bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenomedullin, a New Vasoactive Peptide, Is Increased in Preeclampsia
Authors: Di Iorio Romolo , Marinoni Emanuela , Letizia Claudio , Alò Piero , Villaccio Barbara , Cosmi Ermelando V.
Published: June 2012

Abstract
—Adrenomedullin is a novel peptide that elicits a long-lasting vasorelaxant activity. Recently, we found high concentrations of adrenomedullin in maternal and umbilical cord plasma and in amniotic fluid in full-term human pregnancy, indicating a role of this peptide during gestation. To investigate the possibility that adrenomedullin is involved in the pathophysiology of preeclampsia, we measured its concentration in maternal and fetoplacental compartments. We studied 12 normotensive nonpregnant women, 13 hypertensive nonpregnant subjects, 29 patients with preeclampsia, and 30 normotensive pregnant women. In all patients, plasma was collected from the cubital vein, and amniotic fluid samples were obtained by transabdominal amniocentesis or at elective cesarean section. Plasma samples from umbilical vein and placental tissues were collected at delivery. Adrenomedullin was assayed on plasma and amniotic fluid samples using a specific radioimmunoassay, and its localization and distribution on placental sections was determined by immunohistochemistry. Adrenomedullin concentrations were higher in hypertensive than in normotensive nonpregnant patients. Pregnant women had higher adrenomedullin levels than nonpregnant subjects, although maternal plasma adrenomedullin concentrations did not differ between normal pregnant and preeclamptic women. Preeclamptic patients showed higher concentrations (
P
<0.01) than normotensive pregnant women of adrenomedullin in amniotic fluid (252±29 versus 112±10 fmol/μmol creatinine) and umbilical vein plasma (18.1±2.1 versus 8.5±1.1 fmol/mL). Increased local production of adrenomedullin is associated with preeclampsia. The fetus seems to be responsible for the higher levels of this hormone. Increased adrenomedullin concentrations may be necessary to maintain placental vascular resistance and/or fetal circulation at a physiological level.
Phytoestrogens Inhibit Growth and MAP Kinase Activity in Human Aortic Smooth Muscle Cells
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Imthurn Bruno , Rosselli Marinella , Jackson Edwin K. , Keller Paul J.
Published: June 2012

Abstract
—Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation. However, the use of estrogens as cardioprotective agents is limited by carcinogenic effects in women and feminizing effects in men. If noncarcinogenic and nonfeminizing estrogenlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum–induced proliferation (
3
H-thymidine incorporation and cell number), collagen synthesis (
3
H-proline incorporation), and total protein synthesis (
3
H-leucine incorporation) and on PDGF-BB (25 ng/mL)–induced migration (modified Boydens chambers). Moreover, the effects of phytoestrogens on PDGF-BB (25 ng/mL)–induced mitogen-activated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoestrogens inhibited proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner and in the following order of potency: biochanin A>genistein>equol>daidzein>formononetin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/downregulate MAP kinase activity. Thus, phytoestrogens may confer protective effects on the cardiovascular system by inhibiting vascular remodeling and neointima formation and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.
Safety of Nifedipine in Angina Pectoris
Authors: Stason William B. , Schmid Christopher H. , Niedzwiecki Donna , Whiting Gregory W. , Caubet Jean-Francois , Cory Douglas , Luo Don , Ross Susan D. , Chalmers Thomas C.
Published: June 2012

Abstract
—Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (
P
=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (
P
=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.
A Test of the “Epinephrine Hypothesis” in Humans
Authors: Goldstein David S. , Golczynska Anna , Stuhlmuller John , Holmes Courtney , Rea Robert F. , Grossman Ehud , Lenders Jacques
Published: June 2012

Abstract
—According to the “epinephrine hypothesis,” circulating epinephrine taken up by sympathetic nerves is coreleased with norepinephrine during sympathetic stimulation and binding of coreleased epinephrine to presynaptic β-adrenoceptors augments exocytotic release of norepinephrine, contributing to high blood pressure. This study examined whether infusion of a physiologically active amount of epinephrine affects subsequent vascular responses and the estimated rate of entry of norepinephrine into regional venous plasma (norepinephrine spillover). Each of 3 experiments included intravenous infusion of
3
H-norepinephrine, measurements of forearm vascular resistance, and intra-arterial infusion of epinephrine (3 ng/min per deciliter forearm volume). In experiment 1, subjects underwent lower body negative pressure (LBNP−25 mm Hg) before and after intra-arterial epinephrine; in experiment 2, LBNP and intra-arterial yohimbine before and after intra-arterial epinephrine; and in experiment 3, intravenous nitroprusside before and after intra-arterial epinephrine. In all subjects, intra-arterial epinephrine produced ipsilateral pallor and decreased forearm vascular resistance. Ipsilateral venous epinephrine increased by 10-fold. Epinephrine did not affect forearm vasoconstrictor responses to LBNP or vasodilator responses to intra-arterial yohimbine or intravenous nitroprusside; did not affect venous norepinephrine levels or norepinephrine spillover during LBNP, yohimbine, LBNP during yohimbine, or nitroprusside; and did not increase venous epinephrine levels during any of these manipulations. Loading of forearm sympathetic terminals with epinephrine therefore does not augment subsequent neurogenic vasoconstriction or norepinephrine release in the human forearm in response to sympathetic stimulation. The findings are inconsistent with the epinephrine hypothesis.
Effects of Angiotensin ΙΙ on Sodium Potassium Pumps, Endogenous Ouabain, and Aldosterone in Bovine Zona Glomerulosa Cells
Authors: Shah Jui R. , Laredo James , Hamilton Bruce P. , Hamlyn John M.
Published: June 2012

Abstract
—Angiotensin (Ang) ΙΙ stimulates secretions of aldosterone and an endogenous ouabain-like steroid (EO) from bovine adrenal zona glomerulosa (BAG) cells. The BAG cell sodium pump, a possible target of EO, affects aldosterone secretion although little is known about this pump. Here, we describe the effects of Ang II on the characteristics of this transporter and steroid secretions. Under serum-free conditions,
3
H-ouabain bound to a single class of sites on BAG cells. Binding of label was time and concentration dependent, was sensitive to extracellular potassium ions, and was displaced by ouabain and digoxin with EC
50
of ≈218 and ≈232 nmol/L, respectively. Sodium pump–mediated
86
Rb uptake was inhibited by ouabain (EC
50
≈301 nmol/L). Ang II dose dependently augmented secretions of EO and aldosterone, increased ouabain-sensitive
86
Rb uptake and
3
H-ouabain binding, and increased the affinity for
3
H-ouabain binding (
K
d
, from 205 to 80 nmol/L) with no change in the maximal number of sodium pumps (5.45×10
6
) per cell. Losartan blocked all effects of Ang II except EO secretion, which was inhibited by PD123319. We conclude that BAG cells express sodium pumps in high density and bind ouabain to a single class of low-affinity sites. The characteristics of the sodium pumps protect BAG cells from EO autotoxicity but may exclude them from mediating feedback inhibition of EO secretion. The effects of Ang II on sodium pump activity, ouabain binding affinity, and aldosterone secretion are mediated via Ang II type 1 receptors, whereas Ang II type 2 receptors augment EO secretion. The role of the Ang II–mediated increase in the ouabain sensitivity of BAG cell sodium pumps in the secretions of aldosterone and EO remains to be elucidated.
Increased Central Angiotensin and Osmotic Responses in the Ren-2 Transgenic Rat
Authors: Nishioka Tatsuya , Callahan Michael F. , Li Ping , Ferrario Carlos M. , Ganten Detlev , Morris Mariana
Published: June 2012

Abstract
—We previously demonstrated that the Ren-2 transgenic (TG) rat is sensitive to salt, showing a sodium-induced pressor response. The present studies determined the effect of central stimulation with hypertonic saline (HS) and angiotensin II (Ang II) on mean arterial pressure (MAP), heart rate (HR), and plasma vasopressin. HS (1 mol/L NaCl, 5 μL) or Ang II (100 ng, 5 μL) was injected into the lateral ventricle of conscious male TG and control rats. The pressor responses to HS and Ang were greater in TG than in control rats, increases of 42±4 and 41±4 mm Hg versus 25±3 and 18±2 mm Hg (HS and Ang II and TG and control rats, respectively). The TG rats also showed an increased vasopressin response to Ang II, peak levels of 14±3 versus 28±3 pg/mL (control versus TG rats). HS increased plasma vasopressin levels, although the group responses were not different. HR was not significantly altered by either stimulus. Results demonstrate an increased responsiveness to intraventricular HS and Ang II in Ren-2 transgenic rats, suggesting a relationship between the enhanced angiotensinergic drive and central cardiovascular and vasopressin responses.
Neuroendocrine Effects of Dehydration in Mice Lacking the Angiotensin AT1a Receptor
Authors: Morris Mariana , Li Ping , Callahan Michael F. , Oliverio Michael I. , Coffman Thomas M. , Bosch Susan M. , Diz Debra I.
Published: June 2012

Abstract
—Angiotensin (Ang) type 1a (AT1a) receptors are critical in the control of blood pressure and water balance. Experiments were performed to determine the influence of dehydration on brain Ang receptors and plasma vasopressin (VP) in mice lacking this receptor. Control or AT1a knockout (AT1aKO) male mice were give water ad libitum or deprived of water for 48 hours. Animals were anesthetized with halothane, blood samples were collected by heart puncture, and brains were processed for Ang-receptor autoradiography with
125
I-sarthran (0.4 nmol/L). Dehydration produced an increase in AT1 receptors in the paraventricular nucleus (PVN) and anterior pituitary (AP) in control mice (PVN: 70±16 versus 146±10 fmol/mg protein; AP: 41±7 versus 86±15 fmol/mg protein). No changes were noted in the median preoptic nucleus. The majority of the brain receptors were of the AT1 subtype. There was little or no specific Ang binding in AT1aKO mice and no effect of dehydration. Plasma VP levels were elevated in the halothane-anesthetized animals (>200 pg/mL) with no significant effect of dehydration. A separate experiment was performed with decapitated mice anesthetized with pentobarbital. Dehydration increased plasma VP in control mice, from 3.3±0.6 to 13.3±4.7 pg/mL, whereas no change was noted in the AT1aKO mice, 5.1±0.3 versus 6.1±0.7 pg/mL (water versus dehydration). These results demonstrate a differential response to dehydration in mice lacking AT1a receptors. There was no evidence for AT1 receptors of any subtype in the brain regions examined and no effect of dehydration on VP secretion or brain Ang receptors.
Effect of Chronic Salt Loading on Adenosine Metabolism and Receptor Expression in Renal Cortex and Medulla in Rats
Authors: Zou Ai-Ping , Wu Feng , Li Pin-Lan , Cowley Allen W.
Published: June 2012

Abstract
—Previous studies have shown that chronic salt loading increased renal interstitial adenosine concentrations and desensitized renal effects of adenosine, a phenomenon that could facilitate sodium excretion. However, the mechanisms responsible for the increased adenosine production and decreased adenosine response are poorly understood. This study examined the effects of the dietary high salt intake on adenosine metabolism and receptor expression in the renal cortex and medulla in Sprague Dawley rats. Fluorescent high-performance liquid chromatography analyses were performed to determine adenosine levels in snap-frozen kidney tissues. Comparing rats fed a normal (1% NaCl) versus high salt (4% NaCl) diet, renal adenosine concentrations in rats fed a high salt diet were significantly higher (cortex: 43±3 versus 85±4,
P
<0.05; medulla: 183±4 versus 302±8 nmol/g wet tissue,
P
<0.05). Increased adenosine concentrations were not associated with changes in the 5′-nucleotidase or adenosine deaminase activity, as determined by quantitative isoelectric focusing and gel electrophoresis. Western blot analyses showed that a high salt diet (4% NaCl for 3 weeks) downregulated A
1
receptors (antinatriuretic type), did not alter A
2A
and A
2B
receptors (natriuretic type), and upregulated A
3
receptors (function unknown) in both renal cortex and medulla. The data show that stimulation of adenosine production and downregulation of A
1
receptors with salt loading may play an important role in adaptation in the kidney to promote sodium excretion.
Myocardial Osteopontin Expression Coincides With the Development of Heart Failure
Authors: Singh Krishna , Sirokman Geza , Communal Catherine , Robinson Kathleen G. , Conrad Chester H. , Brooks Wesley W. , Bing Oscar H. L. , Colucci Wilson S.
Published: June 2012

Abstract
—To identify genes that are differentially expressed during the transition from compensated hypertrophy to failure, myocardial mRNA from spontaneously hypertensive rats (SHR) with heart failure (SHR-F) was compared with that from age-matched SHR with compensated hypertrophy (SHR-NF) and normotensive Wistar-Kyoto rats (WKY) by differential display reverse transcriptase–polymerase chain reaction. Characterization of a transcript differentially expressed in SHR-F yielded a cDNA with homology to the extracellular matrix protein osteopontin. Northern analysis showed low levels of osteopontin mRNA in left ventricular myocardium from WKY and SHR-NF but a markedly increased (≈10-fold) level in SHR-F. In myocardium from WKY and SHR-NF, in situ hybridization showed only scant osteopontin mRNA, primarily in arteriolar cells. In SHR-F, in situ hybridization revealed abundant expression of osteopontin mRNA, primarily in nonmyocytes in the interstitial and perivascular space. Similar findings for osteopontin protein were observed in the midwall region of myocardium from the SHR-F group. Consistent with the findings in SHR, osteopontin mRNA was minimally increased (≈1.9-fold) in left ventricular myocardium from nonfailing aortic-banded rats with pressure-overload hypertrophy but was markedly increased (≈8-fold) in banded rats with failure. Treatment with captopril starting before or after the onset of failure in the SHR reduced the increase in left ventricular osteopontin mRNA levels. Thus, osteopontin expression is markedly increased in the heart coincident with the development of heart failure. The source of osteopontin in SHR-F is primarily nonmyocytes, and its induction is inhibited by an angiotensin-converting enzyme inhibitor, suggesting a role for angiotensin II. Given the known biological activities of osteopontin, including cell adhesion and regulation of inducible nitric oxide synthase gene expression, these data suggest that it could play a role in the pathophysiology of heart failure.
Irbesartan Reduces QT Dispersion in Hypertensive Individuals
Authors: Lim Pitt O. , Nys Marleen , Naas Abdul A. O. , Struthers Allan D. , Osbakken Mary , MacDonald Thomas M.
Published: June 2012

Abstract
—Angiotensin type 1 receptor antagonists have direct effects on the autonomic nervous system and myocardium. Because of this, we hypothesized that irbesartan would reduce QT dispersion to a greater degree than amlodipine, a highly selective vasodilator. To test this, we gathered electrocardiographic (ECG) data from a multinational, multicenter, randomized, double-blind parallel group study that compared the antihypertensive efficacy of irbesartan and amlodipine in elderly subjects with mild to moderate hypertension. Subjects were treated for 6 months with either drug. Hydrochlorothiazide and atenolol were added after 12 weeks if blood pressure (BP) remained uncontrolled. ECGs were obtained before randomization and at 6 months. A total of 188 subjects (118 with baseline ECGs) were randomized. We analyzed 104 subjects who had complete ECGs at baseline and after 6 months of treatment. Baseline characteristics between treatments were similar, apart from a slight imbalance in diastolic BP (irbesartan [n=53] versus amlodipine [n=51], 99.2 [SD 3.6] versus 100.8 [3.8] mm Hg;
P
=0.03). There were no significant differences in BP normalization (diastolic BP <90 mm Hg) between treatments at 6 months (irbesartan versus amlodipine, 80% versus 88%;
P
=0.378). We found a significant reduction in QT indexes in the irbesartan group (QTc dispersion mean, –11.4 [34.5] milliseconds,
P
=0.02; QTc max, –12.8 [35.5] milliseconds,
P
=0.01), and QTc dispersion did not correlate with the change in BP. The reduction in QT indexes with amlodipine (QTc dispersion, –9.7 [35.4] milliseconds,
P
=0.06; QTc max, –8.6 [33.2] milliseconds,
P
=0.07) did not quite reach statistical significance, but there was a correlation between the change in QT indexes and changes in systolic BP. In conclusion, irbesartan improved QT dispersion, and this effect may be important in preventing sudden cardiac death in at-risk hypertensive subjects.
Kidney Aminopeptidase A and Hypertension, Part I
Authors: Healy Dennis P. , Song Lijun
Published: June 2012

Abstract
—Tissue and plasma levels of aminopeptidase A (APA), the principal enzyme that hydrolyzes angiotensin II (Ang II) to angiotensin III, were measured in spontaneously hypertensive rats (SHR) and their normotensive control strain at 3 different ages corresponding to prehypertensive (4 weeks), developing (8 weeks), and established (16 weeks) phases of hypertension. Plasma APA activity was significantly but modestly elevated in SHR at all 3 ages compared with normotensive Wistar-Kyoto rats. Likewise, levels of APA in brain, heart, and adrenal gland were generally, but again only moderately, elevated in SHR at all ages. However, a large increase in APA activity was seen within the kidney in which APA levels were elevated 41%, 51%, and 68% in SHR at 4, 8, and 16 weeks of age, respectively. Kidney APA levels were also significantly increased in immunoblots from 8- and 16-week-old SHR. Glomeruli isolated from 16-week-old SHR had 57% higher APA activity and increased immunoreactivity compared with Wistar-Kyoto rats. To determine whether the increase in kidney APA activity in SHR was related to Ang II levels, SHR were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril. Captopril treatment reduced blood pressure to normotensive values and resulted in a 25% reduction in kidney APA activity. These results suggest that APA expression in the kidney may be regulated by activity of the renin-angiotensin system. If so, this would further suggest that upregulation of APA during conditions in which Ang II levels were elevated would have a protective effect against Ang II–mediated cardiovascular diseases, whereas a decrease in APA expression or a failure to upregulate would exacerbate such conditions.
Distribution of Lamellar Deformations
Authors: Dobrin Philip B.
Published: June 2012

Abstract
—Most computations of arterial mechanics treat the wall as a mechanically homogeneous body, but there are no data to support or refute this. To evaluate this assumption, experiments were performed that measured the deformation of 4 elastic lamellae located at 4 equidistant points across the thickness of the media. Data were obtained at 25–mm Hg pressure steps between 0 and 200 mm Hg. To satisfy the constraints of incompressibility in an isovolumetric cylinder, the innermost structures must undergo larger deformations than the outermost structures. This manifests as thinning of the wall. Therefore, each experiment was performed twice: once with a vessel segment in its normal cylindrical configuration, and again with a contiguous vessel segment turned inside-out to form an inverted cylinder. The deformations of individual lamellae obtained in normal and inverted vessel segments were averaged to determine their extensions independent of location. Results showed that the extensibilities of the lamellae were equal at all 4 anatomic locations across the media, suggesting equal stiffnesses of the lamellae. Other studies were performed to examine the distribution of the circumferential retractions of the lamellae that occurs when a vessel is extended longitudinally. Results showed that circumferential retraction also was distributed uniformly across the wall. These findings demonstrate that the elastic lamellae behave uniformly in both the circumferential and longitudinal directions at different locations across the wall thickness. Because of the interlocked structure of the elastin, muscle, and collagen in the media, these findings suggest that although the media is histologically heterogeneous, it acts mechanically as a homogeneous material.
Association of an Apolipoprotein B Gene Marker With Essential Hypertension
Authors: Frossard Philippe M. , Obineche Enyioma N. , Lestringant Gilles G.
Published: June 2012

Abstract
—We designed an association (retrospective, case control) study aimed at evaluating associations between genetic variations of the human apolipoprotein B (apoB) gene and clinical diagnosis of essential hypertension. Our approach was to compare the distribution of the alleles of a highly polymorphic variable number of tandem repeats localized 3′ to the human apoB gene, the apoB 3′ hypervariable region (HVR), in a group of normotensive and a group of hypertensive individuals. We collected DNA samples from 437 unrelated nationals (215 normotensives and 222 hypertensives) from the United Arab Emirates (UAEs), and we determined their apoB 3′ HVR allele and genotype status with a polymerase chain reaction–based assay. In the UAE population, we found 18 alleles underlying a total of 51 genotypes. The distribution of these alleles was significantly different between normotensive and hypertensive UAE nationals. The main peak of the distributions occurred at 35 repeats among hypertensives (with a relative frequency of 25.7% versus 19.6% in normotensives) and at 37 repeats among normotensives (28.8% versus 20.3% in hypertensives). Alleles with 21, 23, 25, 49, and 55 repeats were found in hypertensives only (with a combined relative frequency of 7.6%). We conclude that variations of the apoB gene, or of a nearby gene, that may be in linkage disequilibrium with these alleles play a role in the development of essential hypertension in the UAEs.
A Large Blood Pressure–Raising Effect of Nitric Oxide Synthase Inhibition in Humans
Authors: Sander Mikael , Chavoshan Bahman , Victor Ronald G.
Published: June 2012

Abstract
—In experimental animals, systemic administration of nitric oxide synthase (NOS) inhibitors causes large increases in blood pressure that are in part sympathetically mediated. The aim of this study was to determine the extent to which these conclusions can be extrapolated to humans. In healthy normotensive humans, we measured blood pressure in response to two NOS inhibitors,
N
G
-monomethyl-
l
-arginine (
l
-NMMA) and
N
G
-nitro-
l
-arginine methyl ester (
l
-NAME), the latter of which recently became available for use in humans. The major new findings are 3-fold. First,
l
-NAME produced robust increases in blood pressure that were more than 2 times larger than those previously reported in humans with
l
-NMMA and approximated those seen in experimental animals.
l
-NAME (4 mg/kg) raised mean arterial pressure by 24±2 mm Hg (n=27,
P
<0.001), whereas in subjects who received both inhibitors, a 12-fold higher dose of
l
-NMMA (50 mg/kg) raised mean arterial pressure by 15±2 mm Hg (n=4,
P
<0.05 vs
l
-NAME). Second, the
l
-NAME–induced increases in blood pressure were caused specifically by NOS inhibition because they were reversed by
l
-arginine (200 mg/kg, n=12) but not
d
-arginine (200 mg/kg, n=6) and because
N
G
-nitro-
d
-arginine methyl ester (4 mg/kg, n=5) had no effect on blood pressure. Third, in humans, there is an important sympathetic component to the blood pressure–raising effect of NOS inhibition. α-Adrenergic blockade with phentolamine (0.2 mg/kg, n=9) attenuated the
l
-NAME–induced increase in blood pressure by 40% (
P
<0.05). From these data, we conclude that pharmacological inhibition of NOS causes large increases in blood pressure that are in part sympathetically mediated in humans as well as experimental animals.
Diminished Wave Reflection in the Aorta
Authors: Westerbacka Jukka , Wilkinson Ian , Cockcroft John , Utriainen Tapio , Vehkavaara Satu , Yki-Järvinen Hannele
Published: June 2012

Abstract
—Epidemiological data suggest that insulin may have direct effects on large-vessel function, but thus far insulin has only been shown, after prolonged infusions, to slowly decrease peripheral vascular resistance by increasing muscle blood flow. We determined whether physiological doses of insulin affect function of large arteries, before any changes in peripheral blood flow, in vivo using pulse wave analysis. Nine normal men were studied on 2 occasions: once during a 6-hour infusion of saline and once under normoglycemic hyperinsulinemic conditions (sequential 2-hour insulin infusions of 1, 2, and 5 mU/kg · min). Central aortic pressure waves were synthesized from those recorded in the periphery with the use of applanation tonometry and a validated reverse transfer function every 30 minutes. This allowed determination of central aortic augmentation (the pressure difference between early and late systolic pressure peaks) and augmentation index (augmentation expressed as a percentage of pulse pressure). Both augmentation and augmentation index decreased significantly within 1 hour after administration of insulin (
P
<0.001) but not saline. Systolic and diastolic blood pressure and heart rate remained unchanged for the first 2 hours. A significant increase in peripheral (forearm) blood flow was not observed until 2.5 hours after start of the insulin infusion. These data demonstrate that insulin, in normal subjects, rapidly decreases wave reflection in the aorta. This beneficial effect is consistent with increased distensibility or vasodilatation of large arteries. In contrast to the effect of insulin on peripheral blood flow, this action of insulin is observed under conditions in which both the insulin dose and duration of insulin exposure are physiological. Resistance to this action of insulin could provide a mechanism linking insulin resistance and conditions such as hypertension at the level of large arteries.
Paracrine Role of Adventitial Superoxide Anion in Mediating Spontaneous Tone of the Isolated Rat Aorta in Angiotensin II-Induced Hypertension
Authors: Wang Hui Di , Hope Susan , Du Yue , Quinn Mark T. , Cayatte Antonio , Pagano Patrick J. , Cohen Richard A.
Published: June 2012

Abstract
—The relationship between vascular generation of superoxide anion and spontaneous tone observed in the isolated aorta was studied in hypertensive rats infused with angiotensin II. Aortic rings from hypertensive, but not from sham-operated rats, demonstrated oscillatory spontaneous tone that represented 52±5.6% of the maximal contraction to KCl. Spontaneous tone was prevented by calcium-free buffer or by blocking calcium influx through L-type calcium channels with nifedipine. The production of superoxide anion measured by lucigenin chemiluminescence was up to 15-fold higher than in sham-operated rat aorta. The adventitial site of production of superoxide anion was suggested by the fact that lucigenin chemiluminescence was 5.5-fold higher from the adventitia than from the intima. This was confirmed histochemically by demonstrating that the adventitia was the site of reduction of nitroblue tetrazolium as well as immunohistochemical staining of NAD(P)H oxidase subunit proteins. A causal link between superoxide anion production by NAD(P)H oxidase and the spontaneous tone is suggested by the fact that superoxide dismutase or the inhibitor of NAD(P)H oxidase, diphenylene iodonium, decreased both superoxide anion production and spontaneous tone. L-NAME or removal of the endothelium from the aorta had no significant effect on superoxide anion levels or spontaneous tone. However, although superoxide dismutase decreased superoxide anion levels in the presence of L-NAME or in endothelium-denuded rings, it no longer inhibited the tone. This suggests that the effect on tone of superoxide anion originating in the adventitia is mediated by inactivating endothelium-derived nitric oxide, which promotes smooth muscle calcium influx and spontaneous tone. The adventitia is not a passive bystander during the development of hypertension, but rather it may have an important role in the regulation of smooth muscle tone.
Increased Chymase-Dependent Angiotensin II Formation in Human Atherosclerotic Aorta
Authors: Ihara Makoto , Urata Hidenori , Kinoshita Akio , Suzumiya Junji , Sasaguri Manabu , Kikuchi Masahiro , Ideishi Munehito , Arakawa Kikuo
Published: June 2012

Abstract
—Locally formed angiotensin II (Ang II) and mast cells may participate in the development of atherosclerosis. Chymase, which originates from mast cells, is the major Ang II–forming enzyme in the human heart and aorta in vitro. The aim of the present study was to investigate aortic Ang II–forming activity (AIIFA) and the histochemical localization of each Ang II–forming enzyme in the atheromatous human aorta. Specimens of normal (n=9), atherosclerotic (n=8), and aneurysmal (n=6) human aortas were obtained at autopsy or cardiovascular surgery from 23 subjects (16 men, 7 women). The total, angiotensin-converting enzyme (ACE)-dependent, and chymase-dependent AIIFAs in aortic specimens were determined. The histologic and cellular localization of chymase and ACE were determined by immunocytochemistry. Total AIIFA was significantly higher in atherosclerotic and aneurysmal lesions than in normal aortas. Most of AIIFA in the human aorta in vitro was chymase-dependent in both normal (82%) and atherosclerotic aortas (90%). Immunocytochemical staining of the corresponding aortic sections with antichymase, antitryptase or anti-ACE antibodies showed that chymase-positive mast cells were located in the tunica adventitia of normal and atheromatous aortas, whereas ACE-positive cells were localized in endothelial cells of normal aorta and in macrophages of atheromatous neointima. The density of chymase- and tryptase-positive mast cells in the atherosclerotic lesions was slightly but not significantly higher than that in the normal aortas, and the number of activated mast cells in the aneurysmal lesions (18%) was significantly higher than in atherosclerotic (5%) and normal (1%) aortas. Our results suggest that local Ang II formation is increased in atherosclerotic lesions and that chymase is primarily responsible for this increase. The histologic localization and potential roles of chymase in the development of atherosclerotic lesions appear to be different from those of ACE.
High Stress Responsivity Predicts Later Blood Pressure Only in Combination With Positive Family History and High Life Stress
Authors: Light Kathleen C. , Girdler Susan S. , Sherwood Andrew , Bragdon Edith E. , Brownley Kimberly A. , West Sheila G. , Hinderliter Alan L.
Published: June 2012

Abstract
—High cardiovascular responsivity to stressors has not consistently improved prediction of later blood pressure increases beyond the predictive effects of baseline pressure. Animal models suggest that genetic susceptibility to hypertension and frequent stress exposure are important modulating factors in stress-related hypertension. Thus in 103 men originally tested at age 18 to 22 years and reassessed 10 years later, interactive effects of genetic susceptibility (defined as 1 or more hypertensive parents) with high stress responsivity (defined as top 25% on the basis of blood pressure and cardiac responses during both reaction time and cold pressor tasks) were examined in relation to follow-up systolic and diastolic levels and to change in blood pressure status from normal (diastolic<80 mm Hg) to marginally elevated (diastolic 85 to 95 mm Hg). Men with the combination of high stress response and hypertensive parents demonstrated higher systolic (
P
<0.05) and diastolic levels (
P
<0.05) at follow-up, and they showed a 7-fold increase (7.5, 95% confidence intervals 2.3, 24.3;
P
<0.001) in relative risk of change in blood pressure status versus men with no family history and a 3-fold increase (3.8, confidence intervals 1.5, 9.6;
P
<0.004) versus less stress-responsive men who also had hypertensive parents. In 65 men who also provided ratings of daily stress, family history×stress responsivity×daily stress interactions were significant in predicting follow-up systolic and diastolic levels (
P
<0.006 and 0.03, respectively), with highest pressure levels seen when high life stress was reported by high stress responders and/or men with hypertensive parents. In conclusion, results suggest that stress responsivity as a long-term predictor is modulated by both genetic and environmental factors.
Kallikrein Gene Delivery Inhibits Vascular Smooth Muscle Cell Growth and Neointima Formation in the Rat Artery After Balloon Angioplasty
Authors: Murakami Hideyuki , Yayama Katsutoshi , Miao Robert Q. , Wang Cindy , Chao Lee , Chao Julie
Published: June 2012

Abstract
—Tissue kallikrein cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated in the proliferation of vascular smooth muscle cells (VSMCs). To explore potential roles of the kallikrein-kinin system in vascular biology, we evaluated the effects of adenovirus-mediated human kallikrein gene delivery on the growth of primary cultured VSMCs and in balloon-injured rat artery in vivo. Kallikrein gene transfer into cultured rat VSMCs resulted in time-dependent secretion of recombinant human tissue kallikrein and inhibition of cell proliferation. Balloon angioplasty reduced endogenous rat tissue kallikrein mRNA and protein levels at the injured site. In rats that received adenovirus-mediated human kallikrein gene delivery, we observed a 39% reduction in intima/media ratio at the injured vessel after delivery compared with that of rats that received control virus (n=8,
P
<0.01). Icatibant, a specific bradykinin B
2
receptor antagonist, blocked the protective effect and reversed the intima/media ratio to that of the control rats (n=5,
P
<0.01). After gene delivery, human kallikrein mRNA was identified at the injured vessel and a 3-fold increase occurred in kininogenase activity. cAMP and cGMP levels in balloon-injured aorta increased significantly at 4, 7, and 14 days after kallikrein gene delivery, but icatibant abolished the increase. These results provide new insights into the role of the vascular kallikrein-kinin system and have significant implications for gene therapy to treat restenosis or atherosclerosis.
Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System
Authors: Roks Anton J. M. , van Geel Peter Paul , Pinto Yigal M. , Buikema Hendrik , Henning Robert H. , de Zeeuw Dick , van Gilst Wiek H.
Published: June 2012

Abstract
—The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1–7) to angiotensin-(1–5) and can lead to elevation of angiotensin-(1–7) levels in plasma and tissue. In animal models, angiotensin-(1–7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1–5) is unknown. We investigated whether angiotensin-(1–7) and angiotensin-(1–5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1–7) up to 100%, with an IC
50
of 3.0 and 4.0 μmol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non–ACE-specific substrate [Pro
11
,D-Ala
12
]-angiotensin I were antagonized by angiotensin-(1–7) (10
−5
mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro
10
]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1–5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1–7) blocks angiotensin II–induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1–5) only inhibits ACE. These results show that angiotensin-(1–7) may be an important modulator of the human renin-angiotensin system.
Angiotensinogen Gene Polymorphism Near Transcription Start Site and Blood Pressure
Authors: Ishigami Tomoaki , Tamura Kouichi , Fujita Takayuki , Kobayashi Izumi , Hibi Kiyoshi , Kihara Minoru , Toya Yoshiyuki , Ochiai Hisao , Umemura Satoshi
Published: June 2012

Abstract
—Molecular variants of the angiotensinogen gene, a key component of the renin-angiotensin system, are considered genetic risk factors for primary hypertension. A relation between the angiotensinogen gene locus and hypertension has been found in whites, Japanese, and African Caribbeans but not in Chinese. The lack of a consistent association between M235T polymorphism at exon 2 and hypertension has suggested that another site in linkage disequilibrium with M235T is the causal mutation. We studied the relations among plasma angiotensinogen concentrations, blood pressure, related clinical variables, and mutations of the 5′ upstream core promoter region of the human angiotensinogen gene in 274 subjects recruited from our outpatient clinic. We confirmed that plasma angiotensinogen concentration was significantly correlated with A−20C mutation and percent body fat and found that systolic and diastolic blood pressures were significantly correlated with G−6A and T+68C mutations. These results suggest that mutations near the transcription start site may be associated with increased blood pressure.
Potential Role of Glycerol Leading to Rat Fructose Hypertension
Authors: Damiano Pablo F. , Rosón María I. , Armando Inés , Nowicki Susana , Dascal Eduardo , Cuniberti Luis , Albornoz Liliana E. , Ignacio J. de la Riva ;
Published: June 2012

Abstract
—A fructose-enriched diet promotes hypertension in rats. We thought that an enhancement of the glycolytic and/or lipid disorder (s) that raise blood pressure could be the cause. Therefore, we studied 4 groups of Sprague-Dawley rats (±200 g): (1) control rats received a standard diet and tap water; (2) the glycerol group of rats received a standard diet and 0.54 mol/L glycerol in tap water; (3) the fructose group was given a fructose-enhanced diet (chow had 55% fructose instead of dextrin) and tap water; and (4) the fructose-glycerol group was given the fructose-enhanced diet and 0.54 mol/L glycerol in drinking water. At the end of the second week, the findings were as follows. Blood pressure was 149±2 mm Hg in the fructose-glycerol group versus 129±2 (
P
<0.001), 131±2 (
P
<0.001), and 140±3 (
P
<0.005) mm Hg in the control, glycerol, and fructose groups, respectively. Insulinemia was higher in the fructose-glycerol group than the control (
P
<0.001), glycerol (
P
<0.001), and fructose groups (
P
<0.001); triglyceridemia was higher in the fructose-glycerol (
P
<0.02), fructose (
P
<0.05), and glycerol groups (
P
<0.02) than the control group. Thoracic aorta rings showed a lower ED
50
to 12,13-phorbol dibutyrate in the fructose-glycerol group than in the control (
P
<0.001), glycerol (
P
<0.002), and fructose groups (
P
<0.001). In conclusion, glycerol-fructose administration resulted in hypertriglyceridemia, hyperinsulinemia, and increased vascular sensitivity to 12,13-phorbol dibutyrate (with respect to the control group), and significantly greater expression of protein kinase C α and βII (with respect to the glycerol group).
Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B
2
-Kinin Receptor Knockout Mice
Authors: Loke Kit E. , Curran Christine M. L. , Messina Eric J. , Laycock Sarra K. , Shesely Edward G. , Carretero Oscar A. , Hintze Thomas H.
Published: June 2012

Abstract
—The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (MV̇
o
2
) via a B
2
-kinin receptor/nitric oxide–dependent mechanism. Left ventricular free wall and septum were isolated from normal and B
2
-kinin receptor knockout (B
2
−/−) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline MV̇
o
2
was not significantly different between normal (239±13 nmol of O
2
· min
−1
· g
−1
) and B
2
−/− (263±24 nmol of O
2
· min
−1
· g
−1
) mice. S-nitroso-
n
-acetyl-penicillamine (10
−7
to 10
−4
mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36±3%) and B
2
−/− mice (28±3%). This was also true for the endothelium-dependent vasodilator substance P (10
−10
to 10
−7
mol/L; 22±7% in normal mice and 20±4% in B
2
−/− mice). Bradykinin (10
−7
to 10
−4
mol/L), ramiprilat (10
−7
to 10
−4
mol/L), and amlodipine (10
−7
to 10
−5
mol/L) all caused concentration-dependent decreases in MV̇
o
2
in normal mice. At the highest concentration, tissue O
2
consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in MV̇
o
2
to all 3 drugs was attenuated in the presence of N
G
-nitro-
l
-arginine-methyl ester. However, in the B
2
−/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MV̇
o
2
. Therefore, nitric oxide, through a bradykinin-receptor–dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B
2
−/− mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.
Sympathetic Activation in the Pathogenesis of Hypertension and Progression of Organ Damage
Authors: Mancia Giuseppe , Grassi Guido , Giannattasio Cristina , Seravalle Gino
Published: June 2012

Abstract
—Although animal models of hypertension have clearly shown that high blood pressure is associated with and is probably caused by an increase in sympathetic cardiovascular influences, a similar demonstration in humans has been more difficult to obtain for methodological reasons. There is now evidence, however, of increased sympathetic activity in essential hypertension. This article will review this evidence by examining data showing that plasma norepinephrine is increased in essential hypertension and that this is also the case for systemic and regional norepinephrine spillover, as well as for the sympathetic nerve firing rate in the skeletal muscle nerve district. Evidence will also be provided that sympathetic activation is a peculiar feature of essential hypertension, particularly in its early stages, with secondary forms of high blood pressure not usually characterized by an increased central sympathetic outflow. Humoral, metabolic, reflex, and central mechanisms are likely to be the factors responsible for the adrenergic activation characterizing hypertension, which may also promote the development and progression of the cardiac and vascular alterations that lead to hypertension-related morbidity and mortality, independent of blood pressure values. This represents the rationale for considering sympathetic deactivation one of the major goals of antihypertensive treatment.
Importance of Glycinergic and Glutamatergic Synapses Within the Rostral Ventrolateral Medulla for Blood Pressure Regulation in Conscious Rats
Authors: Araujo Gessi C. , Lopes Oswaldo U. , Campos Ruy R.
Published: June 2012

Abstract
—In this study we used a method that permits bilateral or unilateral microinjections of drugs into the rostral ventrolateral medulla (RVLM) of conscious, freely moving rats. There is only limited information about how sympathetic vasomotor tone is maintained by premotor RVLM neurons in conscious animals. It has long been known that glycine microinjection into the RVLM region leads to a decrease in blood pressure (BP) in anesthetized animals. In the present study we show that both unilateral and bilateral microinjection of glycine at the same dose used for anesthetized rats (50 nmol, 50 nL) into the RVLM increases BP in conscious animals. A similar response was also observed when the excitatory amino acid
l
-glutamate was microinjected into the RVLM. The microinjection of kynurenic acid into the RVLM did not change the basal level of BP but blocked the increase in BP after glycine or glutamate microinjection. A decrease in BP was only observed when low doses of glycine were used (1 to 10 nmol). We conclude that, in conscious animals, the hypertension occurring in response to high doses of glycine into the RVLM is dependent on glutamatergic synapses within the RVLM. A decrease in BP observed when low doses of glycine were used shows that in conscious animals, the RVLM, in association with other premotor neurons, is probably responsible for the maintenance of sympathetic vasomotor tone, because glycine is less effective in decreasing BP under these circumstances than in anesthetized animals
.