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Background Albuminuria is a known marker of mortality risk. Whether the association between albuminuria and mortality differs by demographic and comorbidity factors remains unclear. Therefore, we sought to determine whether albuminuria is differentially associated with mortality. Methods and Results This study included 49 640 participants from the National Health and Nutrition Examination Survey (1999-2018). All-cause mortality through 2019 was linked from the National Death Index. Multivariable-adjusted Poisson regression models were used to determine whether levels of urine albumin-to-creatinine ratio (ACR) were associated with mortality. Models were adjusted for demographic, socioeconomic, behavioral, and clinical factors. Mean age in the population was 46 years, with 51.3% female, and 30.3% with an ACR ≥10 mg/g. Over a median follow-up of 9.5 years, 6813 deaths occurred. Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 132% overall (95% CI, 2.01-2.68), 124% among men (95% CI, 1.84-2.73), 158% among women (95% CI, 2.14-3.11), 130% among non-Hispanic White adults (95% CI: 1.89-2.79), 135% among non-Hispanic Black adults (95% CI, 1.82-3.04), and 114% among Hispanic adults (95% CI, 1.55-2.94). Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 148% among individuals with neither hypertension nor hypercholesterolemia (95% CI, 1.69-3.64), 128% among individuals with hypertension alone (95% CI, 1.86-2.79), and 166% among individuals with both hypertension and hypercholesterolemia (95% CI, 2.18-3.26). Conclusions We found strong associations between albuminuria and mortality risk, even at mildly increased levels of albuminuria. Associations persisted across categories of sex, race or ethnicity, and comorbid conditions, with subtle differences.

Background Among US Hispanics/Latinos, the largest ethnic minority population in the United States, hypertension incidence has not been thoroughly reported. The goal of this study was to describe the incidence of hypertension among US Hispanic/Latino men and women of diverse Hispanic/Latino background. Methods and Results We studied 6171 participants of the Hispanic Community Health Study/Study of Latinos, a diverse group of self-identified Hispanics/Latinos from 4 US urban communities, aged 18 to 74 years, and free from hypertension in 2008 to 2011 and re-examined in 2014 to 2017. Hypertension was defined as self-reported use of anti-hypertension medication, or measured systolic blood pressure ≥130 mm Hg, or diastolic blood pressure ≥80 mm Hg. Results were weighted given the complex survey design to reflect the target population. Among men, the 6-year age-adjusted probability of developing hypertension was 21.7% (95% CI, 19.5-24.1) and differed by Hispanic/Latino background. Specifically, the probability was significantly higher among men of Cuban (27.1%; 95% CI, 20.2-35.2) and Dominican (28.1%; 95% CI, 19.5-38.8) backgrounds compared with Mexican Americans (17.6%; 95% CI: 14.5-21.2). Among women, the 6-year age-adjusted probability of developing hypertension was 19.7% (95% CI, 18.1-21.5) and also differed by Hispanic/Latino background. Specifically, the probability was significantly higher among women of Cuban (22.6%; 95% CI, 18.3-27.5), Dominican (23.3%; 95% CI, 18.0-29.5), and Puerto Rican (28.2%; 95% CI, 22.7-34.4) backgrounds compared with Mexican Americans (16.0%; 95% CI, 13.9-18.4). Conclusions Hypertension incidence varies by Hispanic/Latino background, with highest incidence among those of Caribbean background.

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.

The authors evaluated the blood pressure (BP)-lowering effects of combination valsartan/hydrochlorothiazide (HCTZ) vs. amlodipine/HCTZ in a 16-week, double-blind, randomized, forced-titration study and ambulatory BP monitoring (ABPM) substudy involving centrally obese hypertensive patients 40 years and older. Patients were started on valsartan/HCTZ 160/12.5 mg or HCTZ 12.5 mg monotherapy, force-titrated at week 4 to valsartan/HCTZ 320/25 mg and HCTZ 25 mg, respectively. The HCTZ group initiated amlodipine 5 mg at week 8 and 10 mg at week 12. A subset of patients had 24-hour ABPM at baseline and weeks 8 and 16. At week 16 in the intent-to-treat population (n=401), valsartan/HCTZ and amlodipine/HCTZ lowered office systolic BP (-30.6 vs. -28.3 mm Hg; P=.14). In the ABPM subgroup (n=111), valsartan/HCTZ was more effective than amlodipine/HCTZ in reducing 24-hour systolic BP (-20.6 vs. -14.5 mm Hg; P=.011). In obese hypertensive patients, valsartan/HCTZ reduced office BP similar to amlodipine/HCTZ but lowered 24-hour systolic BP more., (© 2011 Wiley Periodicals, Inc.)

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.

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.

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.

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 (O2-) 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 O2- 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<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7+/-0.2 versus 1.8+/-0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O2- (2632+/-316 versus 1176+/-112 counts/min per milligram in NS; P<0.05) and plasma 8-F2alpha isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5+/-0.3 nmol/min per gram protein) as well as the increase in O2- (1192+/-243 counts/min per milligram) and plasma 8-F2alpha 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.

The functional balance between angiotensin II (Ang II) and nitric oxide (NO) plays a key role in modulating salt sensitivity. Estrogen has been shown to downregulate angiotensin type 1 (AT1) receptor expression and to increase the bioavailability of endothelium-derived NO, which decreases AT1 receptor expression. The present study tests the hypothesis that in the presence of genetic salt sensitivity, deficiency of endogenous estrogens after ovariectomy (OVX) fosters an upregulation of Ang II. Female Dahl salt-resistant (DR), Dahl salt-sensitive (DS), Wistar-Kyoto (WKY), and spontaneously hypertensive (SHR) rats underwent bilateral OVX or sham surgery (SHX) and were fed a normal salt diet (0.5% NaCl) for 14 weeks. Systolic blood pressures were measured every 2 weeks and were not significantly different between OVX and SHX for DR, WKY, and SHR groups. However, at the end of 14 weeks of normal salt diet, hypertension developed in DS OVX but not SHX rats (160+/-3 versus 136+/-3 mm Hg; P<0.05). Hypertension also developed in DS OVX rats pair-fed a normal salt diet (166+/-7 mm Hg). Development of hypertension in DS OVX rats was prevented by estrogen replacement (132+/-3 mm Hg), AT1 receptor blockade (119+/-3 mm Hg), or feeding a very low salt diet (0.1% NaCl; 129+/-4 mm Hg). Renal AT1 receptor protein expression was significantly elevated 2-fold in DS OVX relative to SHX rats and was prevented by estrogen replacement. These data strongly suggest that after OVX in salt-sensitive rats there is a lower threshold for the hypertensinogenic effect of salt that is linked to an activation of Ang II.

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.

BackgroundThe prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control.MethodsThe Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18-74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008-2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure ≥140/90mm Hg or use of antihypertensive medication.ResultsThe total age-adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance.ConclusionsThese findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations.

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]

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 saltsensitive 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 (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 O-2 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 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 (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 O-2 overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues. [ABSTRACT FROM AUTHOR]

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]

Discusses the differences of end stage renal disease in patients with severe hypertension. Analysis of factors which influence the relationships between hypertension and end-organ damage; Increase of mortality from coronary artery disease for a given increase in blood pressure; Influence of end-organ susceptibility conditioned by genetic and environmental factors.

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]