-70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60-70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Catalase; Citrate (si)-Synthase; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Glutathione Peroxidase; Imidazoles; Insulin Resistance; Male; Membrane Glycoproteins; Mitochondria, Heart; Myocardium; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; NF-E2-Related Factor 2; Obesity; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred OLETF; Receptor, Angiotensin, Type 1; RNA, Messenger; Signal Transduction; Succinate Dehydrogenase; Superoxide Dismutase; Tetrazoles; Time Factors; Tyrosine

The metabolic syndrome is a risk factor for the development of renal and vascular complications. Dietary protein intake aggravates renal injury in Zucker obese rats, a model of the metabolic syndrome. This study investigated whether dietary protein intake enhances renal and vascular injuries by oxidative stress, and assessed effects of olmesartan, an angiotensin II type 1 receptor blocker, in this model.. Zucker obese rats were fed either a standard protein diet, high protein diet (OHP), or high protein diet containing olmesartan or hydralazine for 12 weeks. We examined the glomerulosclerosis score, endothelium-dependent relaxation response in the aorta, 4-hydroxy-2-nonenal (HNE) contents in the kidney and aorta, and mRNA expression of NAD(P)H oxidase components (p22phox and p47phox) in the renal cortex.. The OHP rats developed proteinuria, glomerulosclerosis, and endothelial dysfunction. Olmesartan prevented the development of all these damages in OHP rats, whereas hydralazine improved only glomerulosclerosis. The high protein diet also augmented HNE accumulation in glomeruli, renal arteries, and aortas, and increased the mRNA expressions of p22phox and p47phox in the renal cortex in obese rats. Olmesartan, but not hydralazine, inhibited all these changes.. These results suggested that increased dietary protein intake exacerbates renal and vascular injuries, and augments oxidative stress in a rat model of the metabolic syndrome. Olmesartan ameliorated these injuries, presumably through its antioxidative effects, whereas hydralazine improved only glomerulosclerosis through its antihypertensive action. Dietary protein-enhanced injuries in the metabolic syndrome may be associated with hypercholesterolemia and the activated renin-angiotensin system.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Dietary Proteins; Disease Models, Animal; Endothelium, Vascular; Hydralazine; Hypertension, Renovascular; Imidazoles; Kidney; Male; Metabolic Syndrome; NADPH Oxidases; Obesity; Oxidative Stress; Rats; Rats, Zucker; Tetrazoles

Elevated superoxide formation in cardiac extracts of apolipoprotein E-knockout (apoE-KO) mice has been reported. In addition, we previously reported that hypoxia increased oxidative stress in the aortas of apoE-KO mice, although we did not examine the effect of hypoxia on the heart. The aim of this study was to investigate the effect of chronic hypoxia on the left ventricular (LV) remodeling in apoE-KO mice treated with or without an angiotensin II receptor blocker. Male apoE-KO mice (n=83) and wild-type mice (n=34) at 15 weeks of age were kept under hypoxic conditions (oxygen, 10.0+/-0.5%) and treated with olmesartan (3 mg/kg/day) or vehicle for 3 weeks. Although LV pressure was not changed, hypoxia caused hypertrophy of cardiomyocytes and increased interstitial fibrosis in the LV myocardium. Furthermore, nuclear factor-kappaB (NF-kappaB) and matrix metalloproteinase (MMP)-9 activities were increased in apoE-KO mice exposed to chronic hypoxia. Olmesartan effectively suppressed the 4-hydroxy-2-nonenal protein expression and NF-kappaB and MMP-9 activities, and preserved the fine structure of the LV myocardium without affecting the LV pressure. In conclusion, olmesartan reduced oxidative stress, and attenuated the hypoxia-induced LV remodeling, in part through the inhibition of NF-kappaB and MMP-9 activities, in apoE-KO mice.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Apolipoproteins E; Heart Ventricles; Hypertrophy, Left Ventricular; Hypoxia; Imidazoles; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Knockout; Myocytes, Cardiac; NADPH Oxidases; NF-kappa B; Oxidative Stress; Superoxides; Tetrazoles; Ventricular Remodeling