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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.

Diabetic kidney disease is the leading cause of end-stage renal disease worldwide. Podocytes are highly differentiated, pericyte-like cells that are essential for normal function of the kidney filter. Loss of podocytes is a hallmark of progressive kidney diseases including diabetic nephropathy. Podocytes are a direct target for angiotensin II - mediated injury by altered expression and distribution of podocyte proteins. Additionally, angiotensin II promotes podocyte injury indirectly by increasing calcium influx and production of reactive oxygen species. Notwithstanding the convincing rationale for angiotensin II blockade as a treatment modality, the incidence of diabetes-related end stage renal disease has increased steadily despite widespread use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Recently published clinical trials have rekindled a debate on the safety and efficacy of dual blockade of the renin-angiotensin system (RAS). This review summarizes the rationale for blockade of angiotensin II as a therapeutic target in treating diabetic kidney disease, including the critical role played by podocytes. Recent relevant clinical trials on the role of RAS blockade in the treatment of diabetic kidney disease are discussed.

The c-Jun N-terminal kinases (JNKs) belong to the mitogen-activated protein kinases superfamily, which play an important role in the pathogenesis of cardiovascular and metabolic diseases. However, it is still unclear whether JNK participates in the regulation of vascular tone. We investigated the effect of JNK inhibitors on vascular reactivity in aortic rings in organ bath and on angiotensin (Ang) II-induced pressor responses in vivo in Sprague-Dawley (SD) rats. In aortic rings from SD rats, KCl, norepinephrine (NE), Ang II, or endothelin 1 (ET)-1 induced a dose-dependent vasoconstriction. Preincubation with the JNK inhibitor SP600125 (20 micromol/L) slightly inhibited KCl-induced vasoconstriction (Emax: -19%) and markedly inhibited vasoconstriction to NE (-42%), Ang II (-54%), and ET-1 (-42%). SP600125 induced a dose-dependent relaxation in the NE-preconstricted aortic rings (-54%) but exerted minimal relaxation in the KCI-preconstriction rings. To exclude the nonspecific effect of SP600125, we performed additional experiments using JNK peptide inhibitor 1, L-stereoisomer (L-JNKI1), a cell-permeable peptide inhibitor specific for JNK. Compared to SP600125, L-JNKI1 (20 micromol/L) had a smaller but still significant inhibitory effect on NE-induced vasoconstriction (-18%) and did not inhibit KCI-induced vasoconstriction. Next, we investigated the effect of L-JNKI1 (5 mg/kg intravenously [IV]) in vivo on Ang II-induced pressor responses in SD rats. Ang II induces a dose-dependent increase in systolic blood pressure and L-JNKI1 slightly attenuated the Ang II-induced pressor response. These results suggest that JNK signaling plays a role in the regulation of vascular tone.

Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 micromol/l), and angiotensin II (ANG II; 10(-7) mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin (PGI(2)) by 300%. In contrast, FFA did not upregulate COX-2 but increased PGI(2) (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia.

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 (O(2)(-)) 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 (AT(1)R) 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 AT(1)R mRNA (210%) and protein (101%) expression and O(2)(-) production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response (E(max)): 68 +/- 9 vs. 91 +/- 8% in NS, P < 0.05]. ARB or tempol normalized O(2)(-) 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 (E(max): 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 O(2)(-) overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.

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 AT1 receptor 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: Although there is overwhelming evidence that hypertension promotes atherosclerosis, the relative contribution and/or interaction of vasoactive and hemodynamic factors remain undefined. Endothelial dysfunction complicates hypertension and is a precursor of atherosclerosis. It is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide, and an increase in the activity of vasoconstrictors, including angiotensin (Ang) II and reactive oxygen species (ROS). Nitric oxide antagonizes the vasoconstrictive and pro-atherosclerotic effects of Ang II, whereas Ang II decreases nitric oxide bioavailability by promoting oxidative stress., Objectives: The present review will focus on the interaction among nitric oxide, Ang II, and ROS in the endothelium and will examine their role in vascular tone and atherogenesis. In this context, studies from our laboratory will be reviewed demonstrating that salt-sensitive hypertension is a vascular diathesis characterized by a local activation of Ang II and NAD(P)H oxidase-derived ROS in the setting of insufficient nitric oxide. In hypertensive Dahl salt-sensitive rats, a paradigm of human salt-sensitive hypertension, inhibition of Ang II type 1 receptor or NAD(P)H oxidase-derived ROS prevented the development of endothelial dysfunction, upregulation of pro-atherogenic molecules, and vascular ROS generation, independently of blood pressure., Conclusions: Salt sensitivity, an independent risk factor for increased cardiovascular morbidity and mortality, affects approximately 50% of hypertensives. Our studies suggest that, in salt-sensitive hypertension, atherogenesis is more closely linked to oxidative stress than to the hemodynamic stress of hypertension. To prevent or arrest atherosclerosis, antihypertensive therapy should aim at restoring the homeostatic balance between vasoactive factors in the vascular wall.

Hypertension is a major risk factor for cardiovascular disease and renal disease. After menopause, the incidence of hypertension increases in women to levels that equal or exceed that in men, suggesting a protective role of female sex hormones. Salt sensitivity of blood pressure is associated with an increased risk for development of hypertension and cardiovascular disease. We and others have demonstrated that after menopause, the prevalence of salt sensitivity increases, suggesting that female sex hormones influence renal sodium handling and blood pressure regulation. A homeostatic balance between the counteracting effects of nitric oxide (NO) and angiotensin (Ang) II on pressure natriuresis, renal hemodynamics, tubular sodium reabsorption, and oxidative stress plays an important role in modulating salt sensitivity as well as hypertensive end-organ injury. Estrogens modulate the activity and expression of NO and Ang II. We infer that after menopause, estrogen deficiency promotes an unbalance between NO and Ang II, resulting in disturbed renal sodium handling, oxidative stress, and hypertension, particularly in genetically prone women. A better understanding of the mechanisms underlying the development of postmenopausal hypertension and associated cardiovascular and renal diseases should provide insights into preventive and therapeutic strategies., (Copyright 2006 S. Karger AG, Basel)

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. gp91phox, 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 gp91phox. 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 p47phox with gp91phox 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.

Background: Prostaglandins such as prostaglandin E(2) (PGE(2)) and prostaglandin I(2) (PGI(2)) counteract the angiotensin II (Ang II)-induced vasoconstriction in the glomerular microcirculation. We have shown that Ang II promotes mesangial cell hypertrophy via reactive oxygen species (ROS), which originate from nicotinamide adenine dinucleotide phosphate and its reduced form (NADH/NADPH) oxidase. It has been reported that conditions associated with activation of the renin-angiotensin system result in increased glomerular cyclooxygenase-2 (COX-2) expression and activity., Methods: We designed studies to determine (1) whether Ang II induces COX-2 in the glomerulus in vivo in the glomerulus as well as in vitro in mesangial cells, (2) whether ROS originated from Ang II are involved, and (3) whether COX-2-derived prostaglandins modulate the growth promoting effects of Ang II in mesangial cells. Rats were infused with Ang II (0.7 mg/kg/day) for 5 days and glomerular COX-2 expression and activity assessed in isolated glomeruli., Results: Ang II increased glomerular PGE(2) production (100%) accompanied by a concomitant increase in glomerular COX-2 expression at the mRNA (1.7-fold) and protein level (sixfold). In mesangial cells, Ang II significantly increased mesangial cell PGE(2) (200%) and PGI(2) (100%) production as well as COX-2 mRNA that was prevented by the angiotensin type 1 (AT1) receptor blocker irbesartan and the COX-2 inhibitor NS-398. The NADPH oxidase inhibitor diphenyleneiodonium (DPI), the ROS scavenger tiron as well as catalase, inhibited Ang II-induced PGE(2) production suggesting that Ang II-induced ROS mediate COX-2 up-regulation. Strikingly, COX-2 inhibition as well as blockade of the type 1 PGE(2) receptor (EP1) prevented Ang II-induced mesangial cell hypertrophy suggesting that COX-2-derived prostaglandins, and specifically PGE(2), importantly contribute to the growth promoting effects of Ang II., Conclusion: These studies suggest that blockade of specific PGE(2) receptors may be a novel strategy to modulate the pathologic effects of COX-2-derived prostaglandins without simultaneously affecting protective vasodilatory mechanisms.

Objective: Angiotensin (Ang) II increases reactive oxygen species (ROS), decreases nitric oxide (NO) bioavailability and promotes cardiovascular remodeling. ROS have been identified as critical second messengers of the trophic responses by Ang II. In rats with Ang II-induced hypertension, we investigated the role of ROS in cardiac hypertrophy as well as the remodeling of aortas and mesenteric (resistance) arteries., Methods: Sprague-Dawley rats received Ang II (0.7 mg/kg per day by mini-pump, n = 7) or vehicle (n = 7) for 5 days. Endothelium-dependent relaxation to acetylcholine (EDR) in aortas was determined in organ baths and in mesenteric resistance vessels in a pressurized myograph. Superoxide (O2) production was measured by lucigenin chemiluminescence, laser-confocal fluorescence microscopy (LCM) and NADPH oxidase assay., Results: Ang II-treated rats developed hypertension (183 +/- 3 versus 138 +/- 4 mmHg, P < 0.05), increased aortic O2 (50%), aortic hypertrophy (12%) and impaired EDR. Mesenteric arteries manifested impaired EDR, increased NADPH oxidase activity (356%) and eutrophic inward remodeling (decreased lumen diameter and increased wall/lumen ratio). However, although Ang II-treated rats developed cardiac hypertrophy (13%), this was not accompanied by an increase in cardiac O2, as measured by lucigenin, LCM or NADPH oxidase assay. On the other hand, cardiac calcineurin, a molecule that promotes cardiac hypertrophy linked to Ang II, was increased by 40% (52 +/- 8 versus 33 +/- 5 pmol/min per mg protein, P < 0.05)., Conclusion: These studies demonstrate that the role of ROS in Ang II-induced vascular remodeling differ across vascular territories. Although in conduit and resistance vessels, vascular hypertrophy and endothelial dysfunction are linked to increased ROS production, cardiac hypertrophy is not. Instead, cardiac hypertrophy is associated, at least in part, with an increase in calcineurin. These studies unveil novel mechanisms that may play an important role in the pathogenesis of cardiac and vascular injury in hypertension.

A balance among nitric oxide (NO), angiotensin II (Ang II), and reactive oxygen species (ROS) in the endothelium is necessary for maintaining the homeostasis of the vascular wall. Oxidative stress has been shown to play a critical role in the development of hypertension and atherosclerosis. Although there is overwhelming evidence that hypertension promotes atherosclerosis, the relative contribution and/or interaction of hemodynamic and oxidative stress remains undefined. NO is synthesized in the endothelium by NO synthase and antagonizes the vasoconstrictive and proatherosclerotic effects of Ang II. On the other hand, Ang II decreases NO bioavailability by promoting oxidative stress. A better understanding of the pathophysiologic mechanisms involved in the link between hypertension and atherosclerosis may aid in developing therapeutic interventions. We propose that those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents in the endothelium would be more effective in preventing or arresting atherosclerosis.

Although initially adaptive, the changes that accompany hypertension, namely, cell growth, endothelial dysfunction, and extracellular matrix deposition, eventually can become maladaptive and lead to end-organ disease such as heart failure, coronary artery disease, and renal failure. A functional imbalance between angiotensin II (Ang II) and nitric oxide (NO) plays an important pathogenetic role in hypertensive end-organ injury. NO, an endogenous vasodilator, inhibitor of vascular smooth muscle and mesangial cell growth, and natriuretic agent, is synthesized in the endothelium by a constitutive NO synthase. NO antagonizes the effects of Ang II on vascular tone, cell growth, and renal sodium excretion, and also down-regulates the synthesis of angiotensin-converting enzyme (ACE) and Ang II type 1 receptors. On the other hand, Ang II decreases NO bioavailability by promoting oxidative stress. A better understanding of the pathophysiologic mechanisms involved in hypertensive end-organ damage may aid in identifying markers of cardiovascular susceptibility to injury and in developing therapeutic interventions. We propose that those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as Ang II and NO within the vessel wall would be more effective in preventing or arresting end-organ disease.

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<0.05) in aortic superoxide (O2-) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214+/-11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O2- production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg x kg(-1) x d(-1)) an Ang II type 1 receptor blocker (ARB), normalized O2- production. In hypertensive DS rats, the ARB decreased aortic O2- 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 O2- 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 O2- production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O2- synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.

Background: We have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endotheliumdependent 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. [ABSTRACT FROM AUTHOR]

The article discusses a study on whether c-JUN N-terminal kinases (JNKs) plays a role in the regulation of vascular tone. The effect of JNK inhibitors on vascular reactivity in aortic rings in organ bath and on angiotensin (Ang) II-induced pressor responses in vivo in Sprague-Dawley (SD) rats was investigated by the researchers. The results indicate that JNK signaling has a role in the regulation of vascular tone.

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% NaCI), 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-β 1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Abstract: Nitric oxide (NO) has multiple protective effects for regulating the cardiovascular and renal systems. The major functions include endothelium-dependent relaxation, anti-inflammatory effects, as well as antihypertrophic and antithrombotic activities. Many of the activities mediated by NO are systematically antagonized by angiotensin-II (Ang II), a vasconstrictor peptide. Studies described in the review below have demonstrated that the balance between NO and Ang II activities rather than the absolute concentration of each molecule determines their effects on the physiology and pathophysiology of the cardiovascular and renal systems. NO donors have been used for years as therapeutic agents for a range of cardiovascular conditions including angina, myocardial infarction and for the reduction of arterial stiffness. An understanding of the mechanisms underlying the effects of these medications will enable the development of novel therapies to balance the effects of NO in the cardiovascular system. [Copyright &y& Elsevier]

Angiotensin II, nitric oxide, and end-organ damage in hypertension. The adaptive changes that accompany hypertension and involve the kidney, heart, and vessels, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction and extracellular matrix increase can, in fact, be maladaptive and eventually lead to end- organ disease, such as renal failure, heart failure, and coronary disease. However, these changes vary markedly between individuals with similar levels of hypertension. Nitric oxide (NO), an endogenous vasodilator and inhibitor of vascular smooth muscle and mesangial cell growth, is synthesized in the endothelium by a constitutive NO synthase (NOS). NO antagonizes the effects of angiotensin II on vascular tone and growth and also down- regulates the synthesis of angiotensin converting enzyme (ACE) and angiotensin II type 1 (AT-1) receptors. In hypertension, the physiologic response to the increased shear stress and cyclic strain is to upregulate NOS activity in endothelial cells. Upregulation of vascular NOS activity is a homeostatic adaptation to the increased hemodynamic workload that may help in preventing end-organ damage. Indeed, hypertension-prone salt-sensitive rats manifest a decrease (instead of an increase) in vascular NOS activity when hypertensive; these rats develop severe vascular hypertrophy, left ventricular hypertrophy, and renal injury. Studies in hypertensive humans suggest that, independent of the effects of salt on blood pressure, salt sensitivity may be a marker for susceptibility to the development of endothelial dysfunction as well as cardiovascular and renal injury. We hypothesize that in hypertension, recognition of markers of cardiovascular susceptibility to injury and the understanding of the pathophysiological mechanisms involved may open new opportunities for therapeutic intervention. In this context, only those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as angiotensin II and NO within the vessel wall would be effective in preventing or arresting end-organ disease. [ABSTRACT FROM AUTHOR]

Angiotensin II induces superoxide anion production by mesangial cells. Background. The recognized role of angiotensin II (Ang II) in the pathogenesis of the progression of renal disease cannot be solely attributed to Ang II's hemodynamic effects. Indeed, growth stimulating signals driven by Ang II promote mesangial cell (MC) hypertrophy and extracellular matrix production, prominent features of progressive glomerular injury. Superoxide anion (O2 - ) avidly interacts with nitric oxide, an endogenous vasodilator that inhibits growth factor stimulated MC growth and matrix production. In addition, O2 - acting as an intracellular signal is linked to growth related responses such as activation of mitogen activated protein (MAP) kinases. The studies reported herein were designed to investigate: (a ) whether Ang II induces MC O2 - production and (b ) if increased O2 - production elicits growth responses in MC. Methods. MC were exposed to Ang II for 24 or 48 hours. In some experiments, in addition to Ang II, MC were exposed to: diphenylenieodonium (DPI), an inhibitor of the flavin containing NADH/NADPH oxidase; losartan (LOS), an Ang II type 1 (AT1) receptor blocker; PD 98059, a MAP kinases inhibitor; the protein kinase C inhibitors Calphostin C or H-7; and the tyrosine kinase inhibitors, herbymycin A or genistein. Results. Ang II (10-5 M to 10-8 M) dose dependently increased MC O2 - production up to 125% above control (ED 50 5 × 10-7 M). LOS as well as DPI, and the PKC inhibitors blocked Ang II stimulated MC O2 - production. Ang II dose dependently increased MC 3 H-leucine incorporation, and MC protein content, two markers of MC hypertrophy, as well as 3 H-thymidine incorporation, a marker of MC hyperplasia. PD98059, a specific inhibitor of MAP kinases prevented Ang II induced MC... [ABSTRACT FROM AUTHOR]