bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensinogen Concentrations and Renin Clearance
Authors: Bohlender Jürgen , Ménard Joël , Ganten Detlev , Luft Friedrich C.
Published: June 2012

Abstract
—Renin (REN) requires seconds to convert angiotensinogen (AGT) to angiotensin I. We tested the hypothesis that this long catalytic cycle might indicate an influence of AGT concentrations on REN clearance. We studied 2 transgenic rat (TGR) strains for human (h) AGT; one strain has hAGT values ≈7-fold higher than the other (68±18 versus 10±4 μg angiotensin I/mL). hREN (30 000 pg) was bolus-infused into both lines and into nontransgenic controls. The terminal half-life (T1/2β) was increased (130 versus 82 minutes) and the metabolic clearance rate (MCR) was decreased (0.83±0.29 versus 2.2±0.66 μL · min
−1
· g
−1
) in the high hAGT strain compared with the low hAGT strain. The difference was not related to volume of distribution at steady state. Infused hREN blocked with remikiren resulted in T1/2β and MCR values that were not different from control values. Infused unblocked and blocked radiolabeled hREN was distributed similarly in the hAGT TGR strains. Infused mouse REN, which cannot convert hAGT, had similar T1/2β and MCR values in hAGT TGR. Measuring REN with direct radioimmunoassay or by enzyme kinetic assay gave similar results. We next crossed homozygous hAGT TGR from both strains with homozygous hREN TGR. Heterozygous offspring from the low hAGT TGR strain had plasma REN activity, hREN concentration, and rat AGT values that were no different from those of their parents. However, TGR offspring with high hAGT values had massively elevated plasma REN activity and hREN concentration as well as elevated blood pressure, even though both the hREN and rREN genes are downregulated. We conclude that increased AGT concentrations decrease REN MCR and increase REN T1/2β. The REN-AGT complex may stabilize plasma REN concentration and regulate plasma REN activity independent of renal REN secretion and angiotensin II–mediated feedback. These effects could augment angiotensin I generation and influence blood pressure. The notion that AGT is merely a passive substrate reservoir for REN should be revised.
Heme Oxygenase-1 Is Upregulated in the Kidney of Angiotensin II–Induced Hypertensive Rats
Authors: Aizawa Toru , Ishizaka Nobukazu , Taguchi Jun-ichi , Nagai Ryozo , Mori Ichiro , Tang Shiow-Shih , Ingelfinger Julie R. , Ohno Minoru
Published: June 2012

Abstract
—In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2±0.2 versus 1.2±0.2 mL/min with Ang II infusion,
P
<0.01) and increased proteinuria (9.7±1.3 versus 28.1±7.2 mg/d with Ang II infusion,
P
<0.01). In contrast, norepinephrine did not alter these laboratory values. Ang II infusion significantly increased HO-1 expression in mRNA (442±98% of control at day 5,
P
<0.01) and protein levels (314±49% of control at day 5,
P
<0.01). Immunohistochemistry showed that in the kidney of normotensive rats, HO-1 was expressed mainly in the basal side in the renal tubules. After Ang II infusion, HO-1 staining was more extensively dispersed in the tubular epithelial cells. The intraperitoneal administration of zinc protoporphyrin, an HO inhibitor, to Ang II–infused rats further decreased GFR (0.8±0.1 mL/min) and increased proteinuria (52.5±13.0 mg/d). In contrast, the administration of hemin, an HO inducer, ameliorated the Ang II–induced decrease in GFR (2.4±0.2 mL/min) and increase in proteinuria (9.3±4.5 mg/d). These data suggest that HO-1 upregulation in the kidney of Ang II–induced hypertensive rats may exert a renoprotective effect against Ang II–induced renal injury.
Role of Reactive Oxygen Species in Bradykinin-Induced Mitogen-Activated Protein Kinase and c-
fos
Induction in Vascular Cells
Authors: Greene Eddie L. , Velarde Victoria , Jaffa Ayad A.
Published: June 2012

Abstract
—Bradykinin stimulates proliferation of aortic vascular smooth muscle cells (VSMCs). We investigated the action of bradykinin on the phosphorylation state of the mitogen-activated protein kinases p42
mapk
and p44
mapk
in VSMCs and tested the hypothesis that reactive oxygen species (ROS) might be involved in the signal transduction pathway linking bradykinin activation of nuclear transcription factors to the phosphorylation of p42
mapk
and p44
mapk
. Bradykinin (10
−8
mol/L) rapidly increased (4- to 5-fold) the phosphorylation of p42
mapk
and p44
mapk
in VSMCs. Preincubation of VSMCs with either
N
-acetyl-
l
-cysteine and/or α-lipoic acid significantly decreased bradykinin-induced cytosolic and nuclear phosphorylation of p42
mapk
and p44
mapk
. In addition, the induction c-
fos
mRNA levels by bradykinin was completely abolished by
N
-acetyl-
l
-cysteine and α-lipoic acid. Using the cell-permeable fluorescent dye dichlorofluorescein diacetate, we determined that bradykinin (10
−8
mol/L) rapidly increased the generation of ROS in VSMCs. The NADPH oxidase inhibitor diphenylene iodonium (DPI) blocked bradykinin-induced c-
fos
mRNA expression and p42
mapk
and p44
mapk
activation, implicating NADPH oxidase as the source for the generation of ROS. These findings demonstrate that the phosphorylation of cytosolic and nuclear p42
mapk
and p44
mapk
and the expression of c-
fos
mRNA in VSMCs in response to bradykinin are mediated via the generation of ROS and implicate ROS as important mediators in the signal transduction pathway through which bradykinin promotes VSMC proliferation in states of vascular injury.
Effects of Cardiac Natriuretic Peptides on Oxidized Low-Density Lipoprotein– and Lysophosphatidylcholine-Induced Human Mesangial Cell Migration
Authors: Kohno Masakazu , Yasunari Kenichi , Maeda Kensaku , Kano Hiroaki , Minami Mieko , Hanehira Takao , Yoshikawa Junichi
Published: June 2012

Abstract
—The objectives of the present study were (1) to determine whether oxidized LDL and lysophosphatidylcholine (lyso-PtdCho), a major phospholipid component of oxidized LDL, stimulate the migration of cultured human mesangial cells and (2) to investigate the possible effects on mesangial cell migration of the cardiac natriuretic peptides atrial and brain natriuretic peptide (ANP and BNP). Oxidized LDL (10 and 100 μg/mL) and lyso-PtdCho (10
−7
to 10
−5
mol/L) stimulated migration in a concentration-dependent manner. In contrast, the effects of native LDL and phosphatidylcholine were modest or nonexistent. Protein kinase C (PKC) inhibitor and downregulation of PKC activity by phorbol ester inhibited oxidized LDL– and lyso-PtdCho–induced migration. Human ANP(1-28) and human BNP-32 significantly inhibited oxidized LDL– and lyso-PtdCho–induced migration in a concentration-dependent manner. C-ANF {des-[Glu
18
,Ser
19
,Gly
20
,Leu
21
,Gly
22
]ANP(4-23)}, a specific ligand for ANP clearance receptors, could not inhibit oxidized LDL– and lyso-PtdCho–induced migration. Inhibition by ANP and BNP of lyso-PtdCho–induced migration was paralleled by an increase in the cellular level of GMP. Oxidized LDL– and lyso-PtdCho–induced migrations were inhibited by 8-bromo-cGMP. The results suggest that oxidized LDL and lyso-PtdCho stimulate the migration of human mesangial cells, at least in part, through a PKC-dependent process and that ANP and BNP inhibit this stimulated migration, probably through a cGMP-dependent process.
Atrial Natriuretic Peptide Is Involved in Renal Actions of Moxonidine
Authors: Mukaddam-Daher Suhayla , Gutkowska Jolanta
Published: June 2012

Abstract
—Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I
1
-receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 μg/300 μL saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 μg) significantly (
P
<0.001) stimulated urinary volume (0.35±0.04 versus 1.05±0.09 mL/h per 100 g), sodium (14.3±2.5 versus 51.8±6.5 μmol/h per 100 g), potassium (10.5±2.3 versus 32.3±3.2 μmol/h per 100 g), and cGMP (325±52 versus 744±120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 μg per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744±120 versus 381±137 pmol/h per 100 g,
P
<0.02). The α
2
-adrenoceptor antagonist yohimbine (50 μg per rat) partially yet significantly inhibited moxonidine-stimulated diuresis and natriuresis but not cGMP excretion. Plasma ANP was dose-dependently increased by moxonidine and was inhibited by pretreatment with efaroxan (220.8±36.9 versus 100.3±31.7 pg/mL,
P
<0.03) but not by yohimbine. In conclusion, selective in vivo activation of imidazoline receptors by moxonidine is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and urinary cGMP excretion, thus implicating ANP in the renal actions of moxonidine.
Hydrolysis by Cathepsin B of Fluorescent Peptides Derived From Human Prorenin
Authors: Almeida Paulo Cezar , Oliveira Vitor , Chagas Jair Ribeiro , Meldal Morten , Juliano Maria Aparecida , Juliano Luiz
Published: June 2012

Abstract
—Cathepsin B is a lysosomal thiolprotease that, because of its colocalization with renin and its ability to activate prorenin, has been proposed as a prorenin processing enzyme. To characterize the biochemical aspect of this potential cathepsin B activity in more detail, we synthesized and assayed with human cathepsin B the internally quenched fluorescent peptide Abz-FSQPMKRLTLGNTTQ-EDDnp (Abz,
ortho-
aminobenzoic acid fluorescent group and EDDnp, N-[2,4-dinitrophenyl]-ethylenediamine quencher group) that contains 7 amino acids for each side of the R-L bond that is the processing site of human prorenin. Human cathepsin B hydrolyzed this peptide at the correct site (R-L bond), with k
cat
/K
m
=75 mmol/L
−1
s
−1
. Analogues of this peptide obtained by Ala scanning at positions P
5
to P
5
’ were also synthesized and assayed as substrates for human cathepsin B. The obtained specificity constant (k
cat
/K
m
) values have a significant parallel with the previous data of prorenin activation by AtT-20 cells and in vitro by cathepsin B. In addition, we demonstrated the presence of cathepsin B–like activity in rat mesangial cells and the ability of its whole soluble fraction lysates, as well as that of purified cloned rat cathepsin B, to hydrolyze Abz-IKKSSF-EDDnp at the K-S bond, which contains 6 amino acids of rat prorenin processing site. The specificity data of cathepsin B toward peptides derived from prorenin processing site support the view that human or rodent cathepsin B could be involved in the intracellular processing of prorenin that is locally synthesized or taken up from the extracellular compartment.
Low Birth Weight Predicts Elevated Plasma Cortisol Concentrations in Adults From 3 Populations
Authors: Phillips David I. W. , Walker Brian R. , Reynolds Rebecca M. , Flanagan Daniel E. H. , Wood Peter J. , Osmond Clive , Barker David J. P. , Whorwood Christopher B.
Published: June 2012

Abstract
—Low birth weight is linked with raised blood pressure in adult life. Recent evidence has suggested that a neuroendocrine disturbance involving the hypothalamic-pituitary-adrenal axis could mediate this link. We therefore investigated the relation between birth weight and fasting plasma cortisol concentrations and the association of cortisol with current blood pressure in population samples of 165 men and women born in Adelaide, South Australia, from 1975 to 1976, 199 men and women born in Preston, UK, from 1935 to 1943, and 306 women born in East Hertfordshire, UK, from 1923 to 1930. Fasting plasma cortisol was measured in plasma samples obtained between 8 and 10
am
. Blood pressure was measured with an automated sphygmomanometer. Low birth weight was associated with raised fasting plasma cortisol concentrations in all 3 populations. A combined analysis that allowed for differences in the gender composition, age, and body mass index between the studies showed that cortisol concentrations fell by 23.9 nmol/L per kilogram increase in birth weight (95% CI 9.6 to 38.2,
P
<0.001). Fasting plasma cortisol concentrations also correlated positively with the subjects’ current blood pressure. However, the association between cortisol and blood pressure was most marked in subjects who were obese (
P
=0.038 for interaction between body mass index and cortisol,
P
=0.01 for interaction between waist-to-hip ratio and cortisol). These results show that low birth weight is associated with raised fasting plasma cortisol concentrations. Increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with raised blood pressure in adult life.
Effects of the N-Terminal Sequence of ACE on the Properties of Its C-Domain
Authors: Marcic Branislav , Deddish Peter A. , Jackman Herbert L. , Erdös Ervin G. , Tan Fulong
Published: June 2012

Abstract
—Angiotensin I–converting enzyme (ACE, kininase II) has 2 active domains (N and C) in a single peptide chain. Because we found its N-domain more stable than its C-domain, we investigated the effect of the amino-terminus of human ACE on the C-domain with a molecular construct expressed in Chinese hamster ovary cells (CHO) cells and transiently in HEK293 cells. This active N-deleted ACE contained only the first 141 amino acids of the human N-domain but not its active center and was linked to the active C-domain containing the transmembrane and cytosolic portions of ACE. The CHO cells were also transfected with human B
2
bradykinin receptor. ACE inhibitors (5 nmol/L or 1 μmol/L) augmented bradykinin (100 nmol/L) effects, elevated B
2
receptor numbers, and resensitized the receptor desensitized by agonist as measured by arachidonic acid release or [Ca
2+
]
i
mobilization. Arachidonic acid release was mediated by pertussis toxin–sensitive Gα
i
, and [Ca
2+
]
i
mobilization was mediated by pertussis-insensitive Gα
q
protein receptor complex. The properties of the construct were compared with wild-type ACE and separate N- and C-domains. The N-deleted ACE differed from wild-type in activation by Cl
−
and [SO
4
]
2−
ions, hydrolysis ratios of substrates (both short synthetic and endogenous peptides) and heat stability. Thus, the N-terminal peptide of ACE affected the characteristics of the C-domain active center. ACE inhibitors acting on N-deleted ACE, which had only a single C-domain active center anchored to plasma membrane, induced cross-talk between the enzyme and the B
2
receptor (eg, the inhibitors resensitized the receptor) independent of blocking bradykinin inactivation.
Differentiated Long-Term Effects of Intentional Weight Loss on Diabetes and Hypertension
Authors: Sjöström C. David , Peltonen Markku , Wedel Hans , Sjöström Lars
Published: June 2012

Abstract
—The beneficial effects of weight loss in the obese have been widely accepted. Still, there is a lack of controlled studies displaying large maintained weight losses over long periods (>4 years). We wanted to examine the results of long-standing intentional weight loss on the development of diabetes and hypertension in severely obese individuals over an 8-year period. In the ongoing prospective Swedish Obese Subjects (SOS) study, 346 patients awaiting gastric surgery were matched with 346 obese control subjects on 18 variables by a computerized matching program. The controls were drawn from a registry consisting of 1508 obese potential controls examined at primary health care centers in Sweden. Of the 692 selected patients (body mass index 41.2±4.7 kg/m
2
[mean±SD]), 483 (70%) were followed for 8 years. No significant weight changes occurred in the obese control group over 8 years. Gastric surgery resulted in a maximum weight loss of −31.1±13.6 kg after 1 year. After 8 years, the maintained weight loss was still 20.1±15.7 kg (16.3±12.3%). Whereas this weight reduction had a dramatic effect on the 8-year incidence of diabetes (odds ratio 0.16, 95% CI 0.07 to 0.36), it had no effect on the 8-year incidence of hypertension (odds ratio 1.01, 95% CI 0.61 to 1.67). A differentiated risk factor response was identified: a maintained weight reduction of 16% strongly counteracted the development of diabetes over 8 years but showed no long-term effect on the incidence of hypertension.
Effects of Bradykinin on Prostaglandin I
2
Synthesis in Human Vascular Endothelial Cells
Authors: Yamasaki Seiki , Sawada Shohei , Komatsu Sumio , Kawahara Takeshi , Tsuda Yutaka , Sato Toshiyuki , Toratani Akihisa , Kono Yoshihito , Higaki Tadashi , Imamura Hitoshi , Tada Yusuke , Akamatsu Naoaki , Tamagaki Toshiyuki , Tsuji Hajime , Nakagawa Masao
Published: June 2012

Abstract
—The effects of bradykinin on the regulatory mechanisms of prostacyclin synthesis in endothelial cells were investigated in association with intracellular Ca
2+
kinetics, cytosolic phospholipase A
2
(cPLA
2
) activity, and mRNA expression of cPLA
2
and prostaglandin H synthase (PGHS) isoforms. Bradykinin enhanced prostacyclin release from endothelial cells time-dependently, but pretreatment with EGTA H-7 or HOE 140 inhibited bradykinin-induced prostacyclin release. Bradykinin increased both the influx of extracellular Ca
2+
and Ca
2+
release from the intracellular Ca
2+
storage sites. These reactions occurred within 5 minutes after bradykinin stimulation. Within 15 minutes, bradykinin activated cPLA
2
to 1.3-fold the control level. The constitutive expressions of mRNA of cPLA
2
, PGHS-1, and PGHS-2 was 87, 562, and 47 amol/μg RNA, respectively. With the stimulation of bradykinin, cPLA
2
mRNA increased to 746 amol/μg RNA in 15 minutes, PGHS-1 mRNA increased to 10 608 amol/μg RNA, and PGHS-2 mRNA increased to 22 400 amol/μg RNA in 180 minutes. Pretreatment with cycloheximide superinduced cPLA
2
and PGHS-2 mRNA expression but almost completely inhibited PGHS-1. Pretreatment with EGTA had effects similar to pretreatment with cycloheximide in the case of cPLA
2
and PGHS-1 but did not affect PGHS-2. These findings suggest that the elevation of cPLA
2
activity caused by the increase of intracellular Ca
2+
concentration is important in the early phase of bradykinin-induced prostacyclin synthesis and that the mechanisms regulating cPLA
2
are different from those regulating PGHS isoforms in endothelial cells.
Interactions Between Blood Cells and Retinal Endothelium in Endotoxic Sepsis
Authors: Tsujikawa Akitaka , Kiryu Junichi , Yamashiro Kenji , Nonaka Atsushi , Nishijima Kazuaki , Honda Yoshihito , Ogura Yuichiro
Published: June 2012

Abstract
—Platelets and leukocytes are thought to play a leading role in the pathogenesis of many inflammatory conditions. To recruit flowing blood cells to the inflammatory region, it would be necessary for them to interact with vascular endothelial cells. Recently, many reports have indicated the resistance of spontaneous hypertensive rats (SHR) to endotoxic sepsis. Their resistance might be derived from suppressed interaction between these blood cells and endothelial cells. Therefore, SHR and age-matched Wistar-Kyoto rats (WKY) were induced with endotoxic sepsis by intravenous injection of lipopolysaccharide (LPS). At 4, 12, 24, and 48 hours after induction, leukocyte-endothelial interactions in the retina were evaluated in vivo with acridine orange digital fluorography. Fluorescently labeled platelets were also injected to investigate platelet-endothelial interactions in the retina in endotoxic sepsis. Leukocyte rolling in SHR after LPS injection was significantly suppressed; the maximum number of rolling leukocytes was reduced by 80.1% at 12 hours after LPS injection in SHR compared with WKY. Subsequent leukocyte infiltration into the vitreous cavity was significantly inhibited in SHR. Furthermore, platelet-endothelial interactions in the retina were also suppressed in SHR treated with LPS. The maximum numbers of rolling and adherent platelets were reduced by 59.5% and 62.6%, respectively, in SHR compared with WKY. In both strains, leukocyte- and platelet-endothelial interactions were substantially inhibited by the blocking of P-selectin. These suppressed interactions could contribute to the reduction of leukocyte- and platelet-mediated tissue injury in endotoxic sepsis in SHR, resulting in their resistance to endotoxemia.
Converting Enzyme Inhibition Normalizes QT Interval in Spontaneously Hypertensive Rats
Authors: Baillard Christophe , Mansier Pascale , Ennezat Pierre Vladimir , Mangin Laurence , Medigue Claire , Swynghedauw Bernard , Chevalier Brigitte
Published: June 2012

Abstract
—We quantified the repolarization time (so-called QT interval) in a rat, an animal species that does not show a well-characterized T wave on surface ECG. We used spontaneously hypertensive rats (SHR) and converting enzyme inhibition to demonstrate a reversible increase in QT interval in pressure-overloaded hearts in the absence of ischemia. An implanted telemetry system recording ECG data in freely moving rats was used to automatically calculate the RR interval. The QT duration was manually determined by use of a calibrated gauge, and a time-frequency domain analysis was used to evaluate heart rate variability. Left ventricular mass was sequentially assessed by echocardiography. Before treatment, 12-month-old SHR had higher left ventricular mass, QT and RR intervals, and unchanged heart rate variability compared with age-matched Wistar rats. A 2-month converting enzyme inhibition treatment with trandolapril reduces systolic blood pressure, left ventricular mass, and QT interval. The RR interval and heart rate variability remains unchanged. There is a positive correlation between the QT interval and left ventricular mass. The SHR is suitable for longitudinal studies on the QT interval. Thus, the detection of the QT interval reflects the phenotypic changes that occur during mechanical overload and, on the basis of these criteria, allows an in vivo determination of the adaptational process.
Efficacy of Candesartan Cilexetil Alone or in Combination With Amlodipine and Hydrochlorothiazide in Moderate-to-Severe Hypertension
Authors: MacGregor Graham A. , Viskoper J. Reuven , Antonios Tarek F.T. , He Feng J.
Published: June 2012

Abstract
—This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA,
P
<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period.
Beneficial Renal and Hemodynamic Effects of Omapatrilat in Mild and Severe Heart Failure
Authors: Troughton Richard W. , Rademaker Miriam T. , Powell James D. , Yandle Timothy G. , Espiner Eric A. , Frampton Christopher M. , Nicholls M. Gary , Richards A. Mark
Published: June 2012

Abstract
—Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (
P
<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (
P
=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (
P
<0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (
P
<0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (
P
<0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.
Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension
Authors: Johansson Mats , Elam Mikael , Rundqvist Bengt , Eisenhofer Graeme , Herlitz Hans , Jensen Gert , Friberg Peter
Published: June 2012

Abstract
—Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (
P
<0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (
P
<0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.
Blockade of the Renin-Angiotensin and Endothelin Systems on Progressive Renal Injury
Authors: Cao Zemin , Cooper Mark E. , Wu Leonard L. , Cox Alison J. , Jandeleit-Dahm Karin , Kelly Darren J. , Gilbert Richard E.
Published: June 2012

Abstract
—The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-β
1
and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
Gender-Differences in Myocardial Adaptation to Afterload in Normotensive and Hypertensive Rats
Authors: Wallen W. Jack , Cserti Christine , Belanger Michael P. , Wittnich Carin
Published: June 2012

Abstract
—Echocardiographic studies suggest that women appear to exhibit a greater degree of myocardial hypertrophy in response to increased afterload than men. Therefore, gender differences and the role of estrogen and testosterone in the development of myocardial hypertrophy were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Male and female rats were either surgically neutered or underwent a sham operation at 21 days of age. A subgroup of neutered females of each strain received 17β-estradiol replacement. At 6 months, the heart weight–to–body weight ratio was assessed and correlated with systemic blood pressure. Compared with males, females had significantly smaller body and heart weights in both normotensive and hypertensive strains. Despite this, females consistently had significantly greater heart weight–to–body weight ratios. In females, neutering significantly lowered the heart weight–to–body weight ratio in WKY rats, which was returned to intact levels with estrogen replacement. Female SHR showed similar, but not statistically significant, responses. In males, neutering appeared to result in a higher heart weight–to–body weight ratio in WKY rats, but the opposite was seen in SHR. In addition, there was a significant correlation between arterial blood pressure and heart weight–to–body weight ratio (systolic
r
=0.45,
P
=0.0015: diastolic
r
=0.52,
P
=0.0002) in intact males and females of both strains, and for a given diastolic pressure, females always exhibited a greater heart weight–to–body weight ratio than males. Thus, a greater degree of myocardial hypertrophy in females appears to be related to the presence of estrogen in both normotensive and hypertensive rats. Females show a stronger relationship between heart/body weight and blood pressure than males, which occurred independent of the presence of estrogen.
Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca
2+
Content After Activation in Essential Hypertension
Authors: Caimi Gregorio , Presti Rosalia Lo , Carollo Caterina , Musso Maurizio , Porretto Ferdinando , Canino Baldassare , Catania Anna , Cerasola Giovanni
Published: June 2012

Abstract
—The purpose of this research was to obtain further information about the role of polymorphonuclear leukocytes in essential hypertension. These cells could be involved in the pathogenesis of organ injury. Thirty subjects (14 men and 16 women) with essential hypertension were enrolled. In these subjects we determined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate and
N
-formyl-methionyl-leucyl-phenylalanine, the polymorphonuclear leukocyte membrane fluidity, obtained by labeling the cells with 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene, cytosolic Ca
2+
concentration, obtained by marking the cells with Fura 2-AM, and integrin pattern (CD11a, CD11b, CD11c, and CD18), by using the indirect immunofluorescence with a flow cytometer. At baseline there was no difference in membrane fluidity between normal subjects and hypertensives, whereas hypertensives showed an increase in cytosolic Ca
2+
content and an increase of the phenotypical expression of CD11a, CD11b, and CD18. In normal subjects and in hypertensives, after activation, no variation was found in membrane fluidity and cytosolic Ca
2+
content. In normal subjects, after activation, we observed a significant increase of the expression of all adhesion molecules, whereas in hypertensives we found an increase of the expression of CD11b, CD11c, and CD18 but also a decrease of CD11a. The behavior of the polymorphonuclear leukocyte integrin profile may have several explanations, and in particular, the trend of CD11a after chemotactic activation may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance hypothetically present in this clinical condition.
Personality Type and Neural Circulatory Control
Authors: Schroeder Kathleen E. , Narkiewicz Krzysztof , Kato Masahiko , Pesek Catherine , Phillips Bradley , Davison Diane , Somers Virend K.
Published: June 2012

Abstract
—Psychosocial factors, including type A personality, anger, hostility, and anxiety, have been implicated in the pathogenesis of cardiovascular disease. Abnormal sympathetic responses to stress may help explain the link between certain behavior patterns and cardiovascular disease. We tested the hypothesis that in normal humans, type A personality characteristics are associated with exaggerated heart rate, pressor, and sympathetic nerve responses to mental and physical stress. We measured heart rate, blood pressure, and muscle sympathetic nerve activity (obtained with direct intraneural recordings) at rest and during stress in 45 healthy subjects (19 men and 26 women, age 29.2±8.7 years) who had no chronic diseases and were taking no medications. Subjects were divided into tertiles based on type A scores. There were no significant differences in sympathetic or hemodynamic reactivity among the 3 different intensity levels of type A characteristics. Baseline measures and responses to stress tests were similar across the 3 groups. Sympathetic and hemodynamic changes during stress tests were also similar in subject groups stratified according to anger scale and cynicism scale. Sympathetic nerve and hemodynamic measurements at rest and during stress were not different in normal subjects with type A characteristics. Abnormalities in sympathetic or cardiovascular reactivity are unlikely to be implicated in any excess of cardiovascular disease in people with type A personality characteristics.
Plasma Hydrogen Peroxide Production in Human Essential Hypertension
Authors: Lacy Fred , Kailasam Mala T. , O’Connor Daniel T. , Schmid-Schönbein Geert W. , Parmer Robert J.
Published: June 2012

Abstract
—Oxygen free radicals, including hydrogen peroxide, may mediate oxidative stress in target organ tissues and contribute to cardiovascular complications in hypertension. To examine heritability of hydrogen peroxide production, we investigated this trait in a family-based cohort consisting of family members (n=236) ascertained through probands (n=57) with essential hypertension. Significant effects on hydrogen peroxide production were found for gender and ethnicity, with men having greater values than women (
P
<0.001) and white subjects having greater values than black subjects (
P
=0.025). Hydrogen peroxide production correlated directly with plasma renin activity (
P
=0.015), suggesting an important interaction between circulating oxygen radicals and the renin-angiotensin system and a potential mechanism for lower hydrogen peroxide values observed in blacks. Heritability estimates from familial correlations revealed that approximately 20% to 35% of the observed variance in hydrogen peroxide production could be attributed to genetic factors, suggesting a substantial heritable component to the overall determination of this trait. Hydrogen peroxide production negatively correlated with cardiac contractility (
r
=−0.214,
P
=0.001) and renal function (
r
=−0.194,
P
=0.003). In conclusion, these results indicate that hydrogen peroxide production is heritable and is related to target organ function in essential hypertension. Genetic loci influencing hydrogen peroxide production may represent logical candidates to investigate as susceptibility genes for cardiovascular target organ injury.
Action of Angiotensin II on DNA Synthesis by Human Saphenous Vein in Organ Culture
Authors: Ibrahim Jamila , Hughes Alun D. , Sever Peter S.
Published: June 2012

Angiotensin II (Ang II), an effector peptide of the renin-angiotensin system, has been reported to stimulate growth of blood vessels in vivo and smooth muscle cells in culture. In this study, the effect of Ang II on DNA synthesis was examined in deendothelialized human saphenous vein in organ culture. After 7 days’ exposure to medium containing 0.4% fetal calf serum plus Ang II, there was a marked increase in DNA synthesis. The effect of Ang II was comparable to the response to platelet-derived growth factor. Responses to Ang II were partially inhibited by the AT
1
receptor antagonist candesartan. An AT
2
receptor antagonist, PD123319, had no effect on Ang II–induced DNA synthesis, either alone or in combination with candesartan. The Ang II peptide analogues [Sar
1
,Ile
8
]-Ang II (saralasin) and [Sar
1
,Thr
8
]-Ang II (sarthran) acted as agonists, increasing DNA synthesis. In the presence of saralasin, responses to Ang II were inhibited. Tyrphostin-23, a tyrosine kinase inhibitor, prevented Ang II–induced DNA synthesis and reduced DNA synthesis in tissues incubated in medium containing only 0.4% fetal calf serum. In conclusion, Ang II stimulates DNA synthesis in human saphenous vein in organ culture. The effect of Ang II was more marked than has been previously reported in isolated cultured saphenous vein smooth muscle cells, and this effect is mediated in part by an angiotensin type 1 receptor. It is possible that an undefined receptor for Ang II may also be involved in the stimulation of DNA synthesis in this preparation.
Evidence for Genetic Factors Explaining the Birth Weight–Blood Pressure Relation
Authors: IJzerman Richard G. , Stehouwer Coen D. A. , Boomsma Dorret I.
Published: June 2012

Abstract
—Epidemiological studies have consistently shown an inverse association between birth weight and systolic blood pressure in later life after adjustment for current size. To examine whether this association is explained by intrauterine or genetic factors, we investigated birth weight and blood pressure data in 53 dizygotic and 61 monozygotic adolescent twin pairs. Birth weight was obtained from the mothers. Blood pressure measurements were performed 6 times at rest and during mental stress. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a systolic blood pressure measured at rest and during the reaction time experiment that was higher compared with their cotwins with the highest birth weight (dizygotic twins: blood pressure at rest, 119.4±9.7 mm Hg versus 117.3±8.5 mm Hg,
P
=0.07, and during a reaction time task, 126.2±10.8 versus 123.6±9.5,
P
=0.09; monozygotic twins: blood pressure at rest, 117.4±6.4 versus 118.4±9.0,
P
=0.4, and during a reaction time task, 122.9±8.4 versus 124.2±10.8,
P
=0.2). The differences in blood pressure between the cotwins with the lowest and the cotwins with the highest birth weight were different in dizygotic compared with monozygotic twin pairs (for blood pressure at rest,
P
=0.05; for blood pressure during reaction time,
P
=0.03). After adjustment for differences in current weight, intrapair differences in birth weight were negatively and significantly associated with differences in systolic blood pressure at rest and during the reaction time task in dizygotic twins (regression coefficient, −5.7 mm Hg/kg [95% confidence interval, −10.4 to −1.0] and −6.3 [−12.7 to 0], respectively) but not in monozygotic twins (−0.1 [−5.4 to 5.2] and +3.5 [−1.8 to 8.8], respectively). Interaction analysis indicated that the associations were different between dizygotic twins and monozygotic twins (
P
=0.1 and
P
<0.05, respectively). These data suggest that genetic factors may play an important role in the association between birth weight and blood pressure.
Consistency of Hemodynamic Responses to Cold Stress in Adolescents
Authors: Kelsey Robert M. , Patterson Stephen M. , Barnard Marie , Alpert Bruce S.
Published: June 2012

Abstract
—Laboratory research on hypertension often is performed with cold stress to elicit vasoconstriction and increases in blood pressure. Several studies have shown that cardiovascular responses to the cold pressor test predict the development of hypertension. We extended this research by comparing cardiovascular responses to a traditional forehead cold pressor test and a naturalistic whole-body cold exposure. We evaluated blood pressure and impedance cardiographic measures of cardiac output and total peripheral resistance in healthy black (n=69) and white (n=47) adolescents (mean age, 14.7 years) during forehead cold pressor (3°C to 4°C) and passive whole-body exposure to a cold chamber (8°C to 10°C). Both tasks elicited increases in vascular resistance and blood pressure, but forehead cold elicited an increase in cardiac output, whereas whole-body cold elicited a decrease in cardiac output (
P
<0.05). Consistent with previous research, there was a tendency toward greater vasoconstrictive reactivity to cold stress in blacks than in whites, particularly during whole-body cold exposure (
P
<0.05). Cardiovascular reactivity correlated significantly between tasks, but substantial intertask consistency occurred only for cardiac and vascular reactivity in male subjects (
r
>0.30) but not in female subjects (
r
<0.15). These gender differences might reflect diminished adrenergic receptor function in female subjects. We conclude that whole-body cold exposure offers a viable, relatively naturalistic alternative to traditional cold pressor tests for the assessment of cardiovascular reactivity.
Renal Protein Phosphatase 2A Activity and Spontaneous Hypertension in Rats
Authors: Yu Peiying , Asico Laureano D. , Eisner Gilbert M. , Hopfer Ulrich , Felder Robin A. , Jose Pedro A.
Published: June 2012

Abstract
—The impaired renal paracrine function of dopamine in spontaneously hypertensive rats (SHR) is caused by hyperphosphorylation and desensitization of the renal D
1
dopamine receptor. Protein phosphatase 2A (PP
2A
) is critical in the regulation of G-protein–coupled receptor function. To determine whether PP
2A
expression and activity in the kidney are differentially regulated in genetic hypertension, we examined the effects of a D
1
-like agonist, fenoldopam, in renal cortical tubules and immortalized renal proximal tubule cells from normotensive Wistar-Kyoto rats (WKY) and SHR. In cortical tubules and immortalized proximal tubule cells, PP
2A
expression and activities were greater in cytosol than in membrane fractions in both WKY and SHR. Although PP
2A
expressions were similar in WKY and SHR, basal PP
2A
activity was greater in immortalized proximal tubule cells of SHR than WKY. In immortalized proximal tubule cells of WKY, fenoldopam increased membrane PP
2A
activity and expression of the regulatory subunit PP
2A
-B56α, effects that were blocked by the D
1
-like antagonist
SCH23390
. Fenoldopam had no effect on cytosolic PP
2A
activity but decreased PP
2A
-B56α expression. In contrast, in immortalized proximal tubule cells of SHR, fenoldopam decreased PP
2A
activity in both membranes and cytosol but predominantly in the membrane fraction, without affecting PP
2A
-B56α expression; this effect was blocked by the D
1
-like antagonist
SCH23390
. We conclude that renal PP
2A
activity and expression are differentially regulated in WKY and SHR by D
1
-like receptors. A failure of D
1
-like agonists to increase PP
2A
activity in proximal tubule membranes may be a cause of the increased phosphorylation of the D
1
receptor in the SHR.
Nitric Oxide Limits Pressor Responses to Sympathetic Activation in Rat Spinal Cord
Authors: Arnolda Leonard F. , McKitrick Douglas J. , Llewellyn-Smith Ida J. , Minson Jane B.
Published: June 2012

Abstract
—
N
-methyl
d
-aspartate (NMDA) receptor stimulation is known to activate nitric oxide (NO) synthase, an enzyme present in a high proportion of sympathetic preganglionic neurons. In this study, we have examined the possibility that NO modulates the pressor responses elicited by NMDA receptor stimulation in the spinal cord. In experiments on anesthetized rats, we determined whether intrathecal administration of either 3-morpholinylsydnoneimine chloride (SIN-1), an NO donor, or
N
G
-nitro-
l
-arginine methyl ester (L-NAME), an NO synthase inhibitor, affected the response to stimulation of spinal NMDA receptors by NMDA (1 pmol to 1 μmol in 10-μL intrathecal administration). Intrathecal NMDA resulted in dose-dependent increases in blood pressure. SIN-1 (100 nmol) attenuated the pressor responses to NMDA (F
1,70
=12,
P
=0.001). Conversely, L-NAME (1 nmol to 1 μmol) augmented the pressor response to NMDA in a dose-dependent manner (F
3,161
=28.3,
P
<0.001). The effect of L-NAME to amplify the pressor response to NMDA was reversed by
l
-arginine but not by
d
-arginine. These results indicate that endogenous synthesis of NO in the spinal cord limits the pressor response to stimulation of spinal NMDA receptors.