Similar Blood Pressure Levels Research Articles

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

To examine the contribution of vascular membrane-associated prostaglandin E2 synthase-1 (mPGES-1) to acute blood pressure homeostasis. Angiotensin II (AngII, 75 pmol·kg⁻¹·min⁻¹) was continuously infused via the jugular vein into wild-type and mPGES-1(-/-) mice for 30 min, and blood pressure was measured by carotid arterial catheterization. RT-PCR and immunohistochemistry were performed to detect the expression and localization of mPGES-1 in the mouse arterial vessels. Mesenteric arteries were dissected from mice of both genotypes to study vessel tension and measure vascular PGE2 levels. Wild-type and mPGES-1(-/-) mice showed similar blood pressure levels at baseline, and the acute intravenous infusion of AngII caused a greater increase in mean arterial pressure in the mPGES-1(-/-) group, with a similar diuretic and natriuretic response in both groups. mPGES-1 was constitutively expressed in the aortic and mesenteric arteries and vascular smooth muscle cells of wild-type mice. Strong staining was detected in the smooth muscle layer of arterial vessels. Ex vivo treatment of mesenteric arteries with AngII produced more vasodilatory PGE2 in wild-type than in mPGES-1(-/-) mice. In vitro tension assays further revealed that the mesenteric arteries of mPGES-1(-/-) mice exhibited a greater vasopressor response to AngII than those arteries of wild-type mice. Vascular mPGES-1 acts as an important tonic vasodilator, contributing to acute blood pressure regulation.

A variant in the fibrillin-3 gene is associated with TGF-β and inhibin B levels in women with polycystic ovary syndrome

In an attempt to evaluate the association between allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating transforming growth factor (TGF) β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8- PCOS) with 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8- Non-PCOS). A8- PCOS is associated with higher levels of TGF-β1 compared with A8+ PCOS or A8- Non-PCOS, similar levels of TGF-β2 compared with A8+ PCOS but lower levels of TGF-β2 compared with A8- Non-PCOS, and lower levels of inhibin B and aldosterone compared with A8+ PCOS.

Review: Plasma renin and the incidence of cardiovascular disease

Whether renin is involved in the onset of coronary heart disease (CHD) remains unclear. A case-control study in 1972, suggesting a causal association between renin and CHD, has now been followed by three prospective studies. One was based on 1,717 hypertensive subjects in a Work-Site Program in New York. The main results showed an increased risk of CHD the higher the renin level. A second study in occupational groups in North West London, UK, recruited 803 white men not selected according to blood pressure, and found no association. A possible exception was in the minority of those with similar blood pressure levels to participants in the Work-Site Program, in whom the incidence of CHD was higher according to the renin level, but not significantly so. The third study was in Framingham Offspring and included 3,532 participants also not selected according to blood pressure. As in the UK study, there was no clear association between renin and risk of CHD in all participants, or in this study in those with raised blood pressure. The authors considered their results consistent with those of the UK study in finding "no association of renin with overall risk of CHD". Besides the three epidemiological studies, dealing explicitly with renin, other studies in which it has been one of several variables considered have also not found convincing evidence of its involvement in CHD. There is, therefore, little support for the hypothesis that high renin levels increase the risk of CHD, with the possible but uncertain exception of those with raised blood pressure.

Differences in Emotion Processing in Patients With Essential and Secondary Hypertension

An impaired ability to experience and express emotions, known as alexithymia, has previously been associated with hypertension. Alexithymia and related emotion-processing variables, however, have never been examined as a function of the type of hypertension, essential (EH) or secondary (SH). Our working hypothesis was that if dysregulated emotional processes play a key neurobiological role in EH, they would be less present in hypertension due to specific medical causes or SH. A total of 98 consecutive hypertensive patients (73 EH, 25 SH) with similar blood pressure levels completed two complementary measures of emotion processing: the 20-item Toronto Alexithymia Scale (TAS-20) and the Levels of Emotional Awareness Scale (LEAS). After controlling for confounding variables, LEAS score was lower in EH than SH (estimated means: 46.4 vs. 52.0; P = 0.028; effect size 0.52). TAS-20 scores did not differentiate EH from SH, but the differences were in the expected direction, with an effect size of 0.34 for TAS-20 total score. Neither psychometric measure was associated with the duration of hypertension or the presence of cardiovascular (CV) complications. These results are consistent with a contribution of an emotional or psychosomatic component in EH and may have practical implications for the nonpharmacological management of hypertension. They also demonstrate the utility of complementary measures of emotion processing in medically ill patients.

Abstract 5080: Role of Mineralocorticoid Receptor/Rho/Rho-kinase Pathway in Obesity-Related Renal Injury

Both aldosterone and Rho-kinase are demonstrated independently to play an important role in renal injury and impaired insulin signalling. We therefore examined whether aldosterone/Rho/Rho-kinase pathway contributed to obesity-associated nephropathy. C57BL/6J mice were fed a high fat (HFD) or low fat diet (LFD) and mice on HFD were treated with a mineralocorticoid receptor (MR) antagonist, eplerenone. The mice on HFD developed obesity, and hyperglycemia compared with those on LFD, but manifested similar levels of systolic blood pressure. In HFD-fed mice, glomerular hypercellularity and increased mesangial matrix were noted (66.7±3.0 vs. 32.3±2.5 nuclei/gcs, p<0.01), which paralleled the increase in albuminuria (HFD, 0.13±0.04mg/gCr, P<0.01 vs LFD, 0.02±0.01mg/gCr). The treatment with eplerenone alleviated the histological changes and albuminuria (0.04±0.01mg/gCr, P<0.01 vs HFD) without alterations in systemic blood pressure. Adipose tissue weight and adipocyte size of HFD-fed mice were increased, which were ameliorated by eplerenone. Furthermore, enhanced Rho-kinase activity was noted in kidneys (2.0-fold, p<0.05) and adipose tissues (1.8-fold, p<0.05) from HFD-fed mice, as well as increased expressions of MCP-1, TNF- α and PDGF-B. All of these changes were attenuated by eplerenone. In HFD-fed mice, MR protein levels in the nuclear fraction were increased in kidneys (2.3-fold, p<0.05) and adipose tissues (2.0-fold, p<0.05) without elevation in serum aldosterone levels (LFD, 278±14mg/dl, HFD, 297±12mg/dl), and Sgk1, an effector of aldosterone, was upregulated (kidneys; 5.5-fold, p<0.01, adipose tissues; 2.2-fold, p<0.01). Finally, in mesangial cells, stimulation with aldosterone increased Rho-kinase activity, and pre-incubation with eplerenone prevented the aldosterone-induced activation of Rho-kinase. In conclusion, excess fat intake causes obesity and renal injury in C57BL/6J mice, and these changes are mediated by enhanced MR/Rho/Rho-kinase pathway and subsequent inflammatory process. Furthermore, both MR activation and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.

Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial

Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis. Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA. Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus. Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.

Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney diseases.

Sir, In 2004, the Japanese Society of Hypertension recommended calcium channel blockers (CCBs) as second line drugs, with the renin–angiotensin (Ang) system (RAS) inhibitor as the first choice, for the treatment of hypertension associated with chronic kidney disease (CKD). We reported that augmentation index (AI) is related to proteinuria in CKD patients, and that RAS inhibition preserves arterial compliance in CKD [1,2]. However, the effects of CCBs on arterial stiffness remain unclear among CKD patients. A prospective comparative study was performed between 26 non-diabetic CKD patients treated with amlodipine and 27 patients on benidipine (supplemental methods). Patient backgrounds including the prescription of the RAS inhibitor did not differ between groups (supplemental table). Brachial blood pressure was controlled equally well in both groups for a year (supplemental figure). A year later, body weight (to 59 ± 11 kg, P < 0.05) and estimated glomerular filtration rate (eGFR) were decreased, and AI was increased without changes in proteinuria (Figure ​(Figure1)1) in the amlodipine group. However, in the benidipine group, either eGFR, body weight or AI was not altered, but proteinuria was reduced. Fig. 1 Annual changes in urinary protein (UP, left panel), estimated glomerular filtration rate (eGFR, middle panel) and augmentation index (AI, right panel). *P < 0.05 from zero. Significant decreases in UP (116 ± 93 to 82 ± 67 mg/g ... In renal tissue, L-type calcium channels are only found in afferent arterioles, while N-type and T-type calcium channels are localized in both afferent and efferent arterioles [3]. Amlodipine blocks L-type and N-type calcium channels and dilates afferent arterioles much more than efferent arterioles. In contrast, benidipine that inhibits L-type and T-type calcium channels, dilates both afferent and efferent arterioles and reduces glomerular pressure. We have demonstrated that efferent arteriolar constriction is mediated by inositol trisphosphate-induced calcium mobilization and calcium entry through transient receptor potential (TRP) channels [4]. T-type CCBs inhibited AngII-induced calcium mobilization rather than calcium entry in efferent arterioles [3]. TRP channels possess molecular similarity with voltage-dependent calcium channels, but they lack the structure of voltage-sensor, gating independently of voltage. It is possible that some CCBs including benidipine inhibit calcium entry through TRP channels into efferent arteriole. Increasing AI elevates central blood pressure, worsening glomerular hypertension, proteinuria, renal and cardiovascular prognosis [1,2]. Although we would not deny the other possibilities (supplemental discussion), benidipine could reduce oxidative stress on arterial wall by decreasing proteinuria. Albumin passed through slit diaphragm is absorbed by proximal tubular cells. Although a small amount of protein is cleaved by acidification [5], oxidative process is involved in dealing a large amount of protein, generating reactive oxygen species that appear to leak from the kidney. This escalation of AI should worsen glomerular hypertension further, forming a vicious circle of progressive kidney damage [1,2]. Our results provided the evidence that benidipine may be superior to amlodipine in renoprotection as the antihypertensive additional to the RAS inhibitor when similar blood pressure levels are attained. Furthermore, the present data suggest that the influence on AI differs among types of CCBs in patients with CKD. Conflict of interest statement. None declared.

Relationship of transforming growth factor‐beta1 with tumour necrosis factor‐alpha and endothelial activation in patients with stable renal transplantation

To evaluate whether or not transforming growth factor-beta(1) is related to inflammation markers and to intercellular and vascular cell adhesion molecules in patients with stable renal transplantation. Serum concentrations of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules were analysed in 33 renal transplanted patients, 33 patients with chronic renal insufficiency (matched to the transplanted group for level of renal function), and 33 hypertensives with normal renal function. anova, Student's t-test and simple regression analysis were used to analyse the data. Transplanted patients showed higher values than hypertensives of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules (P < 0.0001 for all). Renal insufficiency group exhibited higher concentrations of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules than hypertensives (P < 0.0001 for all). Transplanted and renal insufficiency patients had similar blood pressure and renal function levels, and transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules were not significantly different. In transplanted and in renal insufficiency groups transforming growth factor-beta(1), adhesion molecules and tumour necrosis factor-alpha correlated significantly each other and with glomerular filtration rate (P < 0.001 for all). In long-term renal transplantation inflammation and endothelial activation biomarkers, the pro-fibrotic cytokine transforming growth factor-beta(1) and kidney function are interrelated. Because of the relevant role that inflammation, organ fibrosis and graft dysfunction may play against renal and cardiovascular survival of graft recipients, a better comprehension of the interactions between these variables is needed.

Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans

HomeHypertensionVol. 49, No. 5Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBContribution of Endothelial Nitric Oxide to Blood Pressure in Humans Markus P. Schlaich Roland E. Schmieder Markus P. SchlaichMarkus P. Schlaich Baker Heart Research Institute, Melbourne, Victoria, Australia Search for more papers by this author Roland E. SchmiederRoland E. Schmieder Department of Nephrology and Hypertension, University of Erlangen-Nuernberg, Erlangen, Germany Search for more papers by this author Originally published5 Mar 2007https://doi.org/10.1161/HYPERTENSIONAHA.107.087536Hypertension. 2007;49:e29Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 5, 2007: Previous Version 1 To the Editor:Assessment and dissection of the various components contributing to the complex regulation of blood pressure control is a challenging task, particularly so in humans. Gamboa et al1 are to be complemented on a perceptive and sophisticated study design in their approach to assess the contribution of endothelial-derived NO to blood pressure in humans. Inducing autonomic blockade by infusion of the ganglion blocker trimetaphan to eliminate baroreflex mechanisms, in concert with systemic inhibition of NO synthase, using NG-monomethyl-l-arginine, allowed them to estimate the contribution of endothelium-derived NO to blood pressure in healthy humans, pinning it down to an effect in the magnitude of ≈30 mm Hg. In accordance, the NG-monomethyl-l-arginine–induced increase in blood pressure during autonomic blockade was blunted in smokers assumed to be characterized by impaired NO availability.In a series of experiments using similar methodologies and systemic NO synthase blockade, we have investigated the role of endothelium-derived NO in another circulatory bed known to be strictly controlled by a variety of components, including the sympathetic nervous system, namely, the renal vasculature. In the absence of autonomic blockade, we could not detect any differences in NG-monomethyl-l-arginine–induced changes in systemic blood pressure or renal plasma flow between healthy control subjects and age-matched patients with hypertension,2 diabetes,3 or smokers,4 despite proven impairment of endothelium- dependent vasodilation in the forearm in some of these patients. However, common to all of these pathologic conditions was a substantial and significant augmentation of endothelium-dependent increases in renal plasm flow during concomitant infusion of the antioxidant vitamin C, particularly in smokers, thereby highlighting the profound impact of the abundance of reactive oxygen species on circulatory control, at least in the renal vascular bed in these populations. The absence of differences in response to blockade of endothelial NO synthase by NG-monomethyl-l-arginine and the similar blood pressure levels compared with control subjects could be the result of other mechanisms compensating for impaired endothelial NO availability, such as alterations in other endothelium-derived factors or in regulation of sympathetic nervous system activity. Extrapolating these findings to the data presented by Gamboa et al,1 one could expect that additional introduction of antioxidant measures in their smokers would have helped to further identify and unmask the contribution of oxidative stress as a cause for the impairment of endothelium-derived NO availability. One aspect that has been neglected in the discussion but certainly needs to be taken into account is the potential influence of activation of the renin–angiotensin system, known to interfere with the sympathetic nervous system, as well as the l-arginin/NO pathway, particularly through nicotinamide-adenine dinucleotide phosphate oxidase-dependent production of oxygen-free radicals, both on a central and peripheral level.5DisclosuresNone.1 Gamboa A, Shibao C, Diedrich A, Choi L, Pohar B, Jordan J, Paranjape S, Farley G, Biaggioni I. Contribution of endothelial nitric oxide to blood pressure in humans. Hypertension. 2007; 49: 170–177.LinkGoogle Scholar2 Jacobi J, Schneider MP, John S, Schmieder RE. Impact of NO-synthase inhibition on renal hemodynamics in normotensive and hypertensive subjects. J Hypertens. 2002; 20: 525–530.CrossrefMedlineGoogle Scholar3 Delles C, Schneider MP, Oehmer S, Fleischmann I, Fleischmann EF, Schmieder RE. Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes. Nephrol Dial Transplant. 2004; 19: 2513–2518.CrossrefMedlineGoogle Scholar4 Schneider MP, Klingbeil AU, Delles C, Schmidt BM, John S, Schmieder RE. Vitamin C augments the renal response to L-arginine in smokers. Nephrol Dial Transplant. 2003; 18: 1512–1517.CrossrefMedlineGoogle Scholar5 Ramchandra R, Barrett CJ, Malpas SC. Nitric oxide and sympathetic nerve activity in the control of blood pressure. Clin Exp Pharmacol Physiol. 2005; 32: 440–446.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByGamboa A and Biaggioni I (2007) Response to Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans, Hypertension, 49:5, (e30-e30), Online publication date: 1-May-2007. May 2007Vol 49, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.107.087536PMID: 17339534 Originally publishedMarch 5, 2007 PDF download Advertisement SubjectsAutonomic Nervous SystemEndothelium/Vascular Type/Nitric Oxide

Expression of an angiotensin-(1-7)-producing fusion protein in rats induced marked changes in regional vascular resistance

We have described a transgenic rat line that expresses an angiotensin-(1-7)-producing fusion protein, the TGR(A1-7)3292. In these rats, testis acts as an angiotensin-(1-7) biological pump, increasing its plasma concentration 2.5-fold. In this study, we performed hemodynamic measurements in TGR(A1-7)3292 and age-matched Hannover Sprague-Dawley (SD) control rats, using fluorescent microspheres. Urethane-anesthetized transgenic rats had similar levels of baseline blood pressure (99 +/- 3 mmHg) as did SD rats (101 +/- 3 mmHg). However, pronounced differences were observed in other hemodynamic measurements. TGR(A1-7)3292 rats presented a significant increase in stroke volume (0.29 +/- 0.01 vs. 0.25 +/- 0.01 ml in SD), increased cardiac index (24.6 +/- 0.91 vs. 21.9 +/- 0.65 ml.min(-1).kg) and decreased total peripheral resistance (3.9 +/- 0.13 vs. 4.5 +/- 0.13 mmHg.ml(-1).min.100 g). The increase in stroke volume in transgenic rats may be partially explained by the small decrease in heart rate (326 +/- 7.0 vs. 359 +/- 6.0 beats/min in SD). Strikingly, TGR(A1-7)3292 rats presented a substantial decrease in the vascular resistance in lung, spleen, kidney, adrenals, brain, testis and brown fat tissue with no significant differences in the left ventricle, mesentery, skin, gastrocnemius muscle and white fat tissue. These results corroborate and extend previous results observed after acute angiotensin-(1-7) infusion, showing that chronic increase in circulating angiotensin-(1-7) produces sustained and important changes in regional and systemic hemodynamics. Moreover, our data suggest a physiological role for angiotensin-(1-7) in the tonic control of regional blood flow.

Pregnancy induced sympathetic overactivity: A comparison of different hypertensive states

DIFFERENT HYPERTENSIVE STATES KEITH WILLIAMS, FRANCE GALERNEAU, MARIA SMALL, Yale University, Obstetrics & Gynecology, New Haven, Connecticut, Yale University, Obstetrics and Gynecology, New Haven, Connecticut, Yale University, New Haven, Connecticut OBJECTIVE: Recent studies have shown that elevated sympathetic outflow in patients might contribute to vasoconstriction in Preeclampsia (PET). The ability to assess Blood Pressure Variability (BPV) and baroreflex sensitivity (BRS) have become powerful techniques for assessing autonomic control in cardiac diseases. We questioned whether increased sympathetic activity is associated with other hypertensive pregnant states including chronic hypertension and Pregnancy Induced Hypertension (PIH). The measurement of sympathetic activity could be helpful in differentiating these conditions. STUDY DESIGN: We measured continuously beat to beat outputs of Blood pressure (pilot 9200) for 2 minutes. Time series of systolic as well as systolic beat-to-beat pressure values and RR intervals were extracted to analyze and assess BRS in 20 normotensive, 10 PET, 5 chronic hypertensive and 7 Pregnancy Induced Hypertension (PIH) patients in the third trimester. We measured BRS by the linear spontaneous sequence technique assessing spontaneous sequences of 3 cycles and calculating the linear regression slope between BP and RR interval. The BP variability was calculated as the square root of the mean of the sum of the squares of differences in Systolic BP between adjacent RR intervals. All continuous data was compared between the four groups using ANOVA with Bonferroni correction. RESULTS: We identified a significant difference in BRS between Normotensive, PET, Chr Hypertensive, and PIH patients (13G8.8, vs 4.9G2.5, vs 10.4G5.9, vs 9.4G3.6) (P!.034). There was also a significant difference in BP variability (30.6G16.11, vs16.4G4.2, vs 27.8G16.0, vs 30.8G7.7)(P!.047). The significantly reduced BRS and BPV indicated that increased sympathetic activity is a significant feature of PET. CONCLUSION: Women with PET showed an increase in pregnancy induced sympathetic activity in excess of that seen with chronic hypertension and PIH with similar blood pressure levels. Non invasive assessment of the autonomic nervous system should be investigated in populations at risk for PET as a screening tool.

β2-Adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension

Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. beta(2)-Adrenergic receptors (beta(2)ARs) are up-regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 beta(2)AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy. In a prospective follow-up study we screened 970 hypertensive patients of Caucasian descent for the Gly16Arg, Gln27Glu, and Thr164Ile beta(2)AR polymorphisms and left ventricular echocardiographic hypertrophy and assigned selected patients to enalapril or atenolol to assess left ventricular hypertrophy regression after 2-year follow-up. Results were stratified according to treatment and the Glu27Gln polymorphism of the beta(2)AR. In cells with stable overexpression of the Glu27 or Gln27 variant of beta(2)AR, we also explored the implications of this polymorphism on hypertrophy-related intracellular signal transduction. Among hypertensive patients, the Gly16 allele was found in 63% of patients and the Glu27 allele was found in 40.6%. Both polymorphisms were in linkage disequilibrium, as expected. Four hundred forty-one hypertrophic hypertensive patients completed the 2-year follow-up. At baseline, patients carrying at least 1 allele of the Glu27 variant presented with a larger cardiac size despite similar blood pressure levels (142.9 +/- 22.5 g/m(2) in Glu27 carriers versus 138.2 +/- 18.4 g/m(2) in Gln27 carriers, P < .02). Blood pressure normalization was achieved by both drugs. At follow-up, compared with the Gln27 patients, the Glu27 patients showed a larger reduction in hypertrophy when treated with enalapril (percent change in left ventricular mass, -6.3% +/- 7.7% in Glu27 carriers versus -2.18% +/- 7.9% in Gln27 carriers; P < .05) but not with atenolol therapy (-2.8% +/- 8.9% in Glu27 carriers versus -2.4% +/- 8.8% in Gln27 carriers, P = not significant). In in vitro studies the activation of p38 and extracellular signal-regulated kinase (ERK-) 1/2 (data not shown) and the activity of the atrial natriuretic factor (ANF) promoter after isoproterenol (INN, isoprenaline) stimulation were larger in Glu27 beta(2)AR overexpressing cells than in Gln27 beta(2)AR overexpressing cells (fold difference compared with unstimulated cells, 9.7 +/- 2.9 for Glu27 beta(2)AR versus 4.2 +/- 0.3 for Gln27 beta(2)AR; P < .05). The Glu27 variant of beta(2)AR enhances hypertension-induced left ventricular hypertrophy. In these patients angiotensin-converting enzyme inhibitors are more efficient than beta-blockers in reducing cardiac size.

Leptin Regulates Neointima Formation After Arterial Injury Through Mechanisms Independent of Blood Pressure and the Leptin Receptor/STAT3 Signaling Pathways Involved in Energy Balance

Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear. Arterial injury was induced in wild-type (wt), leptin-deficient (lep(ob/ob)), and leptin receptor-deficient (lepr(db/db)) mice. Compared with wt mice, lep(ob/ob) and lepr(db/db) mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr(db/db) mice indicated that the vascular protection in lepr(db/db) mice was not attributable to lack of leptin receptor expression on bone marrow-derived elements. To investigate the role of the lepr-mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr(s/s) mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr(s/s) mice was significantly increased compared with lepr(db/db) mice. The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.

Inflammation and endothelial activation are linked to renal function in long-term kidney transplantation

The aim of this study was to investigate the relationships between inflammation and adhesion molecules in long-term kidney transplantation. We measured serum concentrations of tumor necrosis factor-alpha (TNFalpha) and intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) in 35 renal transplant recipients (mean age of transplantation 5 +/- 3 years) and in 35 chronic renal insufficiency (CRI) patients; twenty-six healthy subjects were enrolled as controls. Transplanted showed higher values than controls of TNFalpha (P < 0.0001), ICAM-1 (P < 0.0001), and VCAM-1 (P < 0.0001). CRI group as well exhibited higher concentrations than controls of TNFalpha (P < 0.0001), ICAM-1 (P < 0.0001), and VCAM-1 (P < 0.0001). Transplanted and CRI patients had similar blood pressure and renal function levels, and TNFalpha, ICAM-1, and VCAM-1 were not significantly different in the two groups. In transplanted group ICAM-1, VCAM-1, and TNFalpha correlated negatively and independently with glomerular filtration rate (GFR) -P < 0.00001 for all. TNFalpha as well correlated with ICAM-1 and VCAM-1 (P < 0.001, respectively). In CRI group, TNFalpha correlated with serum creatinine, ICAM-1, and VCAM-1 (P = 0.01 for all). In conclusion, in long-term renal transplantation, the level of kidney function and both inflammation and endothelial activation are closely related. In fact, the multiple regression analysis demonstrated that the level of kidney insufficiency and the levels of the studied molecules were independently associated.

World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women

The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery. Randomized placebo-controlled, double-blinded trial in nulliparous normotensive women from populations with dietary calcium < 600 mg/d. Women who were recruited before gestational week 20 received supplements (1.5 g calcium/d or placebo) throughout pregnancy. Primary outcomes were preeclampsia and preterm delivery; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates. The groups comprised 8325 women who were assigned randomly. Both groups had similar gestational ages, demographic characteristics, and blood pressure levels at entry. Compliance were both 85% and follow-up losses (calcium, 3.4%; placebo, 3.7%). Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia (4.1% vs 4.5%) that was evident by 35 weeks of gestation (1.2% vs 2.8%; P = .04). Eclampsia (risk ratio, 0.68: 95% CI, 0.48-0.97) and severe gestational hypertension (risk ratio, 0.71; 95% CI, 0.61-0.82) were significantly lower in the calcium group. Overall, there was a reduction in the severe preeclamptic complications index (risk ratio, 0.76; 95% CI, 0.66-0.89; life-table analysis, log rank test; P = .04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (risk ratio, 0.80; 95% CI, 0.70-0.91). Preterm delivery (the neonatal primary outcome) and early preterm delivery tended to be reduced among women who were < or = 20 years of age (risk ratio, 0.82; 95% CI, 0.67-1.01; risk ratio, 0.64; 95% CI, 0.42-0.98, respectively). The neonatal mortality rate was lower (risk ratio, 0.70; 95% CI, 0.56-0.88) in the calcium group. A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality, albeit these were secondary outcomes.

Role of fibrillin-1 in hypertensive and diabetic glomerular disease

The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease.

Effect of Fixed‐Dose ACE‐Inhibitor/Calcium Channel Blocker Combination Therapy vs. ACE‐Inhibitor Monotherapy on Arterial Compliance in Hypertensive Patients With Type 2 Diabetes

Assessment of vascular compliance may be a useful measurement of the clinical effects of antihypertensive treatment. Both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are known to improve vascular elasticity. A study was performed to test the hypothesis that combined therapy with an ACE inhibitor and a calcium channel blocker would have additive benefits on vascular compliance at similar levels of blood pressure (BP), as compared with monotherapy with an ACE inhibitor. This 12-week, double-blind study was a substudy of a larger clinical hypertension study conducted in patients with hypertension and type 2 diabetes. Subjects (N = 20) were randomized to either a fixed-dose combination of amlodipine besylate/benazepril HCl or to enalapril monotherapy. BP, heart rate, large- and small-vessel compliance, systemic vascular resistance, and urinary microalbumin excretion were assessed at baseline and after treatment. Both treatments were similarly effective in lowering BP, reducing systemic vascular resistance, and decreasing urinary microalbumin excretion. Improvement in large-vessel compliance was significantly greater among subjects who received ACE-inhibitor/calcium channel blocker combination therapy (52%) as compared with those who received ACE-inhibitor monotherapy (32%; p < 0.05). No significant change in small-vessel compliance was observed with either treatment. Greater improvement in large-vessel compliance with combination therapy was independent of BP lowering.

Gender-specific association between pulse pressure and C-reactive protein in a Chinese population

There is growing evidence that low-grade chronic inflammation, as reflected by the raised serum concentration of C-reactive protein, might be a risk factor for hypertension, in particular in women. We therefore investigated gender-specific associations of systolic and diastolic blood pressure and pulse pressure with serum C-reactive protein concentration in a Chinese population sample. In 463 participants, we measured serum C-reactive protein concentration using a high-sensitivity immunonephelometric latex-enhanced assay. We performed single and multiple linear regression analyses. The 224 male and 239 female subjects were of similar age (51.0 years) and had similar levels of systolic blood pressure (124.7 mmHg) and pulse pressure (47.1 mmHg), but men, compared with women, had higher diastolic blood pressure (79.6 vs 75.8 mmHg; P<0.0001) and body mass index (24.3 vs 23.4 kg/m2; P=0.003). Both before and after adjustment for age, age2, body mass index, current smoking, alcohol intake, and use of antihypertensive drugs, pulse pressure was significantly associated with serum C-reactive protein concentration in women (P< or =0.002) but not in men (P>0.10; P=0.02 for interaction between gender and serum C-reactive protein). In women, with one-fold increase in serum C-reactive protein concentration, pulse pressure was 1.94 mmHg higher. The categorical analyses confirmed our findings. With similar adjustments applied, women in the fourth quartile, compared with those in the lowest quartile, had a 7.6 mmHg higher pulse pressure (95% confidence interval 3.5-11.7 mmHg; P=0.0003). Furthermore, when women were analysed according to menopausal status, the association between pulse pressure and C-reactive protein was only significant in postmenopausal (P< or =0.04), but not in premenopausal, subjects (P> or =0.21). In conclusion, taken together with the previous gender-specific observations on carotid lesions and hypertension, our finding suggests that chronic low-grade inflammation might play a role in the widening of pulse pressure in Chinese women. This cross-sectional observation warrants further investigation in prospective studies.

Higher Small Arterial Elasticity in Hypertensive Patients Treated with Angiotensin II Receptor Blockers

Although evidence from basic research suggests the involvement of angiotensin II (Ang II) in the progression of arteriosclerosis, the clinical data are limited. In the present study, hypertensive outpatients who were well controlled with antihypertensive medication and had similar blood pressure levels were studied, and arterial elasticity was compared between those receiving Ang II receptor blockers (ARBs) and those treated with other antihypertensive agents. The effects of HMG-CoA reductase inhibitors (STs) on arterial elasticity were also evaluated. The study enrolled 298 outpatients who had been diagnosed with essential hypertension whose blood pressure was controlled to 150/95 or less by antihypertensive treatment (excluding angiotensin converting enzyme [ACE] inhibitors) for at least 2 months. The small artery elasticity index (SAEI) was determined for each patient from the radial artery pulse waves using a non-invasive pulse wave analysis system CR-2000. The mean of two blood pressure measurements taken from subjects lying in a recumbent position during SAEI analysis was used for the data analysis. The patients were grouped according to the use of ARBs and STs, and two-way analysis of variance (ANOVA) was used for statistical comparisons. A backward stepwise multiple regression analysis was carried out to identify factors contributing to the SAEI. Hypertensive patients receiving ARB treatment had a significantly higher SAEI compared to those not receiving ARBs, despite the similar blood pressure levels of both groups. No significant effects of ST treatment on the SAEI were observed (two-way ANOVA). A backward stepwise multiple regression analysis for the SAEI suggested that ARB treatment was an independent determinant of the SAEI after the adjusting of age, gender, total cholesterol, high density lipoprotein cholesterol, smoking and systolic blood pressure. Our results suggested that while providing blood pressure control similar to that of other antihypertensive agents, ARBs may also increase vascular elasticity and thereby delay the progression of arteriosclerosis.

Ethnic differences in left ventricular structure: relations to hemodynamics and diurnal blood pressure variation

Background Previous studies have suggested that African Americans have a greater left ventricular relative wall thickness than whites with similar levels of blood pressure (BP), whereas other investigators have documented an attenuated nocturnal decline in BP and early remodeling of the resistance vessels in African Americans. Methods To further evaluate the contributions of diurnal BP variation and vascular remodeling to ethnic differences in left ventricular geometry, we measured ambulatory BP, systemic hemodynamics, minimum forearm vascular resistance, and left ventricular structure in a biracial sample of 171 men and women between the ages of 25 and 45 years. Results Despite similar resting BPs, African Americans had a greater indexed peripheral resistance, a greater minimal forearm vascular resistance, and a smaller nocturnal decline in BP than white subjects. African Americans also had a greater left ventricular relative wall thickness (0.41 ± 0.07 v 0.38 ± 0.08, P = .048) and a trend toward a greater indexed left ventricular mass (41.1 ± 8.7 v 38.6 ± 8.6 g/m 2.7, P = .087). Ethnic differences in relative wall thickness were no longer significant when adjusted for either indexed peripheral resistance ( P = .173) or sleep systolic BP ( P = .124). Conclusions In our cohort of young men and women, African Americans had a greater left ventricular relative wall thickness than whites with similar levels of resting BP. This early concentric remodeling of the left ventricle in African Americans may be mediated, in part, by hemodynamic influences, including a greater peripheral vascular resistance and a smaller nocturnal decline in BP.