Search

Oxytocin is a neuropeptide produced primarily in the hypothalamus and plays an important role in the regulation of mammalian birth and lactation. It has been shown that oxytocin has important cardiovascular protective effects. Here we investigated the effects of oxytocin on vascular reactivity and underlying the mechanisms in human umbilical vein endothelial cells (HUVECs)

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.

It has been shown that the inflammatory cytokine tumor necrosis factor α (TNFα) plays a role in the development of hypertension and end-stage renal diseases. We hypothesize that TNFα contributes to endothelial dysfunction and cardiac and vascular injury in deoxycorticosterone acetate (DOCA)/salt-hypertensive mice. The wild-type or TNFα-deficient mice were uninephrectomized and implanted with DOCA pellet treatment for 5 weeks; the mice were given either tap water or 1% NaCl drinking water. DOCA mice developed hypertension (systolic blood pressure (SBP): 167±5 vs. 110±4 mmHg in control group, p<0.05), cardiac and vascular hypertrophy, and the impairment of endothelium-dependent relaxation to acetylcholine (EDR). TNFα deficiency improved EDR and lowered cardiac and vascular hypertrophy with a mild reduction in SBP (152±4 vs. 167±5 mmHg in DOCA group, p<0.05) in DOCA mice. The mRNA expressions of the inflammatory cytokines, including TNFα, interleukin 1β (IL1β), monocyte chemotactic protein 1 (MCP1), and monocyte/macrophage marker F4/80 were significantly increased in the aorta of DOCA-hypertensive mice; TNFα deficiency reduced these inflammatory gene expressions. DOCA-hypertensive mice also exhibited an increase in the vascular oxidative fluorescence intensities, the protein expressions of gp91phox and p22phox, and the fibrotic factors transforming growth factor β and fibronectin. TNFα deficiency reduced oxidative stress and fibrotic protein expressions. The DOCA mice also showed a decrease in the protein expression of eNOS associated with increased miR155 expression; TNFα deficiency prevented a decrease in eNOS expression and an increase in miR155 expression in DOCA mice. These results support the idea that TNFα significantly contributes to vascular inflammation, vascular dysfunction, and injury in hypertension.

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone–releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 μg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation–reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.

Background and Purpose: CAPN1 (calpain1)—an intracellular Ca 2+ -regulated cysteine protease—can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose–deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion–operated rats and oxygen-glucose deprivation–exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia–mediated autophagy-lysosomal pathway defects and neuronal damage.

With the aim of improving corrosion resistance of rod cladding for in-service and accident conditions, six new zirconium alloys (named N1–N6) have been designed. The contents of Sn and Nb were optimized for better behavior at high-temperature pressurized water, and Fe, Cr, V, Cu or Mo elements were added to the alloys to adjust the corrosion behavior. The current work focused on the rapid corrosion behavior in 500 °C/10.3 MPa steam for up to 1960 h, aiming to test the corrosion resistance at high temperature. The structure of matrix and properties of second-phase particles (SPPs) were characterized to find the main differences among these alloys. All the six alloys exhibited better corrosion resistance than N36, and N1 was shown to have the best performance. A careful analysis of the corrosion kinetics curves revealed that Cr was beneficial for severe condition. Elements Fe, Cr, V, Cu or Mo aggregated into SPPs with different concentrations and structures. This was demonstrated to be the main reason for different corrosion resistance. Due to good processing control, all alloys had a uniform structure and a uniform distribution of SPPs. As for N4, N6 and N36, the existing of large-size SPPs (450 nm) might be a contributing factor of the relatively poor corrosion resistance.

Ion extraction time is one of the key parameters for an ion extraction process. Particle-in-cell (PIC) simulation can provide a detailed description on the charged-particle behaviours during the ion extraction process in a decaying plasma. However, the PIC modelling is a very time-consuming task with very small space step (~ Debye length) and time step (~ inverse of plasma frequency), as well as a massive number of macro-particles, especially for the cases in multi-dimensions and large geometrical sizes. In this paper, based on the sheath expansion and ion-acoustic rarefaction wave propagation model, a similarity relation of ion extraction time with different geometrical sizes of the ion extraction regions is established. The theoretical analysis shows that, by changing the magnitude of the externally applied voltage to keep the ion extraction flux equal, the ion extraction time is proportional to the geometrical size ratio. Then, the PIC simulations on the ion extraction process are conducted, which show that there exists a good consistency with the theoretical analysis and previous experimental data. This research is helpful for promoting numerical simulations facing actual ion extraction processes with large geometrical sizes and provides theoretical guidance for improving the ion extraction efficiencies in applications.

Carbon-13 isotope has a wide range of applications in medical diagnosis, scientific research, food safety and other fields, and the market demand for carbon-13 isotope is also showing an upward trend. In order to explore the separation and production methods of carbon-13 isotope, the gas diffusion separation experiment with ethylene as the processing gas was carried out, and the cascade was designed on this basis. Through the single-stage separation experiment, it can be obtained that the overall separation factor of the gas diffusion method for separating ethylene under the existing experimental conditions is 1.014. The gas diffusion cascade enrichment of carbon-13 isotope involves two steps. The first step is to separate ethylene using a squared-off cascade to obtain the heavy fraction with the carbon-13 isotope abundance reaching 49%. The second step is to convert ethylene into carbon dioxide, and then use a squared-off cascade to separate the carbon dioxide to obtain the heavy fraction with the carbon-13 isotope abundance reaching 95%.

Vascular endothelial insulin signaling is critical for the maintenance of vascular and metabolic homeostasis. We have previously shown that in hypertensive Dahl rats, impaired vascular insulin action is linked to angiotensin II activation of the NFκB inflammatory pathway. Macrophage polarization (M1) has implicated in hypertensive and metabolic diseases. Here, we investigated the effect of macrophage depletion using liposome-encapsulated clodronate (LEC) on endothelial insulin resistance and cardiovascular remodeling in Dahl salt-sensitive (DS) rats. High salt intake (HS) for 5 weeks increased systolic blood pressure (SBP: 192±5 vs. 144±4 mmHg in NS, p<0.05), aortic and cardiac hypertrophy, cardiac fibrosis, and impaired acetylcholine- and insulin-induced vasorelaxation, accompanied by impaired insulin activation of endothelial nitric oxide synthases (eNOS)/NO signaling. HS rats had a significant increase in CD68 (a monocyte/macrophage marker) expression in the aorta and the heart. LEC reduced SBP (168±5 mmHg, p<0.05) and cardiovascular injury and improved acetylcholine- and insulin-mediated vasorelaxation and insulin signaling molecules with a reduction in the macrophage infiltration in the aorta and the heart. HS rats also manifested an increase in the aortic expressions of inflammatory cytokines, including the ratio of phosphorylated inhibitory kappa B (Iκb)/Iκb, tumor necrosis factor α, and phosphorylated c-Jun N-terminal kinase (JNK) and oxidative stress, which were reduced in HS/LEC rats. Our results suggest that in salt-sensitive hypertension, macrophage may importantly contribute to endothelial insulin resistance, vascular inflammation, and injury. These findings support the idea that macrophages may be a new target for immunotherapy of vasculopathy in hypertensive and metabolic disorders.

Natural occurring boron has two stable isotopes: boron-10 and boron-11. Boron-10 has high thermal neutron cross section in a wide range of energy and the product of boron-10’s neutron reaction contains alpha particles. So, it is a good material for neutron absorbing and neutron detecting. In order to enrich boron-10 from natural boron, several methods had been proven to be feasible: chemical exchange distillation, cryogenic distillation and ion exchange resin method. The market now places higher demands on the economics of the separation method, so study on production of boron-10 by gas diffusion method is carried out. Using BF3 as processing gas, it is feasible to enrich high abundance of boron-10 by gas diffusion. The single stage separation effect and the hydraulic status of single stage was estimated. Binary gas diffusion cascades were designed and compared. Under given production requirements, the scale of the cascade was estimated and optimized. Finally, step cascade was picked for the production of 96% boron-10. Based on the cascade design, economic estimation of this separation method was conducted, and the target product cost was calculated. This study laid a good foundation for the expansion of boron isotope separation methods.

Background: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress. Methods and Results: Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1-20 μg/mL) or resistin (10-100 ng/mL) for 1 h. Either tunicamycin or resistin increased GRP78 (an ER stress marker) expression associated with the impairment of insulin-stimulated Akt/eNOS phosphorylation, which were prevented by TUDCA (an ER stress suppressor). Resistin increased reactive oxygen species (ROS) production, antioxidant treatment inhibited resistin-induced GRP78 expression and impairment of insulin Akt/eNOS signaling, suggesting that ROS may involve resistin-induced ER stress. Resistin also increased JNK phosphorylation, which was prevented by TUDCA. JNK inhibitor SP600125 relieved the resistin inhibitory effects on endothelial insulin Akt/eNOS signaling. In ex vivo experiments, the incubation of aortic rings with resistin impaired insulin- but not acetylcholine-induced vasodilation, which was restored by TUDCA. LNAME (a NOS inhibitor) abolished insulin-induced vasorelaxation in the control or the resistin-treated aortic rings. In addition, resistin increased the mRNA expressions of proinflammatory cytokines tumor nuclear factor (TNF)α and interleukin (IL)-1β, which were also prevented by TUDCA. Conclusion: Our results support the ideal that ER stress may play an important role for resistin impairment of vascular insulin signaling and insulin action. The mitigation of ER stress may represent a new strategy for prevention and treatment of CVDs in obesity and insulin resistant-related diseases.

Monocyte/macrophage recruitment is closely associated with the degree of hypertensive renal injury. Here we investigated the direct role of macrophage using Liposome encapsulated clodronate (LEC) to deplete monocyte/macrophage in Ang II-induced hypertensive renal injury. C57BL/6 mice were treated with a pressor dose of angiotensin II (Ang, 1.4 mg/kg/day by mini-pump) plus LEC or the PBS-liposome for two weeks. Ang II mice developed hypertension (186 ± 5 vs. 110 ± 4 mmHg in control, p+ cells) and the protein expression of renal tumor necrosis factor α and interleukin β1, which were significantly reduced in Ang II mice treated with LEC. Ang II increased renal oxidative stress (as demonstrated by increased oxidative fluorescence densities, NADPH oxidative activity and the protein expression of NADPH oxidase subunits gp91phox and p22phox) and the expression of profibrotic factors transform growth factor β1 and fibronectin. Ang II also inhibited the phosphorylation of endothelial nitric oxide synthesis (eNOS, ser1177). LEC revised most of the changes in the Ang II-induced molecules as mentioned above. Our results suggest that renal macrophage is a main mediator to contribute to Ang II-induced hypertensive renal injury and fibrosis, the underlying mechanisms may involve reduction in macrophage-drove renal inflammation and restoration of the balance between renal oxidative stress and eNOS. These findings may lead us to develop a novel therapy directed at targeting the infiltration of macrophages or the macrophages-derived cytokines for treatment of hypertensive renal diseases.

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity . The rats were fed either a high fat (HFD) or normal rat chow (NFD) diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP 146 ± 3 vs. 130 ± 5 mmHg in NFD , p2 - 1357 ± 142 vs. 847 ± 102 counts/min/mg in NFD, p2 - (1689 ± 87 counts/min/mg, p

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity. The rats were fed either a high fat (HFD) or normal rat chow diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP), aortic superoxide (O2-) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR). Nicotine further increased SBP, O2- and impaired eNOS and EDR in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2-4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet-induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.

Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36+/CD14+cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE−/−mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36−/−apoE−/−mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration.

Puerarin, a major isoflavonoid compound isolated from the Chinese herb Kudzu roots, has been a long history and widely used for treatment of cerebral and cardiovascular diseases in China and other Asian countries, including coronary artery disease, heart failure and myocardial infarction. However, the underlying mechanisms by which puerarin inhibits vascular atherogenic diseases are largely unknown. The activated macrophages release of inflammatory cytokines and uptake of oxLDL forming foam cells are critical for the development of atherosclerotic plaque. The present study investigated whether puerarin inhibited atherogenic lipid oxLDL-mediated macrophage activation and foam cell formation in human THP1 macrophage. The Cells were cultured and differentiated into macrophages by pre-incubation with 100 ng/ml PMA. Treatment with oxLDL (50 μg/ml) significantly increased the mRNA expression of proinflammatory cytokines tumor necrosis factor α(TNFα, 160%) and interleukin (IL)1β(13 fold) accompanied by upregulation of toll-like receptor 4 (TLR4, 165%) and the ratio of phospho-I κ Bα/I κ Bα in THP1 macrophage. Puerarin dose-dependently prevented an increase in oxLDL-induced proinflammatory gene expression with downregulation of TLR4 and the ratio of phospho-I κ Bα/I κ Bα. Furthermore, puerarin prevented oxLDL-mediated lipid deposition and foam cell formation associated with downregulation of scavenger receptor CD36. Flow cytometry analysis showed that puerarin reduced the number of early apoptotic cells of macrophages induced by oxLDL. Our results show that puerarin has anti-inflammatory and anti-atherogenic effects in vitro, the underling mechanisms may involve the inhibition of TLR4/NF κ B pathway and downregulation of CD36 expression. The results from the present study provide scientific evidence and may expand our armamentarium to use puerarin for prevention and treatment of cardiovascular and atherosclerotic diseases.

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 ± 8 vs. 150 ± 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F2α-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-β (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (−44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg·kg−1·day−1) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-β1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 ± 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-β1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.

Salt-sensitive (SS) hypertension is a vascular diathesis characterized by reduced cardiovascular and renal nitric oxide bioavailability and local upregulation of ANG II. We have demonstrated that rats infused with ANG II manifest increased cortical cyclooxygenase (COX)-2 expression and activity via NADPH oxidase-derived reactive oxygen species (ROS). In the present studies we used Dahl salt-sensitive (DS) rats to test the hypothesis that hypertensive SS rats have increased cortical COX-2 upregulation, which is mediated by ANG II and ROS. DS rats were placed on either a normal-salt diet (0.5% NaCl) or a high-salt diet (4% NaCl) for 6 wk and treated with either the ANG II type 1 (AT1) receptor blocker candesartan (Can, 10 mg·kg−1·day−1) or the SOD mimetic tempol (1 mmol/l). Hypertensive SS rats had a twofold increase in the cortical expression of COX-2 as assessed by Western blot. These changes in COX-2 expression were accompanied by a 10-fold increase in COX-2 mRNA expression and a 2-fold increase in the urinary excretion of PGE2. Treatment with either the AT1receptor blocker Can or the SOD mimetic tempol did not reduce blood pressure but resulted in significant reductions in the cortical expression of COX-2 and the urinary excretion of PGE2. In conclusion, we have demonstrated that local activation of the renin-angiotensin system, via increased ROS generation, mediates COX-2 upregulation in hypertensive SS rats. These studies unveil novel mechanistic pathways that may play a role in the pathogenesis of hypertensive renal injury.

Background We have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endothelium-dependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)κB. Here we investigated whether Ang II activation of NFκB contributed to insulin resistance in the skeletal muscle of this animal model. Methods DS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFκB inhibitor PDTC (150 mg/kg in drinking water). Results DS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IκBα/IκBα ratio, ARB or tempol reduced ROS and phospho-IκBα/IκBα ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFκB SN50 (a specific peptide inhibitor of NFκB) ex vivo reversed changes in hypertension-induced gene expression. Conclusion The current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension.

Puerarin, an isoflavone derived from Kudzu roots, has been widely used for treatment of cardiovascular and cerebral vascular diseases in China and other Asian countries. However, the underlying mechanisms are largely unknown. The present study investigated whether puerarin inhibited atherogenic lipid oxLDL-mediated macrophage activation and foam cell formation in human THP1 macrophage. Treatment with oxLDL significantly increased the mRNA expression of proinflammatory cytokines tumor necrosis factorα(TNFα, 160%) and interleukin (IL) 1β(13 fold) accompanied by upregulation of toll-like receptor 4 (TLR4, 165%) and the ratio of phospho-IκBα/IκBαin THP1 macrophage. Puerarin dose-dependently prevented an increase in oxLDL-induced proinflammatory gene expression with downregulation of TLR4 and the ratio of phospho-IκBα/IκBα. Furthermore, puerarin prevented oxLDL-mediated lipid deposition and foam cell formation associated with downregulation of scavenger receptor CD36. Flow cytometry analysis showed that puerarin reduced the number of early apoptotic cells of macrophages induced by oxLDL. Our results show that puerarin has anti-inflammatory and antiatherogenic effects in vitro; the underlying mechanisms may involve the inhibition of TLR4/NFκB pathway and downregulation of CD36 expression. The results from the present study provide scientific evidence and may expand our armamentarium to use puerarin for prevention and treatment of cardiovascular and atherosclerotic diseases.

We studied the effect of hydrochlorothiazide (HCTZ), the angiotensin-converting enzyme inhibitor benazepril, the calcium channel blocker amlodipine, or a combination of benazepril/amlodipine or benazepril/HCTZ on systolic blood pressure (BP) and end-organ injury (left ventricular hypertrophy, proteinuria, and endothelium-dependent relaxation to acetylcholine) in hypertensive Dahl salt-sensitive rats fed either a normal-salt (0.5% NaCl) or high-salt (4% NaCl) diet for 6 weeks. Rats fed a high-salt diet developed hypertension and significant end-organ injury. Monotherapy with HCTZ (75 mg/L in drinking water) or amlodipine (10 mg/kg/day by gavage) reduced systolic BP and proteinuria; benazepril (40 mg/kg/day by gavage) decreased proteinuria without significantly lowering systolic BP. In rats receiving a high-salt diet, only HCTZ reduced left ventricular hypertrophy, whereas endothelium-dependent relaxation was improved by amlodipine and benazepril but not by HCTZ. Combining benazepril with either amlodipine or HCTZ dramatically reduced systolic BP and end-organ injury. These data clearly support clinical studies suggesting that combination therapy is more effective than monotherapy for systolic BP control and prevention of end-organ injury. Complementary mechanisms of action of agents from different antihypertensive classes appear to facilitate the greater benefit on BP and end-organ injury.

Epidemiological studies have shown that obesity and cigarette smoking (CS) are major cardiovascular (CV) risk factors and when coexisting in the same individuals have additive/synergistic effects upon CVD development. We have shown that stable compounds of CS (ATVB 2004) as well as nicotine, in concentrations found in smoker’s plasma, promote atherosclerotic CVD (AJP 2013). Here we studied in Sprague Dawley (SD) rats with diet -induced obesity the mechanisms involved in nicotine enhancement of CVD. SD rats (N=6-7 each group) were fed either a high fat (HF) or a standard chow (SCH) diet with or without nicotine (100 mg/kg/day in the drinking water) for 20 weeks. The HF rats developed central obesity, characterized by increased body weight gain (22%) and abdominal fat weight (53%), increased plasma levels of cholesterol (33%), non-esterified free fatty acids (68%), insulin (15%) glucose (12%)and systolic blood pressure (SBP: 146 ± 5 vs. 131 ± 5 mmHg SCH rats, p

It has been speculated that if baroafferent signals are only related to the negative feedback control of arterial pressure (AP), then physical activity would increase the range of AP fluctuation in baroafferent-denervated animals. Mean AP (MAP), heart rate (HR), and cardiac output (CO) were measured for 24 h in free-moving conscious rabbits. On the basis of hydrostatic pressure and electromyogram, MAP data taken during periods of physical activity and rest were selected from the overall 24-h MAP data and then converted into histograms. During physical activity, the mode of MAP histogram increased in intact rabbits and was unchanged in sinoaortic-denervated (SAD) rabbits. Movement increased the mode of total peripheral resistance (TPR) but did not significantly change CO in intact rabbits. Conversely in SAD rabbits, movement slightly decreased TPR and slightly increased CO. These findings indicate that arterial baroafferent signals are required to shift MAP to a higher pressure level by an increase in TPR but not in CO during a moving phase. These results suggest that baroafferent signals may not only minimize the fluctuating range of MAP through negative feedback control but also be involved in actively resetting MAP toward a higher pressure level during daily physical activity.

JRAAS 2001;2 (suppl 1):S59-S63 Introduction Many vasoactive substances, such as nitric oxide (NO), endothelin 1 (ET-1), angiotensin II (Ang II), and superoxide anion (O2-) participate in the regulation of cardiovascular function. The balance between these molecules may play a crucial role in maintenance of cardiovascular homeostasis. In most circumstances, NO is an important molecule in terms of cardiac and vascular protection. NO produced by the endothelium modulates vasomotor tone and inhibits platelet aggregation and smooth muscle cell and mesangial cell proliferation. It has also been suggested to have antiatherogenic properties. Ang II, on the other hand, is a powerful vasoconstrictor peptide that has antinatriuretic and prothrombogenic properties. Increased Ang II or overexpression of the Ang II type 1(AT1)-receptor is associated with vascular remodelling in some pathological conditions. O2and other reactive oxygen species (ROS) are often regarded as deleterious molecules. O2can increase vascular constriction, promote growth, and induce oxidant injury. Under normal physiological conditions, O2can be effectively scavenged by antioxidants such as O2dismutase (SOD), which will minimise oxidative damage.Excessive O2interacts with NO to reduce NO bioavailability and generate peroxynitrite, which can induce cardiovascular oxidative injury.

Recent studies have demonstrated that the renin angiotensin system (RAS) has profound effects on atherosclerosis, but the mechanisms underlying remain unclear. Macrophages play a central role in atherogenesis through scavenger receptor-mediated lipid accumulation, production of inflammatory cytokines and transformation of macrophages into foam cells. Macrophages express all components of RAS. Here we investigated the effects of Ang II on macrophage activation and foam cell formation, and underlying the mechanisms involved. In human THP1 macrophages, Ang II (100 nM) in time-dependent manner increased the mRNA expression of proinflammatory cytokines MCP1, TNFa, IL1b, IL6, CXCL9 and PAI1, Ang II also upregulated mRNA expression of CD36, TLR4 and hypoxia induced factor (HIF)1a. Knockdown of HIF1a by SiRNA prevented Ang II upregulation of CD36 and TLR4 expression, and significantly reduced the Ang II-induced proinflammatory cytokine expression. Next, we investigated the effects of Ang II on oxLDL uptake and foam cell formation, Ang II increased oxLDL uptake, which was prevented by either siRNA HIF1a or siRNA CD36. The incubation with oxLDL (50 ug/ml) for 72 hours result in lipid deposition in macrophage or foam cell formation, preincubation with Ang II further increased oxLDL-induced lipid deposition and foam cell formation, which was also prevented by either siRNA HIF1a or siRNA CD36. Infusion of Ang II into Apo E-/- mice significantly increased systolic blood pressure, the peripheral blood CD11b+/LyC6Hi inflammatory monocyte population and mRNA expression of IL1b and TNF1a in the peritoneal macrophages, Ang II also significantly increased atherosclerotic lesion formation. Hydrolazine normalized SBP but did not significantly reduce CD11b+/LyC6hi inflammatory monocyte population and atherosclerotic lesion formation in the apo E-/- mice treated with Ang II. The present study demonstrates, for the first time, that Ang II activates HIFa-CD36 pathway in human macrophage, which potentiate atherogenic lipid-induced macrophage activation and foam cell formation. Our novel findings may elucidate new mechanisms by which Ang II promotes atherogenesis through mediating macrophage activation and lipid metabolism.

In order to investigate the role of acupuncture in the regulation of cellular immune function, the changes of T lymphocyte subsets (CD3+, CD4+, CD8+), soluble interleukin-2 receptor (SIL-2 R) and beta-endorphine (beta-EP) in the peripheral blood of patients with malignant tumors before and after acupuncture were observed with double blind method. Forty patients were divided randomly into two groups, 20 for each. One group treated with acupuncture and the other one for control. Results showed that acupuncture has the effect of enhancing the cellular immunity of patient with malignant tumor. Acupuncture treatment could increase the percentage of T lymphocyte subsets CD3+, CD4+ and the CD4+/CD8+ ratio (P < 0.01) and the level of beta-EP, as well as decrease the level of SIL-2 R (P < 0.01). The correlation analysis of the three criteria showed there was a positive correlation between beta-EP and T lymphocyte subsets and a negative correlation between beta-EP and SIL-2 R, there was also a negative correlation between T lymphocyte subsets and SIL-2 R. Based on these results, a discussion on the acupuncture immunomodulation network was conducted in this article in order to explore the possible mechanism of acupuncture on immunomodulation.

In hypertension aortic (Ao) stiffness is a main determinant of increased systolic (SBP) and pulse- pressure (PP). Brachial and Ao SBP and PP often differ; Ao pressures predict cardiovascular events more accurately than brachial pressures. It is surmised that increased pressure-workload is cause and effect of Ao stiffening but the mechanisms involved are poorly understood. Rho Kinase is a master regulator of vascular tone and remodeling: In endothelium Rho kinase decreases eNOS expression and NO production. In VSMC Ang II/ AT1R specifically activates Rho Kinase via phosphorylation of Jak2 /Arhgef1 which phosphorylates (inhibits) myosin light chain phosphatase (MYPT1) thereby promoting vasoconstriction. Groups (n= 6) of Dahl SS (DS) rats fed either 0.5% or 4% NaCl diets for 10 weeks were matched with SHR of similar age (6 and 16weeks old) and SBP (147+8 & 211+7). Hypertensive DS rats, but not SHR showed increased Ao weight/length (17%, P Clinically the variable end-organ disease observed in individuals with similar severity of hypertension may be linked, at least in part, to genetically conditioned differences in Angll/AT1R, Jak-2 activation in response to high dietary salt. These novel studies extend and complement previous studies by us and others implicating abnormal bioactivity of NO and aldosterone in salt sensitive hypertension and unravel a new and intricate pathway in which Rho Kinase plays a pivotal role.

The incidence of metabolic syndrome is rapidly increasing in the United States and worldwide. The metabolic syndrome is a complex metabolic and vascular disorder that is associated with inappropriate activation of the renin–angiotensin–aldosterone system (RAAS) in the cardiovascular (CV) system and increased CV morbidity and mortality. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes nitric oxide (NO) production in the endothelium and glucose uptake in insulin-sensitive tissues. Angiotensin (Ang) II inhibits insulin-mediated PI3K pathway activation, thereby impairing endothelial NO production and Glut-4 translocation in insulin-sensitive tissues, which results in vascular and systemic insulin resistance, respectively. On the other hand, Ang II enhances insulin-mediated activation of the mitogen-activated protein kinase (MAPK) pathway, which leads to vasoconstriction and pathologic vascular cellular growth. Therefore, the interaction of Ang II with insulin signaling is fully operative not only in insulin-sensitive tissues but also in CV tissues, thereby linking insulin resistance and CV disease. This notion is further supported by an increasing number of experimental and clinical studies indicating that pharmacological blockade of RAAS improves insulin sensitivity and endothelial function, as well as reduces the incidence of new-onset diabetes in high-risk patients with CV disease. This article reviews experimental and clinical data elucidating the physiological and pathophysiological role of the interaction between insulin and RAAS in the development of insulin resistance as well as CV disease.

Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important endogenous system in the maintenance of endothelial integrity and vascular homeostasis. Cardiovascular risk factors are associated with a reduced number and functional capacity of EPCs. Here we investigated the effect of transplantation of bone marrow-derived cells from Dahl salt-resistant rat into age-matched Dahl salt-sensitive (DS) rat on blood pressure, endothelial function, and circulating EPC number. The recipient DS rats were fed a normal (0.5% NaCl, NS) or high-salt (4% NaCl, HS) diet for 6 weeks after bone marrow transplantation (BMT). DS rats on a NS or a HS diet without BMT were used as controls. Hypertensive DS (HS-DS) rat (systolic blood pressure: 213 ± 4 mm Hg vs. 152 ± 4 mm Hg in NS, P.05) manifested impaired endothelium-dependent relaxation to acetylcholine (EDR), increased gene expression of vascular oxidative stress and proinflamamtory cytokines, and decreased eNOS expression. BMT on HS-DS rat significantly improved EDR and eNOS expression, reduced oxidative stress without reduction in SBP (206 ± 6 mm Hg). Flow cytometry analysis showed that there was no difference in the number of circulating EPCs, demonstrated by expression of EPC markers CD34, cKit, and vascular endothelial growth factor, between hypertensive and normotensive rats. Surprisingly, BMT resulted in a 5- to 10-fold increase in the previously mentioned EPC markers in hypertensive, but not normotensive rat. These results suggest that DS rat has an impaired ability to increase bone marrow-derived EPCs in response to HS diet challenge, which may contribute to endothelial dysfunction.

Reduced numbers and activity of circulating progenitor cells are associated with aging and have been linked with coronary artery disease. To determine the impact of aging and atherosclerotic disease on the chemotaxic activity of bone marrow derived cells (BMCs), we examined CXCR4 surface expression on BMCs from aged and atherosclerotic mice.CXCR4 expression and cellular mobility were compared between BMCs of young (6-week old) ApoE null mice (ApoE(-/-)) and aged ApoE(-/-) mice that had been fed with a high-fat, high-cholesterol diet for 6-months.Age and atherosclerosis correlated with significantly lower surface expression of CXCR4 that was less inducible by calcium. The impaired calcium response was associated with defective calcium influx and was partially recovered by treatment with the calcium ionophore ionomycin. ApoE(-/-) mice fed high fat diet for 6-months had defective CXCR4 expression and SDF-1 regulation that is equivalent to that of 24-month old wild type mice. BMCs from aged, atherogenic ApoE(-/-) mice also displayed defective homing to SDF-1, and the animals had lower serum and bone marrow levels of SDF-1.Evolution of atherosclerosis in ApoE(-/-) mice is paralleled by progressive loss of mobility of BMCs with reductions of CXCR4 expression, and reduced levels of SDF-1 in both serum and bone marrow. These changes mute the homing capability of BMCs and may contribute to the progression of atherosclerosis in this model.

Insulin activation of the phosphatidylinositol 3-kinase (PI3K) pathway stimulates glucose uptake in peripheral tissues and synthesis of nitric oxide (NO) in the endothelium. Insulin resistance (IR) and hypertension frequently coexist, particularly among individuals with salt-sensitive hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of salt-sensitive hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide anion (O2−) linked to local ANG II. Dahl salt-sensitive rats were fed, for 6 wk, a normal salt diet (NS; 0.5% NaCl), high-salt diet (HS; 4% NaCl), HS plus the ANG II type 1 receptor (AT1R) blocker (ARB) candesartan (10 mg·kg−1·day−1), or HS plus the antioxidant tempol (172 mg/l in drinking water). Hypertensive (mean arterial pressure: 145 ± 4 vs. 102 ± 5 mmHg in NS, P < 0.05) rats manifested increased aortic AT1R mRNA (210%) and protein (101%) expression and O2− production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response ( Emax): 68 ± 9 vs. 91 ± 8% in NS, P < 0.05]. ARB or tempol normalized O2− and EDR despite that they did not normalize mean arterial pressure, which was reduced only 25%. Hypertensive rats manifested metabolic IR (36% reduction in the glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR ( Emax: 12 ± 5 vs. 32 ± 4% in NS, P < 0.05), and impaired insulin activation of PI3K/endothelial NO synthase. ARB or tempol improved insulin-mediated EDR, PI3K, Akt/ endothelial NO synthase phosphorylation, and metabolic IR (all P < 0.05). This study provides insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that O2− overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.

To the Editor: We read with great interest the article by Strazzullo et al1 in which they report a meta-analysis of 20 randomized, controlled trials of statin therapy and show that statins slightly but significantly reduced systolic blood pressure (−1.9 mm Hg in total patients and −4.0 mm Hg in the patients with systolic blood pressure >130 mm Hg). Statins have pleiotropic effects on the vasculature, including upregulation of endothelial NO synthase expression and activity, downregulation of endothelin-1 and angiotensin II receptor subtype 1 expression, …

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase–derived reactive oxygen species (ROS), plays a critical role in ED. gp91 phox , predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91 phox . We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47 phox with gp91 phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168±5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159±5 mm Hg; P >0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.

Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O 2 − ) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O 2 − in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200±8 versus 150±2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P P 2 − (2632±316 versus 1176±112 counts/min per milligram in NS; P 2 α isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5±0.3 nmol/min per gram protein) as well as the increase in O 2 − (1192±243 counts/min per milligram) and plasma 8-F 2 α isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174±8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.

Calcium channel blockers such as amlodipine are effective antihypertensive agents. In this study we investigated the effects of amlodipine on vascular oxidative stress, expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1), and endothelial function in angiotensin (Ang) II-infused rats.Sprague-Dawley rats were treated with Ang II (0.7 mg/kg/day subcutaneously injected by mini-pump), with or without amlodipine (10 mg/kg/day by gavage), for 5 days and compared with control rats. Levels of aortic ring superoxide (O(2)(-)) and peroxynitrite (ONOO(-)) were determined, and systolic blood pressure (SBP) and endothelium-dependent relaxation were evaluated.Compared with control rats, Ang II-infused rats developed hypertension (175 +/- 3 v 135 +/- 2 mm Hg, P.05), aortic hypertrophy (16.9 +/- 1.3 v 13.2 +/- 0.3 mg/cm, P.05), left ventricular hypertrophy (0.236 +/- 0.003 v 0.204 +/- 0.004 g/100 g body weight, P.05), and impaired endothelium-dependent relaxation (ED(50): 6.6 +/- 0.2 v 8.0 +/- 0.2 -log mol/L acetylcholine concentration, P.05). Compared with control rats, Ang II-infused rats also had higher aortic levels of LOX-1 mRNA expression, O(2)(-)production (1005 +/- 140 v 608 +/- 159 counts/min/mg, P.05), ONOO(-) production (1875 +/- 295 v 782 +/- 115 counts/min/mg, P.05), and plasma free 8-F(2)alpha-isoprostanes (67.4 +/- 19.1 v 27.2 +/- 6.1 pg/mL, P.05). In Ang II-infused rats SBP, aortic hypertrophy, endothelial dysfunction, LOX-1 expression, aortic O(2)(-) and ONOO(-) production, and plasma free 8-F(2)alpha-isoprostane levels were significantly reduced by amlodipine treatment.Amlodipine has antihypertensive and antioxidant activity in vivo, which effectively inhibits many of the oxidative stress-dependent mechanisms involved in Ang II-mediated cardiovascular injury.

The balance between endothelial nitric oxide (NO) and angiotensin II (Ang II) maintains the homeostasis of the cardiovascular and renal systems. We tested the hypothesis that increased oxidant stress linked to a functional imbalance between NO and Ang II might play a central pathogenetic role in salt-sensitive (SS) hypertension. We studied Dahl SS (DS) rats during the prehypertensive (5 days) and hypertensive (12 weeks) phases of a high-salt (4% NaCl) diet. Control rats received a normal-salt (0.5% NaCl, [NS]) diet. Prehypertensive DS rats (systolic blood pressure [SBP] 138±2 mm Hg) manifested a 35% increase ( P 2 − ) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214±11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O 2 − production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg · kg −1 · d −1 ) an Ang II type 1 receptor blocker (ARB), normalized O 2 − production. In hypertensive DS rats, the ARB decreased aortic O 2 − production by 71% and normalized EDR without affecting SBP (212±8 mm Hg), aortic hypertrophy, LVH, or proteinuria. Switching hypertensive DS rats to an NS diet did not affect SBP (208±8 mm Hg), LVH, aortic hypertrophy, or proteinuria and had minimal effects on O 2 − and EDR. Concomitant ARB administration plus a switch to an NS diet normalized SBP (138±8 mm Hg) as well as end-organ damage. Dahl salt-resistant rats fed an HS diet for 12 weeks did not show hypertension or increased O 2 − production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O 2 − synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.