Angiotensin II-induced Hypertensive Mice Research Articles

Allopurinol Attenuates Oxidative Stress and Cardiac Fibrosis in Angiotensin II‐Induced Cardiac Diastolic Dysfunction

Oxidative stress and fibrosis is implicated in cardiac remodeling and failure. We tested whether allopurinol could decrease myocardial oxidative stress and attenuate cardiac fibrosis and left ventricular diastolic dysfunction in angiotensin II (AngII)-induced hypertensive mice. We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or allopurinol in daily doses, which did not lower blood pressure. Allopurinol improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of cardiac fibrosis. However, allopurinol showed no effect on the increased systolic blood pressure by angiotensin II infusion. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) [GSH/GSSG] was decreased and malondialdehyde levels were increased in the hearts of AngII-treated mice. Allopurinol also inhibited both the decrease in the GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. Infusion of AngII-induced upregulation of transfer growth factor (TGF)-β1, Smad3 expression and downregulation of Smad7 expression. Treatment with allopurinol reduced cardiac levels of TGF-β1, Smad3, and increased Smad7 expression. These results suggest that allopurinol prevents pathological remodeling of the heart in AngII-induced hypertensive mice. The antioxidative effect of allopurinol contributes to the regression of AngII-induced cardiac diastolic dysfunction. These effects of allopurinol to prevent cardiac fibrosis are mediated at least partly through modulation of the TGF-β1/Smad signaling pathway.

High Salt Intake Delayed Angiotensin II-Induced Hypertension in Mice With a Genetic Variant of NADPH Oxidase

gp91(PHOX), a catalytic subunit of NAD(P)H oxidase, is involved in angiotensin II (Ang II)-induced superoxide (O₂⁻) generation. This study was designed to examine the hypothesis that an enhancement in O₂⁻ generation due to elevated Ang II induces salt-sensitivity, which contributes to the development of hypertension. Assessment of blood pressure and renal excretory responses to Ang II infusion (2.2 ng·min/g) for 2 weeks via osmotic minipump was made in knockout (KO; n = 20) mice lacking the gene for gp91(PHOX) which were fed on either normal-salt (NS; 0.04% NaCl) or high-salt (HS, 4% NaCl) diet and compared these responses with those in wild-type (WT; n = 23) mice. Ang II induced increase in systolic blood pressure (SBP) was started within the 4th day in all groups except in HS fed KO mice in which SBP increased after the 10(th) day of Ang II infusion. The increases in SBP were lower in KO than WT mice at the end of 2-week infusion period. In Ang II + HS fed KO mice, the urinary excretion rate of nitrite/nitrate (U(NOx)V) markedly increased but 8-isoprostane excretion rate remained unchanged. These findings indicate that an increase in nitric oxide (NO) with a lack of O₂⁻ formation was involved in the delayed hypertension in Ang II + HS fed KO mice. These data suggest that an enhanced O₂⁻ activity and its interaction with NO contribute to the early developmental phase of Ang II-induced salt-sensitive hypertension.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.173.

Pravastatin Attenuates Left Ventricular Remodeling and Diastolic Dysfunction in Angiotensin II-Induced Hypertensive Mice

A substantial proportion of patients with heart failure have a normal ejection fraction and diastolic dysfunction. However, there are few data available to guide the therapy of these patients. The effects of statins on cardiac remodeling are well documented in animal models and it is reported that statin therapy revealed a survival benefit in patients with diastolic heart failure (DHF). However, the exact mechanisms of statins possibly explaining the decreased cardiovascular morbidity and mortality in patients with DHF have not been elucidated. We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or pravastatin in daily doses, which did not lower the serum cholesterol levels and blood pressure. Pravastatin improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of left ventricular hypertrophy and remodeling. However, statin treatment showed no effect on the increased systolic blood pressure or cholesterol levels by angiotensin II infusion. The cardioprotective effects of pravastatin were closely associated with the downregulation of collagen I, transforming growth factor-beta, matrix metalloproteinases-2 and -3, atrial natriuretic factor, interleukin-6, tumor necrosis factor-alpha, ROCK1 gene expression, and the upregulation of endothelial nitric oxide synthase gene expression. The beneficial effects of pravastatin on DHF and structural remodeling are through cholesterol- independent mechanism of statins or "pleiotropic" effects of statins involving improving or restoring endothelial function and decreasing vascular inflammation. These findings suggest the potential involvement of ROCK1. Thus, treatment with pravastatin might be beneficial in patients with DHF.

Blood Pressure in Mutant Rats Lacking the 5-Hydroxytryptamine Transporter

To the Editor: Although 5-HT uptake inhibitors are widely used as antidepressants, the role of 5-HT in the control of systemic blood pressure is far from clear.1 In a recent issue of Hypertension , Ni et al reported that 5-hydroxytryptamine (5-HT) transporter (SERT) expression was increased, whereas SERT function was decreased in aorta of rats with DOCA salt and Nω-nitro-L-arginine (L-NNA)-induced hypertension.2 We have observed that several 5-HT receptors are induced in leukocytes of hypertensive patients.3 These 2 observations could point at a functional response of the serotonin system …

Angiotensin II-induced hypertension in mice caused an increase in insulin secretion

Objective and design Insulin action was determined in a mouse model of human hypertension via chronic angiotensin II administration followed by a glucose tolerance test. Methods Angiotensin II or saline was infused systemically into mice via osmotic pump for 2 or 4 weeks. In angiotensin II-treated mice versus saline controls we compared blood pressure, blood glucose, and serum insulin concentrations during an intravenous glucose tolerance test and assessed glucose transport and insulin signaling in muscle. Results Blood pressure increased at 2 and 4 weeks following angiotensin II treatment. Mice treated with angiotensin II for 4 weeks cleared a glucose bolus faster than mice treated with saline despite similar basal serum insulin concentrations. Upon glucose administration, the increase in serum insulin was greater in angiotensin II-treated mice, 38.8±6.5 pmol/l, compared to saline-treated mice, 21.8±2.9 pmol/l, but only at 4 weeks of angiotensin II treatment while no difference was observed at 2 weeks of angiotensin II administration. At 4 weeks of angiotensin II treatment, insulin signaling in the liver and in the skeletal muscle was not affected, since both the number of insulin receptors and phosphorylation of Akt were unchanged. Also at 4 weeks of angiotensin II treatment, ex vivo soleus muscle did not exhibit any change in basal and insulin-stimulated glucose uptake. Conclusions This study suggests that long-term angiotensin II treatment for 4 weeks enhances glucose-stimulated insulin secretion in mice. Angiotensin II-induced hyperinsulinemia may play a role in the development of insulin resistance in patients with hypertension.