Hypertension current issue

[AHA/ASH/PCNA Scientific Statements] Call to Action on Use and Reimbursement for Home Blood Pressure Monitoring: Executive Summary: A Joint Scientific Statement From the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association

2008-06-18

Home blood pressure monitoring (HBPM) overcomes many of the limitations of traditional office blood pressure (BP) measurement and is both cheaper and easier to perform than ambulatory BP monitoring. Monitors that use the oscillometric method are currently available that are accurate, reliable, easy to use, and relatively inexpensive. An increasing number of patients are using them regularly to check their BP at home, but although this has been endorsed by national and international guidelines, detailed recommendations for their use have been lacking. There is a rapidly growing literature showing that measurements taken by patients at home are often lower than readings taken in the office and closer to the average BP recorded by 24-hour ambulatory monitors, which is the BP that best predicts cardiovascular risk. Because of the larger numbers of readings that can be taken by HBPM than in the office and the elimination of the white-coat effect (the increase of BP during an office visit), home readings are more reproducible than office readings and show better correlations with measures of target organ damage. In addition, prospective studies that have used multiple home readings to express the true BP have found that home BP predicts risk better than office BP (class IIa; level of evidence A). This call-to-action article makes the following recommendations: (1) It is recommended that HBPM should become a routine component of BP measurement in the majority of patients with known or suspected hypertension; (2) Patients should be advised to purchase oscillometric monitors that measure BP on the upper arm with an appropriate cuff size and that have been shown to be accurate according to standard international protocols. They should be shown how to use them by their healthcare providers; (3) Two to 3 readings should be taken while the subject is resting in the seated position, both in the morning and at night, over a period of 1 week. A total of ≥12 readings are recommended for making clinical decisions; (4) HBPM is indicated in patients with newly diagnosed or suspected hypertension, in whom it may distinguish between white-coat and sustained hypertension. If the results are equivocal, ambulatory BP monitoring may help to establish the diagnosis; (5) In patients with prehypertension, HBPM may be useful for detecting masked hypertension; (6) HBPM is recommended for evaluating the response to any type of antihypertensive treatment and may improve adherence; (7) The target HBPM goal for treatment is <135/85 mm Hg or <130/80 mm Hg in high-risk patients; (8) HBPM is useful in the elderly, in whom both BP variability and the white-coat effect are increased; (9) HBPM is of value in patients with diabetes, in whom tight BP control is of paramount importance; (10) Other populations in whom HBPM may be beneficial include pregnant women, children, and patients with kidney disease; and (11) HBPM has the potential to improve the quality of care while reducing costs and should be reimbursed. (Hypertension. 2008;52:1-9.)

[Letters to the Editor] High-Normal Blood Pressure and Cognition: Supplying the Missing Data

Elias, M. F., Elias, P. K., Dore, G. A., Robbins, M. A. — 2008-06-18

[Letters to the Editor] Response to High-Normal Blood Pressure and Cognition: Supplying the Missing Data

Knecht, S., Wersching, H., Berger, K. — 2008-06-18

[Letters to the Editor] Central Pulse Pressure: Is It Really an Independent Predictor of Cardiovascular Risk?

Kopec, G., Podolec, P. — 2008-06-18

[Letters to the Editor] Response to Central Pulse Pressure: Is It Really an Independent Predictor of Cardiovascular Risk?

Jankowski, P., Kawecka-Jaszcz, K. — 2008-06-18

[AHA/ASH/PCNA Scientific Statements] Call to Action on Use and Reimbursement for Home Blood Pressure Monitoring: A Joint Scientific Statement From the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association

2008-06-18

Home blood pressure monitoring (HBPM) overcomes many of the limitations of traditional office blood pressure (BP) measurement and is both cheaper and easier to perform than ambulatory BP monitoring. Monitors that use the oscillometric method are currently available that are accurate, reliable, easy to use, and relatively inexpensive. An increasing number of patients are using them regularly to check their BP at home, but although this has been endorsed by national and international guidelines, detailed recommendations for their use have been lacking. There is a rapidly growing literature showing that measurements taken by patients at home are often lower than readings taken in the office and closer to the average BP recorded by 24-hour ambulatory monitors, which is the BP that best predicts cardiovascular risk. Because of the larger numbers of readings that can be taken by HBPM than in the office and the elimination of the white-coat effect (the increase of BP during an office visit), home readings are more reproducible than office readings and show better correlations with measures of target organ damage. In addition, prospective studies that have used multiple home readings to express the true BP have found that home BP predicts risk better than office BP (Class IIa; Level of Evidence A). This call-to-action article makes the following recommendations: (1) It is recommended that HBPM should become a routine component of BP measurement in the majority of patients with known or suspected hypertension; (2) Patients should be advised to purchase oscillometric monitors that measure BP on the upper arm with an appropriate cuff size and that have been shown to be accurate according to standard international protocols. They should be shown how to use them by their healthcare providers; (3) Two to 3 readings should be taken while the subject is resting in the seated position, both in the morning and at night, over a period of 1 week. A total of ≥12 readings are recommended for making clinical decisions; (4) HBPM is indicated in patients with newly diagnosed or suspected hypertension, in whom it may distinguish between white-coat and sustained hypertension. If the results are equivocal, ambulatory BP monitoring may help to establish the diagnosis; (5) In patients with prehypertension, HBPM may be useful for detecting masked hypertension; (6) HBPM is recommended for evaluating the response to any type of antihypertensive treatment and may improve adherence; (7) The target HBPM goal for treatment is <135/85 mm Hg or <130/80 mm Hg in high-risk patients; (8) HBPM is useful in the elderly, in whom both BP variability and the white-coat effect are increased; (9) HBPM is of value in patients with diabetes, in whom tight BP control is of paramount importance; (10) Other populations in whom HBPM may be beneficial include pregnant women, children, and patients with kidney disease; and (11) HBPM has the potential to improve the quality of care while reducing costs and should be reimbursed. (Hypertension. 2008;52:10-29.)

[Brief Reviews] Thiazide-Induced Dysglycemia: Call for Research From a Working Group From the National Heart, Lung, and Blood Institute

2008-06-18

[Brief Reviews] Lewis K. Dahl Memorial Lecture: The Renin-Angiotensin System and Aging

Diz, D. I. — 2008-06-18

[Brief Reviews] Developmental Programming of Hypertension: Insight From Animal Models of Nutritional Manipulation

Ojeda, N. B., Grigore, D., Alexander, B. T. — 2008-06-18

[Hypertension Highlights] Angiotensin II-Dependent Superoxide: Effects on Hypertension and Vascular Dysfunction

Welch, W. J. — 2008-06-18

[Editorial Commentaries] Weight Loss and Vascular Function: The Good and the Unknown

Shankar, S. S., Steinberg, H. O. — 2008-06-18

[Editorial Commentaries] Gender Differences in the Regression of Electrocardiographic Left Ventricular Hypertrophy During Antihypertensive Therapy

Agabiti-Rosei, E., Salvetti, M. — 2008-06-18

[Editorial Commentaries] Treatment-Sensitive Premature Renal and Heart Senescence in Hypertension

Bergmann, M. W., Zelarayan, L., Gehrke, C. — 2008-06-18

[Editorial Commentaries] Antihypertensive and Renoprotective Mechanisms of Renin Inhibition in Diabetic Rats

Carey, R. M. — 2008-06-18

[Original Articles] Cerebrovascular Support for Cognitive Processing in Hypertensive Patients Is Altered by Blood Pressure Treatment

Jennings, J. R., Muldoon, M. F., Price, J., Christie, I. C., Meltzer, C. C. — 2008-06-18

Hypertension is associated with mild decrements in cognition. In addition, regional cerebral blood flow responses during memory processing are blunted in parietal and thalamic areas among untreated hypertensive adults, who, compared with normotensive subjects, manifest greater correlation in blood flow response across task-related brain regions. Here, we test whether pharmacological treatment of hypertension normalizes regional cerebral blood flow responses and whether it does so differentially according to drug class. Treatment with lisinopril, an angiotensin-converting enzyme blocker, known to enhance vasodilative responsivity, was compared with treatment with atenolol, a β-blocker. Untreated hypertensive volunteers (n=28) were randomly assigned and treated for 1 year. Whole brain and regional cerebral flow responses to memory processing and acutely administered acetazolamide, a vasodilator, were assessed pretreatment and posttreatment. Peripheral brachial artery dilation during reactive hyperemia was also measured. Quantitative blood flow measures showed no difference in the magnitude of regional cerebral blood flow responses pretreatment and posttreatment to either memory tasks or acetazolamide injection. Brachial artery flow-mediated dilation increased with treatment. No differences between medications were observed. In brain regions active in memory processing, however, regional cerebral blood flow responses were more highly correlated after treatment. Specificity of cerebral blood flow to different regions appears to decline with treatment of hypertension. This greater correlation among active brain regions, which is present as well in untreated hypertensive relative to normotensive volunteers, may represent compensation in the face of less region-specific responsivity in individuals with hypertension.

[Original Articles] Weight Loss Alone Improves Conduit and Resistance Artery Endothelial Function in Young and Older Overweight/Obese Adults

2008-06-18

Obesity is associated with vascular endothelial dysfunction, as indicated by impaired endothelium-dependent dilation. Presently there is no direct evidence that energy intake–restricted weight loss alone improves conduit or resistance artery endothelium-dependent dilation, the mechanisms involved, or whether improvements differ with patient age. A total of 40 overweight or obese (body mass index: ≥25<40 kg/m²) nondiabetic men and women aged 21 to 69 years completed 12 weeks of reduced energy intake (n=26; 15 male) or attention control (n=14; 9 male) and 4 weeks of weight maintenance (randomized trial). Energy intake restriction reduced estimated total energy intake (33%), body weight (10.5%), total and abdominal body fat, plasma leptin, oxidized low-density lipoprotein, and improved several metabolic risk factors. Brachial artery flow-mediated dilation was increased by 30% (6.0±0.7% versus 7.9±0.7%; P=0.01; n=17). Peak forearm blood flow during intrabrachial artery infusion of acetylcholine was increased by 26% (16.8±1.4 versus 21.1±1.9 mL/100 mL per minute; P<0.05; n=15); this was inversely related to the reduction in the abdominal visceral:subcutaneous fat ratio (r=–0.46; P<0.05) and was abolished by inhibition of NO synthesis with N^G-monomethyl-l-arginine. Improvements in endothelium-dependent dilation were not related to age: mean increases in subjects >50 years of age were similar to or greater than those <50 years of age. Energy intake–restricted weight loss alone is an effective intervention for improving peripheral conduit and resistance artery endothelial function in young and older overweight/obese adults. The improvements in resistance artery function are mediated by an increase in NO bioavailability and are related to reductions in abdominal visceral fat.

[Original Articles] Endothelial Function and Aminothiol Biomarkers of Oxidative Stress in Healthy Adults

2008-06-18

Endothelial dysfunction is known to precede the development of atherosclerosis and results primarily from increased oxidative degradation of NO. We hypothesized that assessment of oxidative stress in the bloodstream will reliably predict endothelial function in healthy adults. A total of 124 healthy nonsmokers had endothelial function assessed using ultrasound measurement of brachial artery flow-mediated vasodilation. Plasma oxidative stress was estimated by measuring the levels of the reduced and oxidized forms of thiols, including glutathione (reduced glutathione and oxidized glutathione) and cysteine (cysteine and cystine), respectively, and the mixed disulfide. Among the traditional risk factors, there were significant and independent correlations between flow-mediated vasodilation and high-density lipoprotein level, body mass index, gender, and the Framingham risk score. Among the thiol markers, plasma cystine (r=–0.23; P=0.009) and the mixed disulfide (r=–0.23; P=0.01) levels correlated with endothelium-dependent but not endothelium-independent vasodilation, even after adjusting for the Framingham risk score and high-sensitivity C-reactive protein level. A higher level of oxidized metabolites was associated with worse endothelial function. In conclusion, the oxidative stress markers, cystine, and the mixed disulfide are independent predictors of endothelial function. These markers, in combination with the Framingham risk score, may help in the early identification of asymptomatic subjects with endothelial dysfunction who are at potentially increased risk for future atherosclerotic disease progression.

[Original Articles] Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Attenuates Restenosis of the Artery After Injury

2008-06-18

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein that can support the binding, internalization, and proteolytic degradation of oxidized low-density lipoprotein. The LOX-1 expression increases in the neointima after balloon injury. To develop an efficient compound to inhibit LOX-1, we designed and synthesized a novel gene silencer pyrrole-imidazole (PI) polyamide targeting the rat LOX-1 gene promoter (PI polyamide to LOX-1) to the activator protein-1 binding site. We examined the effects of PI polyamide to LOX-1 on the LOX-1 promoter activity, the expression of LOX-1 mRNA and protein, and neointimal hyperplasia of the rat carotid artery after balloon injury. PI polyamide to LOX-1 significantly inhibited the rat LOX-1 promoter activity and decreased the expression of LOX-1 mRNA and protein. After balloon injury of the arteries, PI polyamide to LOX-1 was incubated for 10 minutes. Fluorescein isothiocyanate–labeled PI polyamide was distributed to almost all of the nuclei in the injured artery. PI polyamide to LOX-1 (100 µg) significantly inhibited the neointimal thickening by 58%. PI polyamide preserved the re-endothelialization in the injured artery. PI polyamide significantly inhibited the expression of LOX-1, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9 mRNAs in the injured artery. The synthetic PI polyamide to LOX-1 decreased the expression of LOX-1 and inhibited neointimal hyperplasia after arterial injury. This novel gene silencer PI polyamide to LOX-1 is, therefore, considered to be a feasible agent for the treatment of in-stent restenosis.

[Original Articles] Erythropoietin Increases Endothelial Biosynthesis of Tetrahydrobiopterin by Activation of Protein Kinase B{alpha}/Akt1

d'Uscio, L. V., Katusic, Z. S. — 2008-06-18

Tetrahydrobiopterin (BH₄) is an essential cofactor required for enzymatic activity of endothelial NO synthase. Recently, it has been shown that vascular protective effects of erythropoietin (EPO) are dependent on activation of endothelial NO synthase. Therefore, our objective was to characterize the effect of EPO on the biosynthesis of BH₄ in the vascular wall. Incubation of isolated C57BL/6J mouse aortas for 18 hours with recombinant human EPO (1 to 50 U/mL) caused a concentration-dependent increase in intracellular BH₄ levels and activity of GTP-cyclohydrolase I. Maximal biosynthesis of BH₄ was detected at therapeutic concentrations of 5 U/mL. Removal of the endothelium abolished EPO-induced biosynthesis of BH₄ demonstrating that the vascular endothelium is a major source of BH₄. Treatment with a selective phosphatidylinositol 3-kinase inhibitor wortmannin significantly reduced BH₄ biosynthesis stimulated by EPO. The stimulatory effect of EPO on vascular GTP-cyclohydrolase I activity, BH₄ production, and phosphorylation of endothelial NO synthase was also detected in vivo in mice treated with recombinant human EPO. These effects of EPO were abolished in protein kinase B/Akt1-deficient mice. In addition, EPO significantly increased systolic blood pressure and the number of circulating platelets in Akt1-deficient mice. Our results demonstrate that EPO stimulates biosynthesis of BH₄ in vascular endothelium and that the increase in BH₄ levels is caused by de novo biosynthesis of BH₄ via the phosphatidylinositol 3-kinase/Akt1 pathway. This effect is most likely designed to provide optimal intracellular concentration of the cofactor necessary for EPO-induced elevation of endothelial NO synthase activity.

[Original Articles] Gender Differences in Regression of Electrocardiographic Left Ventricular Hypertrophy During Antihypertensive Therapy

2008-06-18

Although men and women differ in the magnitude of ECG left ventricular hypertrophy, whether gender differences exist in the degree of regression of ECG left ventricular hypertrophy during antihypertensive therapy is unclear. ECG left ventricular hypertrophy defined using gender-adjusted Cornell product and Sokolow-Lyon voltage criteria was assessed serially in 9193 hypertensive patients treated with losartan- or atenolol-based regimens. Changes in ECG left ventricular hypertrophy were measured from baseline to last in-study visit, and above-average regression of hypertrophy was identified by a ≥236-mm · ms reduction in Cornell product or ≥3.5-mm reduction in Sokolow-Lyon voltage. During mean follow-up of 4.8±0.9 years, women had less reduction in Cornell product (–149±823 versus –251±890 mm · ms) and Sokolow-Lyon voltage (–3.0±6.8 versus –4.8±7.7 mm) than men (both P<0.001). After adjusting for baseline ECG left ventricular hypertrophy levels, baseline and change in systolic and diastolic pressures, treatment group, age, and other baseline gender differences, women had significantly less reduction in both Cornell product (adjusted means: –137 versus –276 mm · ms; P<0.001) and Sokolow-Lyon voltage (–3.6 versus –4.1 mm; P=0.005) than men and were 32% less likely to have had greater than the median level of regression of Cornell product left ventricular hypertrophy (95% CI: 24% to 39%; P<0.001) and 15% less likely to have had regression of left ventricular hypertrophy by Sokolow-Lyon criteria (95% CI: 5% to 23%; P=0.003). Thus, women have less regression of ECG left ventricular hypertrophy than men in response to antihypertensive therapy, independent of baseline gender differences in the severity of ECG left ventricular hypertrophy and after taking into account treatment effects and blood pressure changes.

[Original Articles] Left Ventricular Filling Pressure by Doppler Echocardiography in Patients With End-Stage Renal Disease

2008-06-18

Left ventricular hypertrophy and systolic dysfunction predict mortality in patients with end-stage renal disease. However, the prognostic value of left ventricular filling pressure has remained uncertain in this population. We evaluated whether the early mitral inflow velocity to peak mitral annulus velocity (E/Em) ratio, an estimate of left ventricular filling pressure by tissue Doppler imaging, has significant additional prognostic value to conventional echocardiographic parameters and other clinical and biochemical parameters in 220 patients with end-stage renal disease. The E/Em ratio was elevated (>15) in 62% of the patients. Multivariate analysis showed that an elevated E/Em ratio had the highest correlation with left ventricular volume index, followed by loss of residual glomerular filtration rate, increasing age, worsening ejection fraction, and diabetes. During the median follow-up of 48 months, the E/Em ratio emerged as an independent predictor of all-cause mortality (adjusted hazard ratio: 1.027; 95% CI: 1.003 to 1.051; P=0.026) and cardiovascular death (adjusted hazard ratio: 1.033; 95% CI: 1.002 to 1.065; P=0.035) in the multivariable Cox regression analysis. In addition, the E/Em ratio added significant incremental prognostic value for all-cause mortality (P=0.035) and cardiovascular death (P=0.035) beyond the standard clinical, biochemical, and dialysis parameters and echocardiographic measurements. In conclusion, the E/Em ratio displayed important additional long-term prognostic information above and beyond that of left ventricular mass and systolic function. Our data suggest that left ventricular filling pressure should be estimated during echocardiographic examination for additional prognostication in patients with end-stage renal disease.

[Original Articles] Interaction Between Renal Function and Microalbuminuria for Cardiovascular Risk in Hypertension: The Nordic Diltiazem Study

2008-06-18

We investigated whether renal function and microalbuminuria are independent predictors and whether any interaction exists between them, regarding future cardiovascular disease in hypertensive patients (n=10 881) followed for 4.5 years. The primary end points (PEs) were fatal and nonfatal myocardial infarction and stroke and other cardiovascular deaths. Creatinine and glomerular filtration rate (GFR), estimated using the formulas of the Modification of Diet in Renal Disease study group and Cockroft and Gault and in a subsample (n=4929) of microalbuminuria and interaction terms of microalbuminuria and renal function, were related to the risk of the PE using Cox proportional hazards model after full adjustment. Increased creatinine (P<0.001), decreased GFR from Cockroft and Gault (P=0.001), and decreased GFR from the Modification of Diet in Renal Disease study group (P=0.001) were all independent risk factors for the PE. Stepwise exclusion of patients with the poorest renal function excluded the possibility that the relationship between decreasing renal function and the PE was driven only by patients with severely impaired renal function. Microalbuminuria and all 3 of the indices of renal function predicted the PE independent of each other. There was a significant interaction between microalbuminuria and GFR from Cockroft and Gault (P=0.040) in prediction of the PE. Both renal function and microalbuminuria add independent prognostic information regarding cardiovascular risk in hypertensive patients. The cardiovascular risk associated with microalbuminuria increases with a decline in GFR, as demonstrated by a significant interaction between microalbuminuria and GFR from Cockroft and Gault. Because estimation of the total cardiovascular risk is essential for the aggressiveness of risk factor interventions, simultaneous inclusion of GFR and microalbuminuria in global cardiovascular risk assessment is essential.

[Original Articles] Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16INK4a

2008-06-18

There is increasing evidence for a role of somatic cellular senescence in physiological aging but also in injury and disease. Cell cycle inhibitor p16^INK4a is the key mediator for stress and aberrant signaling induced senescence. Here we report that elevated blood pressure markedly induced p16^INK4a expression in rat kidneys and hearts, as well as in human kidneys. In kidneys from deoxycorticosterone acetate-salt–treated rats, p16^INK4a induction was found in tubular, glomerular, interstitial, and vascular cells and correlated with the typical histopathologic features of hypertensive target organ damage. p16^INK4a expression also correlated with phospho-p38, a positive upstream regulator of p16^INK4a expression. In left ventricles, increased p16^INK4a expression was found in myocardium and cardiac arteries. Antihypertensive medication consistent of hydrochlorothiazide, hydralazine, and reserpine ameliorated the histopathologic changes and attenuated p16^INK4a expression in kidneys of deoxycorticosterone acetate-salt–treated rats. Nonantihypertensive administration of spironolactone also reduced kidney damage and p16^INK4a expression. p16^INK4a induction was further observed in kidneys from hypertensive transgenic rats heterozygous for the mouse Ren-2 gene and was prevented by the angiotensin II type 1 receptor blocker losartan. In human kidney biopsies showing hypertensive nephrosclerosis, increased p16^INK4a expression was found compared with age-matched normotensive control subjects. Thus, hypertension induces cellular senescence via p16^INK4a, possibly through p38, thereby contributing to hypertensive target organ damage. This detrimental effect can be overcome by different therapeutic drug strategies.

[Original Articles] Effects of Aliskiren on Blood Pressure, Albuminuria, and (Pro)Renin Receptor Expression in Diabetic TG(mRen-2)27 Rats

2008-06-18

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-β and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 µmol/L to 10 µmol/L) did not inhibit binding of ¹²⁵I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.

[Original Articles] Acute Angiotensin II Infusions Elicit Pressure Natriuresis in Mice and Reduce Distal Fractional Sodium Reabsorption

Zhao, D., Navar, L. G. — 2008-06-18

Acute angiotensin II (Ang II) infusions into mice increase arterial pressure (AP) and elicit pressure natriuresis. We used this model of pressure natriuresis to delineate the distal nephron responses to AP-mediated increases in distal sodium delivery. In the first group, we measured changes in urinary sodium excretion (U_NaV) in male C57/BL6 anesthetized mice (n=9) before and during acute Ang II infusions (5 ng/g of body weight per minute). Acute Ang II infusions increased AP (98±3 to 126±5 mm Hg; P<0.001), urine flow (2.7±0.5 to 6.0±0.8 µL/min; P<0.01), and U_NaV (0.6±0.2 to 1.3±0.2 µEq/min; P<0.05). There were significant relationships between U_NaV and urine flow (y=0.207x+0.030; P<0.0001) and between U_NaV and AP (y=0.027x–2.100). In a separate series, distal sodium delivery and fractional reabsorption of distal sodium delivery were determined in control (n=12) and Ang II–infused mice (n=8) by comparing U_NaV before and after blockade of the 2 major distal nephron sodium transporters with amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight). A positive relationship was found between U_NaV (y=0.015x–1.100; P<0.0001) or distal sodium delivery (y=0.027x–0.900; P<0.0001) and AP. An inverse relationship was found between fractional reabsorption of distal sodium delivery and AP (y=–0.511x+128.300; P<0.01). These data indicate that Ang II–mediated pressure natriuresis involves an increase in distal sodium delivery combined with a reduced distal nephron fractional sodium reabsorption, suggesting that increased AP prevents the distal nephron transport mechanisms from accommodating the increased distal delivery.

[Original Articles] Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II-Induced Adventitial Myofibroblast Migration

Haurani, M. J., Cifuentes, M. E., Shepard, A. D., Pagano, P. J. — 2008-06-18

The vascular adventitia is emerging as an important modulator of vessel remodeling. Adventitial myofibroblasts migrate to the neointima after balloon angioplasty, contributing to restenosis. We postulated that angiotensin II (Ang II) enhances adventitial myofibroblast migration in vitro via reduced nicotinamide-adenine dinucleotide phosphate oxidase–derived H₂O₂ and that Nox4-based oxidase promotes migration. Ang II increased myofibroblast migration in a concentration-dependent manner, with a peak increase of 1023±83%. Rat adventitial myofibroblasts were cotransfected with human Nox4 and human p22-phox plasmids or an empty vector. PCR showed an 8-fold increase in human Nox4 and human p22-phox plasmid expression. Using RT-PCR with primers specifically designed for rat reduced nicotinamide-adenine dinucleotide phosphate oxidases, endogenous Nox levels were determined. Ang II decreased endogenous Nox4 and Nox1 mRNA to 41% and 27% of control, respectively, but had no effect on Nox2. Cotransfection with human Nox4 and human p22-phox plasmids combined with Ang II reduced endogenous Nox4 mRNA levels (37±5% of control; P<0.05), whereas it had no significant effect on Nox1 or Nox2. In empty vector–transfected cells, Ang II increased myofibroblast migration by 192±32% versus vehicle (P<0.01) while increasing H₂O₂ (473±22% versus control; P<0.001). Cotransfection with human Nox4 and human p22-phox plasmids decreased Ang II-induced migration (46±6%; P<0.001) in parallel with attenuation of H₂O₂ production (23±8% versus empty vector; P<0.05). Our data suggest that Nox4 promotes Ang II-induced myofibroblast migration via an H₂O₂-dependent pathway. The data also suggest that Nox4 causes feedback inhibition of its own expression in adventitial myofibroblasts.

[Original Articles] Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries: Role of Angiotensin II Metabolites and Endothelial Nitric Oxide

Gauthier, K. M., Zhang, D. X., Cui, L., Nithipatikom, K., Campbell, W. B. — 2008-06-18

Angiotensin (Ang) II regulates adrenal steroidogenesis and adrenal cortical arterial tone. Vascular metabolism could decrease Ang II concentrations and produce metabolites with vascular activity. Our goals were to study adrenal artery Ang II metabolism and to characterize metabolite vascular activity. Bovine adrenal cortical arteries were incubated with Ang II (100 nmol/L) for 10 and 30 minutes. Metabolites were analyzed by mass spectrometry. Ang (1-7), Ang III, and Ang IV concentrations were 146±21, 173±42 and 58±11 pg/mg at 10 minutes and 845±163, 70±14, and 31±3 pg/mg at 30 minutes, respectively. Concentration-related relaxations of U46619-preconstricted cortical arteries to Ang II (maximum relaxation=29±3%; EC₅₀=3.4 pmol/L) were eliminated by endothelium removal and inhibited by the NO synthase inhibitor, nitro-l-arginine (30 µmol/L; maximum relaxation=14±7%). Ang II relaxations were enhanced by the angiotensin type-1 receptor antagonist losartan (1 µmol/L; maximum relaxation=41±3%; EC₅₀=11 pmol/L). Losartan-enhanced Ang II relaxations were inhibited by nitro-l-arginine (maximum relaxation=18±5%) and the angiotensin type-2 receptor antagonist PD123319 (10 µmol/L; maximum relaxation=27±5%). Ang (1-7) and Ang III caused concentration-related relaxations with less potency (EC₅₀=43 and 24 nmol/L, respectively) but similar efficacy (maximum relaxations=39±3% and 48±5%, respectively) as losartan-enhanced Ang II relaxations. Ang (1-7) relaxations were inhibited by nitro-l-arginine (maximum relaxation=16±4%) and the Ang (1-7) receptor antagonist 7^D-Ala-Ang (1-7) (1 µmol/L; maximum relaxation=10±3%) and eliminated by endothelium removal. Thus, Ang II metabolism by adrenal cortical arteries to metabolites with decreased vascular activity represents an inactivation pathway possibly decreasing Ang II presentation to adrenal steroidogenic cells and limits Ang II vascular effects.

[Original Articles] Postnatal Intermittent Hypoxia and Developmental Programming of Hypertension in Spontaneously Hypertensive Rats: The Role of Reactive Oxygen Species and L-Ca2+ Channels

2008-06-18

Obstructive and central apneas during sleep are associated with chronic intermittent hypoxia (CIH) and increased cardiovascular morbidity. Spontaneously hypertensive rats exposed to CIH during postnatal days 4 to 30 develop exaggerated hypertension as adults. We hypothesized that reactive oxygen species and altered L-Ca²⁺ channel activity may underlie the postnatal programming of exaggerated blood pressure and cardiac remodeling. Newborn male spontaneously hypertensive rats were exposed to CIH (10% and 21% O₂ alternating every 90 seconds, 12 h/d, for postnatal days 4 to 30) or normoxia (room air). In each condition, spontaneously hypertensive rats received daily (SC) 1 of 3 treatments: l-calcium channel blocker nifedipine (5 mg/kg), superoxide dismutase mimetic MnTMPyP pentachloride (10 mg/kg), or vehicle (polyethylene glycol). Blood pressure was evaluated monthly for 6 months after birth, and echocardiographic assessments were conducted at 6 months of age. CIH vehicle-treated rats presented higher systolic blood pressure (187±5 mm Hg) as compared with normoxic vehicle treated controls (163±2 mm Hg; P<0.001). Postnatal CIH elicited marked increases in left ventricular wall thickness in a pattern of concentric hypertrophy with augmented systolic contractility. The treatment with nifedipine in the CIH group attenuated blood pressure (159±2 mm Hg; P<0.001) and normalized left ventricular wall thickness and systolic function, whereas the treatment with SOD mimetic decreased blood pressure (165±2 mm Hg; P<0.001) and reduced left ventricular wall thickness without changes in the systolic function. We conclude that Ca²⁺ and reactive oxygen species–mediated signaling during intermittent hypoxia are critical mechanisms underlying postnatal programming of an increased severity of hypertension and hypertrophic cardiac remodeling in a genetically susceptible rodent model.

[Abstracts From the 29th Annual Scientific Meeting of the High Blood Pressure Research Council of Australia] Proceedings of the High Blood Pressure Research Council of Australia 2007 Annual Scientific Meeting

2008-06-18