bluuebunny/crossref_metadata_2025 huggingface dataset:
Proadrenomedullin N-Terminal 20 Peptide (PAMP), Acting Through PAMP(12–20)-Sensitive Receptors, Inhibits Ca
2+
-Dependent, Agonist-Stimulated Secretion of Human Adrenal Glands
Authors: Belloni Anna S. , Rossi Gian Paolo , Andreis Paola G. , Aragona Francesco , Champion Hunter C. , Kadowitz Philip J. , Murphy William A. , Coy David H. , Nussdorfer Gastone G.
Published: June 2012

Abstract
—Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20–amino acid hypotensive peptide expressed in the adrenal medulla. We investigated the localization and function of PAMP receptors in the human adrenal gland. Autoradiography showed the presence of [
125
I]PAMP-binding sites in both zona glomerulosa and adrenal medulla that were displaced by cold PAMP and PAMP(12–20) but not by other preproadrenomedullin-derived peptides. PAMP, but not PAMP(12–20), counteracted, in a concentration dependent manner, both aldosterone response of zona glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK-8644, the selective agonist of voltage-activated Ca
2+
channels, as well as to K
+
and angiotensin II. PAMP(12–20) partially reversed this antisecretagogue effect of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca
2+
-dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via specific receptors and through a mechanism involving the impairment of Ca
2+
influx; and (2) that PAMP(12–20) acts as a weak antagonist of PAMP receptors, thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are required for this peptide to exert its antisecretagogue action on the human adrenal gland.
Brain Mineralocorticoid Receptor Control of Blood Pressure and Kidney Function in Normotensive Rats
Authors: Rahmouni Kamal , Barthelmebs Mariette , Grima Michèle , Imbs Jean-Louis , De Jong Wybren
Published: June 2012

Abstract
—Brain mineralocorticoid receptors appear to contribute to mineralocorticoid hypertension and may be involved in blood pressure control in normotensive rats. We examined the effect of blockade of central mineralocorticoid receptors with the use of a selective antagonist (RU28318) on cardiovascular and renal function in conscious normotensive rats. The contribution of renal innervation was evaluated in rats with bilaterally denervated kidneys. Young adult, male Wistar rats were trained for systolic blood pressure measurement by a tail sphygmographic method and accustomed to metabolic cages for collection of urine. One week before experimentation, an intracerebroventricular cannula was implanted. Systolic blood pressure was diminished 30 minutes after an intracerebroventricular dose of 10 ng of RU28318. The effect was maximal at 8 hours and was still present after 24 hours. Blood pressure returned to the basal level by 48 hours. During the period 0 to 8 hours after intracerebroventricular injection, rats treated with the antagonist showed an increase in diuresis and urinary electrolyte excretion. No significant effect on plasma renin activity, measured 8 and 30 hours after administration of RU28318, was observed. In denervated rats, the decrease in systolic blood pressure after administration of RU28318 was reduced. The difference was statistically significant compared with controls at 2 hours but not at 8 hours, and blood pressure returned to the basal value by 24 hours. The increases in diuresis and urinary electrolyte excretion induced by RU28318 were abolished in denervated rats. These results show that brain mineralocorticoid receptors are involved in blood pressure regulation and kidney function homeostasis in conscious normotensive rats. The renal nerves appear to participate in the brain mineralocorticoid receptor control of blood pressure.
Type 2 Bradykinin-Receptor Antagonism Does Not Modify Kinin or Angiotensin Peptide Levels
Authors: Campbell Duncan J. , Kladis Athena , Briscoe Todd A. , Zhuo Jialong
Published: June 2012

Abstract
—Type 2 bradykinin (B
2
)-receptor antagonists have been used to define the role of endogenous kinin peptides. However, interpretation of the effects of B
2
-receptor antagonists has been limited by lack of information concerning the effects of these antagonists on endogenous kinin and angiotensin peptide levels. If kinin levels were subject to short-loop-feedback regulation mediated through B
2
receptors, then a reactive increase in kinin levels might blunt the effects of B
2
-receptor antagonism and stimulate type 1 bradykinin receptors. Moreover, kinins have been implicated in the control of renin secretion. We investigated whether endogenous kinin levels are subject to short-loop-feedback regulation mediated by the B
2
receptor and whether endogenous kinins acting through the B
2
receptor influence plasma renin levels and circulating and tissue angiotensin peptide levels. The B
2
-receptor antagonist icatibant (1 mg/kg) was administered to rats by intraperitoneal injection, and circulating and tissue levels of angiotensin and kinin peptides were measured after 4 hours. Icatibant produced 75% occupancy of B
2
receptors in the inner stripe of the renal medulla. Icatibant did not influence plasma levels of renin, angiotensinogen, angiotensin-converting enzyme, neutral endopeptidase, or circulating or tissue levels of angiotensin and bradykinin peptides. This study demonstrated that kinin levels are not subject to short-loop-feedback regulation mediated through B
2
receptors and that endogenous kinin levels acting through the B
2
receptor do not modulate the renin-angiotensin system.
Enhanced Blood Pressure Variability in eNOS Knockout Mice
Authors: Stauss Harald M. , Gödecke Axel , Mrowka Ralf , Schrader Jürgen , Persson Pontus B.
Published: June 2012

Abstract
—It has been shown previously that endogenous nitric oxide can buffer arterial blood pressure variability in dogs and rats. In these former studies, all isoforms of the nitric oxide synthase were blocked pharmacologically and an increased blood pressure variability was observed. Thus the question as to which isoform of the nitric oxide synthase is responsible for the blood pressure buffering effect of endogenous nitric oxide remains unraveled. In the present study, we therefore compared blood pressure variability in knockout mice that lack specifically the gene for endothelial nitric oxide synthase with their respective wild-type controls. One day after carotid artery cannulation, blood pressure was recorded in these conscious mice. During resting conditions, blood pressure variability was markedly enhanced in knockout mice compared with wild-type mice (10.5±1.5 mm Hg
2
vs 6.0±0.8 mm Hg
2
,
P
<0.05). Power spectral analysis revealed that this increase in blood pressure variability is manifested at low frequencies that range from 0.05 to 0.40 s
−1
(Hz) (5.1±1.0 mm Hg
2
vs 2.5±0.5 mm Hg
2
,
P
<0.05). On the basis of these results, we conclude that the blood pressure buffering effect of endogenous nitric oxide is mediated by the endothelial isoform of the nitric oxide synthase. In addition, endothelial nitric oxide is most effective in buffering blood pressure oscillations at frequencies that range from 0.05 to 0.40 s
−1
(Hz) in conscious mice.
Angiotensin-Converting Enzyme Inhibition Restores Hepatocyte Growth Factor Production in Patients With Congestive Heart Failure
Authors: Yasuda Satoshi , Goto Yoichi , Sumida Hitoshi , Noguchi Teruo , Baba Takeshi , Miyazaki Shunichi , Nonogi Hiroshi
Published: June 2012

Abstract
—Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. For vascular endothelium, hepatocyte growth factor (HGF) is one of the most potent and specific growth factors, which acts protectively against endothelial dysfunction. HGF production is downregulated by angiotensin II (Ang II) in vitro. We hypothesized that HGF production is impaired as the result of increased Ang II in patients with congestive heart failure, and that if so, the impaired production should be restored with angiotensin-converting enzyme inhibitors (ACE-I). We studied 16 patients with congestive heart failure caused by previous anterior myocardial infarction in whom left ventricular ejection fraction was 35±8% (mean±SD). Before and ≈4 weeks after the treatment with ACE-I, blood samples were collected to measure the levels of HGF, Ang II, and brain natriuretic peptide as a biochemical marker for severity of heart failure. We also studied 5 control subjects, in whom heparin increased HGF production to 48±5-fold. However, in patients with heart failure, HGF response to heparin was significantly attenuated (24±5-fold,
P
<0.05 vs control). Therapy with ACE-I decreased the levels of Ang II and brain natriuretic peptide and restored HGF production in response to heparin by 43±7-fold, comparable to the control response. In conclusion, impaired HGF production was restored after the treatment with ACE-I probably by the mechanism of Ang II suppression. This novel effect of ACE-I may contribute to the clinical improvement in patients with heart failure and thereby may have an important therapeutic implication.
Intravascular Source of Adenosine During Forearm Ischemia in Humans
Authors: Costa Fernando , Sulur Paulgun , Angel Mark , Cavalcante José , Haile Virginia , Christman Brian , Biaggioni Italo
Published: June 2012

Abstract
—It is believed that adenosine is released in ischemic tissues and contributes to reactive hyperemia. We tested this hypothesis in the human forearm using microdialysis to estimate interstitial and intravascular levels of adenosine and caffeine withdrawal to potentiate endogenous adenosine and determine its effect on reactive hyperemia. Forearm blood flow response to ischemia was measured by air plethysmography before and 60 hours after the last dose of caffeine (250 mg TID for 7 days, n=6). Forearm blood flow increased by 274±66% and 467±97% after 3 minutes of forearm ischemia, before and during caffeine withdrawal, respectively (
P
<0.05). Thus, caffeine withdrawal enhances reactive hyperemia. To determine the source of adenosine, we measured interstitial adenosine with the use of a microdialysis probe inserted into the flexor digitorum superficialis muscle of the forearm, and we measured intravascular adenosine with the use of a microdialysis probe inserted retrogradely into the medial cubital vein. Dialysate samples were collected at 15-minute intervals during resting, forearm ischemia, and recovery periods. Forearm ischemia failed to increase muscle dialysate concentrations of adenosine but did increase intravascular dialysate adenosine 2.1-fold, from 0.61±0.12 to 1.28±0.39 μmol/L (
P
<0.01, n=8). Intravascular dialysate concentrations of thromboxane B
2
did not increase during ischemia, ruling out platelet aggregation as a source of adenosine. These results support the hypothesis that endogenous adenosine contributes to reactive hyperemia and indicate that the major source of adenosine in the human forearm is intravascular. We speculate that endothelial cells are the source of intravascular adenosine during ischemia.
Thermoregulatory and Cardiac Responses of Infant Spontaneously Hypertensive and Wistar-Kyoto Rats to Cold Exposure
Authors: Kirby Robert F. , Sokoloff Greta , Perdomo Edison , Blumberg Mark S.
Published: June 2012

Abstract
—Cardiovascular function during cold exposure is dependent on effective thermoregulation. This dependence is particularly apparent in infants. For example, we have previously demonstrated that in infant rats during cold exposure, cardiac rate is directly related to their ability to produce heat endogenously. The primary source of endogenous heat production for infant rats is brown adipose tissue (BAT). Because of the dependence of cardiac rate on effective thermoregulation in the cold and because hypertension in spontaneously hypertensive rats (SHR) is influenced by the preweanling environment, in this study we examined the thermoregulatory and cardiac rate responses of infant SHR and Wistar-Kyoto rats (WKY) to varying levels of cold exposure. In experiment 1, 7- to 8-day-old SHR and WKY were acclimated at a thermoneutral air temperature (35°C) and then exposed to successive decreases in ambient temperature (30.5°C, 26.5°C, 23°C, and 17°C) while thermal and metabolic measures were recorded. Although both strains increased BAT thermogenesis and oxygen consumption in response to cold exposure, SHR cooled more than WKY and exhibited lower levels of oxygen consumption at the lowest air temperatures. Experiment 2 was identical to experiment 1 except that cardiac rate was also measured. Again, SHR exhibited substantial thermoregulatory deficits compared with WKY; in addition, they were less able than WKY to maintain cardiac rate at the 2 lowest air temperatures tested. Finally, in experiment 3, infant SHR exhibited diminished BAT thermogenesis in response to a range of doses of a selective β
3
-adrenoceptor agonist. We hypothesize that long-term thermoregulatory deficits during the early postnatal period influence cardiovascular function and contribute to the development of hypertension in SHR.
Role of Sympathetic Nervous System in Cyclosporine-Induced Rise in Blood Pressure
Authors: Carvalho Mario J. , van den Meiracker Anton H. , Boomsma Frans , Freitas Joao , Man in ‘t Veld Arie J. , Costa Ovidio , de Freitas Antonio Falcão
Published: June 2012

Abstract
—To clarify the role of the sympathetic nervous system in the development of cyclosporine A (CsA)-induced rise in blood pressure (BP), the effects of CsA on 24-hour ambulatory BP (ABP) were studied in patients with familial amyloid polyneuropathy (FAP) who underwent a liver transplantation. On the basis of autonomic function tests, patients with absent or mild-to-moderate sympathetic damage (Group A, n=11, age 29 to 43 years, disease duration 2 to 6 years) and patients with severe sympathetic damage (Group B, n=9, age 27 to 38 years, disease duration 3 to 9 years) were identified. Both groups were followed for 1 year. The daily doses of CsA and the CsA whole blood trough levels between the groups did not differ. Pretransplantation values of daytime and nighttime ABP were, respectively, 117±8/76±7 mm Hg and 108±12/68±9 mm Hg in group A and 107±6/66±4 mm Hg (
P
<0.05 group A versus group B) and 102±6/62±4 mm Hg in group B. In response to CsA, BP increased in all patients, but more so in patients of group B than in patients of group A. One year after transplantation, daytime and nighttime ABP had increased by 6±9/3±11% and 12±10/14±14% in group A and by 12±6/13±10% (
P
<0.05) and 21±11/27±21% (
P
<0.01) in group B. In both groups, the increase in nighttime ABP was greater than the increase in daytime ABP, which resulted in an attenuation or, even, a reversal of the diurnal BP rhythm. Because the rise in BP was greater in patients with more advanced sympathetic dysfunction, the sympathetic nervous system appears to counteract the CsA-induced rise in BP rather than causing it. This implies involvement of factors other than sympathetic activation in the pathogenesis of CsA-induced rise in BP in patients with familial amyloid polyneuropathy.
Contribution of Extracellular Signal-Regulated Kinase to Angiotensin II–Induced Transforming Growth Factor-β1 Expression in Vascular Smooth Muscle Cells
Authors: Hamaguchi Akinori , Kim Shokei , Izumi Yasukatsu , Zhan Yumei , Yamanaka Shinya , Iwao Hiroshi
Published: June 2012

Abstract
—We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-β
1
(TGF-β
1
) mRNA levels in hypertensive rats. However, the molecular mechanism whereby Ang II promotes TGF-β
1
expression in vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the role of extracellular signal–regulated kinase (ERK) in Ang II–mediated TGF-β
1
expression in VSMCs and the role of Ang II in aortic ERK activity of stroke-prone spontaneously hypertensive rats. Treatment of quiescent VSMCs with 100 nmol/L Ang II induced rapid phosphorylation and activation of ERK1 and ERK2 with a peak at 5 minutes followed by an increase in activator protein-1 (AP-1) DNA binding activity, as shown by gel mobility shift assay. An increase in TGF-β
1
mRNA was shown by Northern blot analysis. Treatment of VSMCs with PD98059, a specific inhibitor of the ERK pathway, attenuated both the activation of AP-1 and the increase in TGF-β
1
mRNA induced by Ang II. Inhibition of Ang II–induced AP-1 activation with c-
fos
antisense oligodeoxynucleotide led to a significant reduction of TGF-β
1
mRNA in VSMCs. Furthermore, in vivo treatment of stroke-prone spontaneously hypertensive rats with losartan, an Ang II type 1 receptor antagonist, decreased aortic ERK activity. Thus, we show that ERK, through AP-1 activation, is involved in Ang II–induced TGF-β
1
mRNA expression in VSMCs and suggest that ERK may participate in vascular remodeling of hypertension. However, it remains to be determined whether the increase in TGF-β
1
mRNA leads to the increase in its active protein.
Genistein Inhibits Pressure-Induced Expression of c-
fos
in Isolated Mesenteric Arteries
Authors: Miriel Victor A. , Allen Steven P. , Schriver Suzanne D. , Prewitt Russell L.
Published: June 2012

Abstract
—We have previously demonstrated that elevating intraluminal pressure from 90 to 140 mm Hg in isolated mesenteric arteries increases the expression of proto-oncogenes. These proto-oncogenes encode nuclear transcription factors that regulate the expression of target genes during various stages of the cell cycle. Thus, pressure-induced proto-oncogene expression may represent a mechanism by which pressure can induce growth and/or proliferation of vascular smooth muscle. The purpose of this study was to determine the intracellular signals that contribute to the pressure-induced increase in c-
fos
expression. Small mesenteric arteries were isolated from male Wistar rats and transferred to a dual-vessel chamber. The arteries were cannulated and slowly equilibrated to initial conditions (90 mm Hg, 37°C) while being continuously superfused with a HEPES-bicarbonate–buffered Krebs’ solution. After the equilibration period, the intraluminal pressure in 1 artery was increased to 140 mm Hg for 1 hour. In experiments designed to determine the intracellular signals involved in the pressure-induced increase in c-
fos
expression, specific inhibitors were introduced to the superfusate reservoir of both arteries before the pressure increase. The arteries were then fixed in phosphate-buffered formalin and embedded in paraffin blocks. Sections of paraffin-embedded arteries were fixed on slides, and the expression of c-
fos
was determined by in situ hybridization with the use of
35
S-labeled riboprobes. The pressure-induced expression of c-
fos
was not inhibited by nitrendipine (10 μmol/L), a calcium-free Krebs’ solution containing EGTA (1 to 2 mmol/L), calphostin C (0.1 μmol/L), or cytochalasin D (0.4 μmol/L) but was inhibited by genistein (30 μmol/L). The results suggest that activation of a tyrosine kinase is required for pressure-induced c-
fos
expression, but the signaling pathway does not require extracellular calcium entry, intact actin filaments, or protein kinase C. As we have shown previously, the expression of c
-fos
correlated with wall stress.
Impact of Nativity and Race on “Stroke Belt” Mortality
Authors: Lackland Daniel T. , Egan Brent M. , Jones Patricia J.
Published: June 2012

Abstract
—The southeastern region of the United States has been recognized for 6 decades as an area of excess cerebrovascular mortality rates. While the reasons for the disease variation remain an enigma, South Carolina has consistently been the forerunner of the “Stroke Belt.” To determine the effects of nativity (birthplace) on stroke mortality rates in South Carolina, proportional mortality ratios (PMRs) were calculated for stroke deaths in South Carolina during 1980–1996 according to birthplace and stratified by gender, race, age, and educational status. The analyses revealed a graded risk of stroke by birthplace, with the highest PMRs (95% CI) among individuals born in South Carolina (104.8 [103.4 to 106.3]), intermediate PMRs in those born in the Southeast other than South Carolina (92.5 [90.2 to 94.9]), and lowest PMRs for those born outside the Southeast (77.4 [74.9 to 80.1]). The lower stroke PMRs for individuals born outside the Southeast were more striking in blacks (51.8 [45.2 to 59.3]) than in whites (84.9 [82.0 to 88.0]) and for men (73.3 [69.5 to 77.3]) than women (83.5 [79.9 to 87.3]). The findings, particularly in blacks, were not explainable by gender, differences in age, and/or markers of educational and socioeconomic status. These findings suggest that nativity is a significant risk marker for the geographic variation in stroke mortality. Moreover, the regional disparities for nativity and subsequent stroke mortality appear to be greater in blacks than in whites and for men than for women. An understanding of factors linking birthplace to risk for cerebrovascular mortality could facilitate efforts directed at stroke prevention.
Cyclooxygenase-2 Inhibition Decreases Renin Content and Lowers Blood Pressure in a Model of Renovascular Hypertension
Authors: Wang Jun-Ling , Cheng Hui-Fang , Harris Raymond C.
Published: June 2012

Abstract
—It has been proposed that the macula densa participates in the regulation of increased renin expression in renovascular hypertension (RVH) and that prostaglandins may be among the mediators of macula densa function. We have previously shown that in renal cortex, cyclooxygenase-2 (COX-2) expression is localized to the macula densa and surrounding cortical thick ascending limb and increases in high-renin states, such as salt restriction and angiotensin-converting enzyme inhibition. In the present studies, we examined the effect of the selective COX-2 inhibitor SC58236 on plasma renin activity (PRA) and renal renin expression in RVH in rats. The aorta was coarcted between right and left renal arteries, and animals received either SC58236 or vehicle for 1 week. At day 8, vehicle-treated coarcted rats were hypertensive (mean carotid arterial blood pressure: 138±3 versus 87±2 mm Hg in sham-operated controls; n=9 to 11;
P
<0.001) and exhibited a disparity of kidney size (ratio left/right kidney: 0.78±0.04 versus 1.02±0.02; n=9 to 10;
P
<0.001). PRA increased significantly (84.6±6.5 versus 9.0±1.4 ng angiotensin I [Ang I] per milliliter per hour; n=8 to 9;
P
<0.01). In the coarcted rats, neither renin mRNA expression nor renin activity of the right kidney was altered (renin/GAPDH mRNA: 1.12±0.05-fold levels in control rats; n=6;
P
=NS; renin activity: 23.4±1.8 versus 27.1±3.4 ng Ang I per hour per milligram protein; n=8 to 9;
P
=NS). However, the renin mRNA of the left kidney increased to 3.0±0.6-fold of control (n=6), and the renin activity increased to 189.0±28.6 ng Ang I per hour per milligram protein (n=8;
P
<0.01). Expression of COX-2 mRNA and immunoreactive protein increased in the affected left kidney but was not different from control in the unaffected right kidney. SC58236 treatment to coarcted rats did not affect kidney size (ratio left/right kidney: 0.79±0.06; n=9). However, PRA was significantly decreased compared with the vehicle-treated coarcted rats (19.8±2.8 ng Ang I per milliliter per hour; n=9;
P
<0.01). The left kidney renin mRNA and renin content were also decreased (1.7±0.3-fold control; n=6;
P
<0.05; and 45.7±7.6 ng Ang I per hour per milligram protein; n=9;
P
<0.01, respectively), while renin mRNA and renin content of the right kidney were not altered. SC58236 lowered mean arterial blood pressure (122±5 mm Hg; n=14;
P
<0.05 compared with vehicle). A significant correlation was observed between PRA and mean blood pressure (
r
=0.75;
P
<0.01). In summary, these studies indicate that the selective COX-2 inhibitor SC58236 decreases renin production and release in RVH and suggest an important role for COX-2 regulation of the renin-angiotensin system.
Genetic Isolation of a Chromosome 1 Region Affecting Susceptibility to Hypertension-Induced Renal Damage in the Spontaneously Hypertensive Rat
Authors: St. Lezin Elizabeth , Griffin Karen A. , Picken Maria , Churchill Monique C. , Churchill Paul C. , Kurtz Theodore W. , Liu Weizhong , Wang Ning , Kren Vladimir , Zidek Vaclav , Pravenec Michal , Bidani Anil K.
Published: June 2012

Abstract
—Linkage studies in the fawn-hooded hypertensive rat have suggested that genes influencing susceptibility to hypertension-associated renal failure may exist on rat chromosome 1q. To investigate this possibility in a widely used model of hypertension, the spontaneously hypertensive rat (SHR), we compared susceptibility to hypertension-induced renal damage between an SHR progenitor strain and an SHR congenic strain that is genetically identical except for a defined region of chromosome 1q. Backcross breeding with selection for the markers
D1Mit3
and
Igf2
on chromosome 1 was used to create the congenic strain (designated SHR.BN-
D1Mit3/Igf2
) that carries a 22 cM segment of chromosome 1 transferred from the normotensive Brown Norway rat onto the SHR background. Systolic blood pressure (by radiotelemetry) and urine protein excretion were measured in the SHR progenitor and congenic strains before and after the induction of accelerated hypertension by administration of DOCA-salt. At the same level of DOCA-salt hypertension, the SHR.BN-
D1Mit3/Igf2
congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage have been trapped in the differential chromosome segment of the SHR.BN-
D1Mit3/Igf2
congenic strain. This congenic strain represents an important new model for the fine mapping of gene(s) on chromosome 1 that affect susceptibility to hypertension-induced renal injury in the rat.
Diagnosis of White Coat Hypertension by Ambulatory Blood Pressure Monitoring
Authors: Owens Patrick , Atkins Neil , O’Brien Eoin
Published: June 2012

Abstract
—White coat hypertension (WCH) is common in referred hypertensive patients. Ambulatory blood pressure monitoring (ABPM) is not free from the white coat syndrome. We examined the use of the elevation of the first and last measurements of ABPM for diagnosis of WCH in a hypertensive population that had been referred to a hospital-based hypertension unit. Data were obtained on 1350 patients for clinic and ABPM parameters. WCH, as diagnosed by conventional clinic blood pressure (BP) measurement, was compared with a variety of alternative methods determined from ABPM. In all cases, mean daytime pressure was <135 mm Hg/85 mm Hg with an elevation of clinic BP ≥140 mm Hg systolic or 90 mm Hg diastolic. The definitions tested for this elevation were first hour mean pressure, first reading, maximum reading in first hour, last hour mean pressure, last reading, maximum reading in the last hour and maximum reading in first or last hour. Elevation of the maximum pressure in the first hour or last hour above 140 mm Hg systolic or 90 mm Hg diastolic showed a high level of agreement (κ=0.91) with classical WCH for diagnosis of the white coat syndrome. Termed ambulatory white coat hypertension, patients with this finding were older than classic white coat patients and had higher daytime (127±6/78±5 mm Hg versus 121±5.5/74±6 mm Hg,
P
<0.005 for systolic and diastolic) and nighttime (114±11/67±8 mm Hg versus 106±9/61±6 mm Hg,
P
<0.005 for systolic and diastolic) pressures. They also had a significantly greater Sokolow-Lyon index (leads V
1
+V
5
, 21±7 mV versus 18±6 mV). Elevation of BP above 140 mm Hg systolic or 90 mm Hg diastolic in the first or last hour of monitoring diagnoses patients with a white coat response in whom there is a higher BP profile than in patients with classic white coat response alone. We suggest, therefore, that this is a better measure of the white coat phenomenon.
Hypertension and Hormone-Related Neoplasms in Women
Authors: Soler Maria , Chatenoud Liliane , Negri Eva , Parazzini Fabio , Franceschi Silvia , La Vecchia Carlo
Published: June 2012

Abstract
—The relation between hypertension and the risk of selected hormone-related neoplasms in women was investigated in a network of case-control studies conducted in Italy during 1983–1996. Cases were women younger than 75 years with histologically confirmed cancer of the breast (n=3406), endometrium (n=745), ovary (n=970), and thyroid (n=145). Controls were 3054 women admitted in the same geographic area for acute, nonneoplastic, non–hormone-related diseases. Odds ratios (ORs) of treated hypertension were computed after allowance for sociodemographic factors, smoking habits, alcohol consumption, parity, menopausal status, and body mass index (BMI) by means of unconditional logistic regression. The ORs were 1.2 (95% CI, 1.1 to 1.4) for breast cancer and 1.6 (95% CI, 1.3 to 1.9) for endometrial cancer, and the elevated ORs persisted after ≥5 years since diagnosis of hypertension. No significant association was observed for ovarian and thyroid cancer. For breast cancer, the association was apparently stronger at age 55 years or over and consequently after menopause. No appreciable effect modification was evident for endometrial cancer. Allowance for BMI did not explain the association of postmenopausal breast cancer and endometrial cancer with hypertension. The OR of postmenopausal breast cancer was 1.5 (95% CI, 1.1 to 2.0) in hypertensive women with BMI ≥30 kg/m
2
compared with normotensive women with BMI <25 kg/m
2
. The corresponding figure for all endometrial cancers was 4.9 (95% CI, 3.4 to 6.9). Even in the absence of a clear understanding of biological mechanisms, the definition of a role of hypertension on female hormone–related cancers can have relevant implications on individual risk assessment.
Genetic, Biochemical, and Clinical Studies of Patients With A328V or R213C Mutations in 11βHSD2 Causing Apparent Mineralocorticoid Excess
Authors: Morineau Gilles , Marc Jean-Michel , Boudi Ahmed , Galons Herve , Gourmelen Micheline , Corvol Pierre , Pascoe Leigh , Fiet Jean
Published: June 2012

Abstract
—Apparent mineralocorticoid excess is a recessively inherited hypertensive syndrome caused by mutations in the 11β-hydroxysteroid dehydrogenase type 2 gene, which encodes the enzyme normally responsible for converting cortisol to inactive cortisone. Failure to convert cortisol to cortisone in mineralocorticoid-sensitive tissues permits cortisol to bind to and activate mineralocorticoid receptors, causing hypervolemic hypertension. Typically, these patients have increased ratios of cortisol to cortisone and of 5α- to 5β-cortisol metabolites in serum and urine. We have studied 3 patients in 2 families with severe, apparent mineralocorticoid excess and other family members in terms of their genetic, biochemical, and clinical parameters, as well as normal controls. Two brothers were homozygous for an A328V mutation and the third patient was homozygous for an R213C mutation in the 11β-hydroxysteroid dehydrogenase type 2 gene; both mutations caused a marked reduction in the activity of the encoded enzymes in transfection assays. The steroid profiles of the 7 heterozygotes and 2 other family members studied were completely normal. The results of a novel assay used to distinguish 5α- and 5β-tetrahydrometabolites suggest that 5β-reductase activity is reduced or inhibited in apparent mineralocorticoid excess. In 1 patient undergoing renal dialysis for chronic renal insufficiency, direct control of salt and water balance completely corrected the hypertension, emphasizing the importance of mineralocorticoid action in this syndrome.
Effects of Vitamin E and Glutathione on Glucose Metabolism
Authors: Barbagallo Mario , Dominguez Ligia J. , Tagliamonte Maria Rosaria , Resnick Lawrence M. , Paolisso Giuseppe
Published: June 2012

Abstract
—Vitamin E is an antioxidant that has been demonstrated to improve insulin action. Glutathione, another natural antioxidant, may also be important in blood pressure and glucose homeostasis, consistent with the involvement of free radicals in both essential hypertension and diabetes mellitus. Our group has recently suggested that the effects of reduced glutathione on glucose metabolism may be mediated, at least in part, by intracellular magnesium levels (Mg
[i]
). Recent evidence suggests that vitamin E enhances glutathione levels and may play a protective role in magnesium deficiency–induced cardiac lesions. To directly investigate the effects of vitamin E supplementation on insulin sensitivity in hypertension, in relation to the effects on circulating levels of reduced (GSH) and oxidized (GSSG) glutathione and on Mg
[i]
, we performed a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo in 24 hypertensive patients and measured whole-body glucose disposal (WBGD) by euglycemic glucose clamp, GSH/GSSG ratios, and Mg
[i]
before and after intervention. The relationships among WBGD, GSH/GSSG, and Mg
[i]
in both groups were evaluated. In hypertensive subjects, vitamin E administration significantly increased WBGD (25.56±0.61 to 31.75±0.53 μmol/kg of fat-free mass per minute;
P
<0.01), GSH/GSSG ratio (1.10±0.07 to 1.65±0.11;
P
<0.01), and Mg
[i]
(1.71±0.042 to 1.99±0.049 mmol/L;
P
<0.01). In basal conditions, WBGD was significantly related to both GSH/GSSG ratios (
r
=0.58,
P
=0.047) and Mg
[i]
(
r
=0.78,
P
=0.003). These data show a clinical link between vitamin E administration, cellular magnesium, GSH/GSSG ratio, and tissue glucose metabolism. Further studies are needed to explore the cellular mechanism(s) of this association.
Cardiovascular Effects of Clonidine-Like Drugs in Pithed Rabbits
Authors: Pompermayer Kenia , Salgado Maria Cristina O. , Feldman Josiane , Bousquet Pascal
Published: June 2012

Abstract
—Administration (3 to 100 μg/kg IV) of clonidine, rilmenidine, and an imidazoline derivative, 2-(2-chlorophenylamino)imidazoline, in pithed nonstimulated rabbits caused a dose-dependent increase in mean arterial pressure without affecting heart rate. Prazosin (0.1 mg/kg IV) almost abolished the pressor responses to 2-(2-chlorophenylamino)imidazoline, partially inhibited those induced by clonidine, but failed to affect those elicited by rilmenidine. In contrast, yohimbine (1 mg/kg IV) blunted the pressor responses of the 3 drugs. In sympathetically stimulated pithed rabbits, 2-(2-chlorophenylamino)imidazoline induced only pressor effects, whereas clonidine and rilmenidine caused a transient pressure increase followed by a dose-dependent depressor effect. Yohimbine abolished the depressor effect of both drugs, which may have involved presynaptic α
2
-adrenoceptors. In conclusion, peripheral effects of 2-(2-chlorophenylamino)imidazoline and clonidine involved at least α
1
- and α
2
-adrenoceptor activation, whereas pressor and depressor effects of rilmenidine were mediated by α
2
-adrenoceptors.
Administration Time–Dependent Effects of Aspirin in Women at Differing Risk for Preeclampsia
Authors: Hermida Ramón C. , Ayala Diana E. , Fernández José R. , Mojón Artemio , Alonso Ignacio , Silva Inés , Ucieda Rafael , Codesido José , Iglesías Manuel
Published: June 2012

Abstract
—This study extends previous results on the effects of low-dose aspirin on blood pressure in pregnant women at differing risk of developing hypertension in pregnancy and who received aspirin at different times according to their rest-activity cycle. A double-blind, randomized, placebo-controlled trial was conducted in 240 pregnant women randomly assigned to 1 of 6 groups according to treatment (placebo or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Blood pressure and heart rate for each subject were automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery, as well as at puerperium (6 to 8 weeks after delivery). Subjects were further divided for comparative purposes according to the results of the tolerance-hyperbaric test for early identification of those with a higher risk for developing hypertensive complications in pregnancy. Results indicated that there was no effect of aspirin on blood pressure at time 1 (compared with placebo). A blood pressure reduction was, however, highly statistically significant at time 2 and, to a greater extent, at time 3 (mean reductions of 14.2 and 9.6 mm Hg in 24-hour means for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). Effects of aspirin on blood pressure were significantly larger for women with a positive test at the time of recruitment (
P
<0.001). Differences in blood pressure among pregnant women receiving aspirin at different times in the circadian cycle disappeared at puerperium (
P
>0.212). There was no effect of aspirin or placebo on heart rate. This study corroborates the statistically significant, time-dependent effect of low-dose aspirin on blood pressure in pregnant women with differing risk of developing hypertensive complications in pregnancy. Although the mechanism involved in the administration-time–dependent responsiveness of blood pressure to aspirin still remains uncertain, the use of doses of aspirin <80 mg/d that do not affect placental thromboxane, initiation of the use of aspirin after 16 weeks’ gestation, and the lack of circadian timing for aspirin administration could all explain the lack of positive results in previous clinical trials.
Mutants of 11β-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity
Authors: Nunez B. Scott , Rogerson Fraser M. , Mune Tomoatsu , Igarashi Yoshio , Nakagawa Yuichi , Phillipov George , Moudgil Asha , Travis Luther B. , Palermo Mario , Shackleton Cedric , White Perrin C.
Published: June 2012

Abstract
—Mutations in the kidney isozyme of human 11-hydroxysteroid dehydrogenase (11-HSD2) cause apparent mineralocorticoid excess, an autosomal recessive form of familial hypertension. We studied 4 patients with AME, identifying 4 novel and 3 previously reported mutations in the
HSD11B2
(
HSD11K
) gene. Point mutations causing amino acid substitutions were introduced into a pCMV5/11HSD2 expression construct and expressed in mammalian CHOP cells. Mutations L179R and R208H abolished activity in whole cells. Mutants S180F, A237V, and A328V had 19%, 72%, and 25%, respectively, of the activity of the wild-type enzyme in whole cells when cortisol was used as the substrate and 80%, 140%, and 55%, respectively, of wild-type activity when corticosterone was used as the substrate. However, these mutant proteins were only 0.6% to 5.7% as active as the wild-type enzyme in cell lysates, suggesting that these mutations alter stability of the enzyme. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, demonstrated in whole cells, when cortisol was used as the substrate. These included the ratio of urinary cortisone to cortisol metabolites (
R
2
=0.648,
P
<0.0001), age at presentation (
R
2
=0.614,
P
<0.0001), and birth weight (
R
2
=0.576,
P
=0.0004). Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1.
State-of-the-Art Lecture
Authors: Krieger Eduardo Moacyr , Brum Patrícia Chakur , Negrão Carlos Eduardo
Published: June 2012

Abstract
—Exercise training plays an important role in the reduction of high blood pressure. In this review, we discuss the effect of distinct intensities of exercise training on the reduction of high blood pressure in spontaneously hypertensive rats (SHR). In addition, we present some hemodynamic mechanisms and associated neural controls by which exercise training attenuates hypertension in SHR. Low-intensity exercise training is more effective in reducing high blood pressure than is high-intensity exercise training in SHR. The decrease in blood pressure is due to resting bradycardia, and in consequence, lower cardiac output. Sympathetic attenuation to the heart is the major explanation for the resting bradycardia. Recovery of the sensitivity of baroreflex control of heart rate, which is usually impaired in SHR, is an important neurogenic component involved in the benefits elicited by exercise training.
Effects of Acute AV3V Lesions on Renal and Hindlimb Vasodilation Induced by Volume Expansion
Authors: Colombari Débora S. A. , Cravo Sérgio L.
Published: June 2012

Abstract
—The role of the anteroventral third ventricle (AV3V) region in the cardiovascular adjustments to volume expansion (VE) with 4% Ficoll (1% body weight, 1.4 mL/min) was studied in urethane-anesthetized rats. In sham-lesioned animals, VE produced a transitory (≤20 minutes) increase in mean arterial pressure, which peaked at 10 minutes (10±3 mm Hg), and sustained increases of renal (123±10% and 127±6% of baseline, respectively, 10 and 40 minutes after VE) and hindlimb vascular (157±19% and 153±9% of baseline) conductance. After AV3V lesions, VE induced a sustained increase in mean arterial pressure. Although renal blood flow increased in response to VE, renal vascular conductance was unaffected, indicating that renal vasodilation was abolished. On the other hand, after AV3V lesions, the increases in hindlimb blood flow and vascular conductance were higher than those observed in sham-lesioned rats. Results obtained demonstrated that the AV3V region is essential for the renal vasodilation induced by VE.
Exercise Reverses Peripheral Insulin Resistance in Trained L-NAME–Hypertensive Rats
Authors: d’Avila Kátia De Angelis Lobo , Gadonski Giovani , Fang Jiao , Dall’Ago Pedro , Albuquerque Vera Lúcia , Peixoto Livia Rodrigues de Araújo , Fernandes Tânia Gatelli , Irigoyen Maria Cláudia
Published: June 2012

Abstract
—Several studies have demonstrated an increase in peripheral resistance to insulin associated with hypertension. To assess the hemodynamic and metabolic effects of exercise training, normotensive and
N
ω
-nitro-
l
-arginine methyl ester (L-NAME)–hypertensive male Wistar rats were submitted to low-intensity treadmill exercise training for 10 weeks and compared with their sedentary controls. Blood pressure signals were obtained and processed with a data acquisition system (CODAS, 1 kHz) to evaluate mean arterial pressure, heart rate, autonomic control of heart rate, and baroreflex sensitivity. Exercise training induced a nonsignificant 6.5-mm Hg decrease in mean arterial pressure in trained hypertensive rats (163±9 mm Hg) compared with sedentary hypertensive rats (169.5±5.5 mm Hg). The hypertensive groups showed impairment of baroreflex function in response to changes in arterial pressure compared with sedentary controls. Furthermore, exercise training improved the tachycardic response to decreasing arterial pressure and reduced intrinsic heart rate in trained control rats compared with all other groups. Sedentary hypertensive rats presented a decrease in body weight compared with normotensive animals. Basal evaluation of the glucose/insulin ratio showed increased insulin resistance in sedentary (28.4±3) and trained (23.5±2.7) hypertensive rats compared with sedentary control rats (40.5±3). However, the glucose/insulin ratio evaluated during the exercise session in trained rats showed an improvement in insulin resistance (54.5±5 for control rats and 44±9 for hypertensive rats). In conclusion, L-NAME–induced hypertension is accompanied by an increase in insulin resistance in rats. The improvement in peripheral insulin sensitivity during exercise and the body weight gain observed in trained hypertensive rats may support the positive role of physical activity in the management of hypertension.
The Aging Process Modifies the Distensibility of Elastic but not Muscular Arteries
Authors: Bortolotto Luiz A. , Hanon Olivier , Franconi Giovanna , Boutouyrie Pierre , Legrain Sylvie , Girerd Xavier
Published: June 2012

Abstract
—Aging decreases the distensibility of large elastic arteries; however, the effects of age on the functional parameters of muscular, medium-sized arteries are not well determined. This study evaluated the consequences of aging on the functional parameters of the carotid and radial arteries in normotensive men. A total of 62 elderly subjects (aged 74±2 years) were compared with 87 young subjects (aged 35±3 years). Internal diameter and intima-media thickness (IMT) were measured by a high-resolution echo-tracking system to calculate distensibility and incremental elastic modulus (Einc). Although in the normal range, systolic and diastolic blood pressure levels were statistically different in the 2 groups at 128±19 and 74±13 mm Hg versus 121±27 and 71±18 mm Hg in the young and elderly subjects, respectively (
P
<0.05). At the carotid artery level, elderly subjects exhibited a greater IMT (742±144 versus 469±132 μm;
P
<0.01) and internal diameter (7067±828 versus 6062±1026 μm;
P
<0.01) than young subjects; elderly subjects also had lower distensibility (12±2 versus 21±2 kPa
-1
· 10
-3
;
P
<0.01) and higher Einc (0.9±0.2 versus 0.7±0.3 kPa · 10
3
;
P
<0.01). At the radial artery level, both IMT (240±42 versus 218±51 μm;
P
<0.01) and internal diameter (2685±432 versus 2491±444 μm;
P
<0.01) were greater in elderly subjects, but no differences in distensibility and Einc were observed between the 2 groups. All differences remained significant, even after adjusting for mean blood pressure. These results indicate that the increase of the internal diameter and IMT observed during the aging process can have opposite effects on the functional parameters of large elastic or medium-sized muscular arteries.
Proteoglycan Production by Vascular Smooth Muscle Cells From Resistance Arteries of Hypertensive Rats
Authors: Castro Claudia Magdalena , Cruzado Montserrat Cecilia , Miatello Roberto Miguel , Risler Norma Raquel
Published: June 2012

Abstract
—Extracellular matrix (ECM) modifications in the vascular wall contribute to the narrowing of arteries in hypertension. Because direct evidence for the role of proteoglycans (PGs) in the pathological process of resistance-sized arteries has not already been demonstrated, we examined the effect of growth factors on secreted and membrane-bound PG synthesis by cultured mesenteric vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and Wistar rats. After 48 hours of stimulation with angiotensin II (Ang II), platelet-derived growth factor (PDGF-BB), and 10% fetal calf serum (FCS) or 0.1% FCS as control, PG synthesis (in dpm/ng DNA) was evaluated in the medium (M-ECM) and in the cell layer (P-ECM) by a double-isotopic label method with both [
3
H]-glucosamine and [
35
S]-sodium sulfate, which are incorporated into all complex carbohydrates or only into sulfated disaccharides, respectively. VSMC from SHR displayed a significantly lower level of synthesis of M-ECM [
3
H]-PGs than those of Wistar rats in all the experimental groups, including the control group (0.1% FCS), but no differences in M-ECM [
35
S] uptake were found in any case. In the P-ECM, Ang II was the only factor that produced a lesser effect on [
3
H]-glucosamine and a greater effect on [
35
S]-sodium sulfate uptakes in VSMC from SHR than from Wistar rats. The most prominent change seen in VSMC from SHR was an increased sulfation, assessed by [
35
S]/[
3
H] ratio, in nonstimulated cells and in response to 10% FCS and Ang II but not to PDGF-BB compared with VSMC from Wistar rats. These data indicate the existence of changes in PG modulation in the resistance vessels of SHR, which suggests that PGs may contribute to the development of structural and functional modifications in hypertensive states.