bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Review:
Hypertension in Pregnancy
Authors: Solomon Caren G. , Seely Ellen W.
Published: June 2012

Pregnancy-induced hypertension (PIH), which includes both gestational hypertension and preeclampsia, is a common and morbid pregnancy complication for which the pathogenesis remains unclear. Emerging evidence suggests that insulin resistance, which has been linked to essential hypertension, may play a role in PIH. Conditions associated with increased insulin resistance, including gestational diabetes, polycystic ovary syndrome, and obesity, may predispose to hypertensive pregnancy. Furthermore, metabolic abnormalities linked to the insulin resistance syndrome are also observed in women with PIH to a greater degree than in normotensive pregnant women: These include glucose intolerance, hyperinsulinemia, hyperlipidemia, and high levels of plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-α. These observations suggest the possibility that insulin resistance may be involved in the pathogenesis of PIH and that approaches that improve insulin sensitivity might have benefit in the prevention or treatment of this syndrome, although this requires further study.
Ascorbic Acid Status and Subsequent Diastolic and Systolic Blood Pressure
Authors: Block Gladys , Mangels Ann R. , Norkus Edward P. , Patterson Blossom H. , Levander Orville A. , Taylor Philip R.
Published: June 2012

Free radicals and oxidation are involved in several aspects of blood pressure physiology. We investigated the relationship between blood pressure and antioxidants, including plasma ascorbic acid (AscA), in a 17-week controlled-diet study. Study subjects included 68 men aged 30 to 59 years who had a mean diastolic blood pressure of 73.4 mm Hg and a mean systolic blood pressure of 122.2 mm Hg. One month of vitamin C depletion was followed by 1-month repletion with 117 mg/d, repeated twice. All food and drink were provided in the study. Subjects did not smoke or drink alcohol, all consumed fruits and vegetables, and body weight was maintained. Plasma was assayed periodically for AscA, α-tocopherol, carotenoids, and lipids. Plasma AscA was inversely related to diastolic blood pressure 1 month later (correlation −0.48,
P
<0.0001). Persons in the bottom fourth of the plasma AscA distribution had >7 mm Hg higher diastolic blood pressure than did those in the top fourth of the plasma AscA distribution. Multivariate analysis with control for age, body mass index, other plasma antioxidants, and dietary energy, calcium, fiber, sodium, and potassium did not reduce the plasma AscA effect. One fourth of the variance in diastolic blood pressure was accounted for by plasma AscA alone. Plasma AscA was also significantly associated with systolic blood pressure in logistic regression. Vitamin C may be an important component of the effectiveness of fruits and vegetables in the reduction in blood pressure, and tissue AscA levels may be important in the maintenance of low blood pressure. Long-term intervention studies are warranted.
Angiotensin II Relaxes Microvessels Via the AT
2
Receptor and Ca
2+
-Activated K
+
(BK
Ca
) Channels
Authors: Dimitropoulou Christiana , White Richard E. , Fuchs Leslie , Zhang Hanfang , Catravas John D. , Carrier Gerald O.
Published: June 2012

Angiotensin II (Ang II) is one of the most potent vasoconstrictor substances, yet paradoxically, Ang II may dilate certain vascular beds via an undefined mechanism. Ang II–induced vasoconstriction is mediated by the AT
1
receptor, whereas the relative expression and functional importance of the AT
2
receptor in regulating vascular resistance and blood pressure are unknown. We now report that Ang II induces relaxation of mesenteric microvessels and that this vasodilatory response was unaffected by losartan, an AT
1
receptor antagonist, but was inhibited by PD123,319, a selective antagonist of AT
2
receptors. In addition, reverse transcriptase–polymerase chain reaction studies revealed high amounts of AT
2
receptor mRNA in smooth muscle from these same microvessels. Ang II–induced relaxation was inhibited by either tetraethylammonium or iberiotoxin, suggesting involvement of the large-conductance, calcium- and voltage-activated potassium (BK
Ca
) channel. Subsequent whole-cell and single-channel patch-clamp studies on single myocytes demonstrated that Ang II increases the activity of BK
Ca
channels. As in our tissue studies, the effect of Ang II on BK
Ca
channels was inhibited by PD123,319, but not by losartan. In light of these consistent findings from tissue physiology, molecular studies, and cellular/molecular physiology, we conclude that Ang II relaxes microvessels via stimulation of the AT
2
receptor with subsequent opening of BK
Ca
channels, leading to membrane repolarization and vasodilation. These findings provide evidence for a novel endothelium-independent vasodilatory effect of Ang II.
Alterations in Blood Pressure and Heart Rate Variability in Transgenic Rats With Low Brain Angiotensinogen
Authors: Baltatu Ovidiu , Janssen Ben J. , Bricca Giampiero , Plehm Ralph , Monti Jan , Ganten Detlev , Bader Michael
Published: June 2012

To study whether the brain renin-angiotensin system plays a role in the long-term and short-term control of blood pressure and heart rate variability, we examined in transgenic rats [TGR(ASrAOGEN)] with low brain angiotensinogen levels the 24-hour variation of blood pressure and heart rate. Telemetry recordings were made during basal and hypertensive conditions induced by a low-dose subcutaneous infusion of angiotensin II for 7 days. Short-term blood pressure and heart rate variability were evaluated by spectral analysis, and as a measure of baroreflex sensitivity, the average transfer gain between the pressure and heart rate variations was calculated. During the angiotensin II infusion in control but not TGR(ASrAOGEN) rats, the 24-hour rhythm of blood pressure was inverted (5.8±2 versus −0.4±1.8 mm Hg/group of day-night differences of blood pressure,
P
<0.05, respectively). In both the control and TGR(ASrAOGEN) rats, the 24-hour heart rate rhythms remained unaltered and paralleled those of locomotor activity. The transfer gain between 0.3 to 0.6 Hz was significantly higher in TGR(ASrAOGEN) than in control rats during control (0.71±0.1 versus 0.35±0.06,
P
<0.05) but not during angiotensin II infusion (0.6±0.07 versus 0.4±0.1,
P
>0.05). These results demonstrate that the brain renin-angiotensin system plays an important role in mediating the effects of angiotensin II on the circadian variation of blood pressure. Furthermore, these data indicate that a permanent deficiency in the brain renin-angiotensin system alters the reflex control of heart rate in rats.
Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes
Authors: Mervaala Eero M. A. , Cheng Zhong Jian , Tikkanen Ilkka , Lapatto Risto , Nurminen Kaisa , Vapaatalo Heikki , Müller Dominik N. , Fiebeler Anette , Ganten Ursula , Ganten Detlev , Luft Friedrich C.
Published: June 2012

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II–induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F
2α
, a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NO
x
) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F
2α
levels, renal XOR activity, and, to a degree, NO
x
excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II–induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.
Endothelial Dysfunction in Salt-Sensitive Essential Hypertension
Authors: Bragulat Ernesto , Alejandro de la Sierra  , Antonio María Teresa , Coca Antonio
Published: June 2012

The aim of this study was to evaluate endothelium-dependent and -independent vasodilation, as well as endothelium biochemical markers, in a group of essential hypertensive patients classified on the basis of salt sensitivity. Changes in forearm blood flow in response to acetylcholine, sodium nitroprusside, and
N
G
-monomethyl-
l
-arginine (L-NMMA) infusion were determined by means of strain-gauge plethysmography. Moreover, plasma and urinary concentrations of nitrates, cGMP, and endothelin were measured during low (50 mmol/d) and high (250 mmol/d) salt intake. Salt-sensitive hypertension was diagnosed in 26 patients who exhibited a significant increase in 24-hour mean blood pressure assessed by ambulatory blood pressure monitoring after 1 week of high salt intake. Nineteen patients were considered salt resistant. Compared with salt-resistant hypertensives, salt-sensitive patients presented a significant lower (
P
=0.005) maximal acetylcholine-induced vasodilation (21±6.3 versus 28±7.5 mL · 100 mL
−1
· tissue · min
−1
). On the contrary, maximal sodium nitroprusside–induced vasodilation did not significantly differ between groups (22.4±4.5 versus 23.9±5.3 mL · 100 mL
−1
· tissue · min
−1
). The decrease in maximal acetylcholine-induced vasodilation promoted by the coadministration of L-NMMA was significantly more pronounced in salt-resistant compared with salt-sensitive patients (
P
=0.003). Finally, high salt intake promoted a significant decrease in 24-hour urinary nitrate excretion in salt-sensitive patients (from 443±54 to 312±54 μmol/d;
P
=0.033) compared with salt-resistant hypertensives (from 341±50 to 378±54 μmol/d). We conclude that salt-sensitive hypertension is associated with endothelial dysfunction characterized by a defective endothelium-dependent vasodilation. Impairment of the
l
-arginine–nitric oxide pathway may be responsible for this abnormal endothelial response.
NO Inhibits NaCl Absorption by Rat Thick Ascending Limb Through Activation of cGMP-Stimulated Phosphodiesterase
Authors: Ortiz Pablo A. , Garvin Jeffrey L.
Published: June 2012

In the isolated, perfused rat thick ascending limb (THAL),
l
-arginine (
l
-Arg) stimulates endogenous nitric oxide (NO) production, which inhibits NaCl absorption. However, the intracellular cascade responsible for the effects of NO has not been studied. We hypothesized that endogenous NO inhibits THAL NaCl transport by increasing cGMP, which activates protein kinase G (PKG) and cGMP-stimulated phosphodiesterase (PDE II), which, in turn, decreases cAMP levels. THALs from rats were isolated and perfused, and net chloride flux (
J
Cl−
) was measured.
l
-Arg was used to stimulate NO production. Adding
l
-Arg (0.5 mmol/L) to the bath decreased
J
Cl−
from 154.4±9.9 to 101.9±14.1 pmol · mm
−1
· min
−1
, a 35.2% decrease (n=6;
P
<0.05). In the presence of the soluble guanylate cyclase inhibitor LY-83583 (10 μmol/L), adding
l
-Arg to the bath did not affect THAL
J
Cl−
(143.7±28.1 versus 136.7±22.2 pmol · mm
−1
· min
−1
; n=6). LY-83583 alone had no effect on
J
Cl−
. In the presence of the PDE II inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) 50 μmol/L,
l
-Arg reduced
J
Cl−
by only 13% (142.1±8.9 versus 122.7±11.5 pmol · mm
−1
· min
−1
;
P
<0.05; n=6). EHNA alone had no effect on THAL
J
Cl−
. In the presence of 10
−5
mol/L dibutyryl (db)-cAMP,
l
-Arg did not significantly reduce
J
Cl−
(116.3±18.2 versus 102.6±15.6 pmol · mm
−1
· min
−1
; n=6). db-cAMP (10
−5
mol/L) had no effect on THAL
J
Cl−
. In the presence of the PKG inhibitor KT-5823 (2 μmol/L),
l
-Arg lowered
J
Cl−
from 142.6±14.1 to 85.9±8.3 pmol · mm
−1
· min
−1
, a decrease of 35.6% (n=8;
P
<0.05). We conclude that (1) endogenous NO inhibits THAL
J
Cl−
by stimulating soluble guanylate cyclase and increasing cGMP; (2) NO inhibits THAL
J
Cl−
by stimulation of PDE II, which, in turn, decreases cAMP levels; and (3) PKG does not mediate NO-induced inhibition of THAL
J
Cl−
.
Src and Rac Mediate Endothelin-1 and Lysophosphatidic Acid Stimulation of the Human Brain Natriuretic Peptide Promoter
Authors: He Quan , LaPointe Margot C.
Published: June 2012

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A
2
(PLA
2
), and the resulting metabolites are important second messengers. We studied how ET and PLA
2
metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from −1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA
2
isoforms, transfected cells were treated with various PLA
2
inhibitors before stimulation with ET. Only Ca
2+
-independent PLA
2
blockade prevented ET-stimulated hBNP promoter activity. The PLA
2
metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin–sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of
cis
elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from −1818 to −408 and from −408 to −40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA
2
, is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal
cis
elements.
Endothelin Type A Receptor Blockade Attenuates the Hypertension in Response to Chronic Reductions in Uterine Perfusion Pressure
Authors: Alexander Barbara T. , Rinewalt A. Nicole , Cockrell Kathy L. , Massey Matthew B. , Bennett William A. , Granger Joey P.
Published: June 2012

A chronic reduction in uterine perfusion pressure in pregnant rats is associated with a significant elevation in mean arterial pressure (MAP) and reduction in kidney function. The purpose of this study was to examine the role of endothelin in mediating the hypertension in response to chronic reductions in uterine perfusion pressure in conscious, chronically instrumented, pregnant rats. MAP in pregnant rats with chronic reductions in uterine perfusion pressure (123.0±1.8 mm Hg) was significantly higher than that in control pregnant rats (101.3±4.0 mm Hg). Renal expression of preproendothelin mRNA as determined by ribonuclease protection assay was also significantly elevated in the medulla (>45%,
P
<0.05) and in the cortex (>22%,
P
<0.05) of the pregnant rats with chronic reductions in uterine perfusion pressure compared with control pregnant rats. Chronic administration of the selective endothelin type A receptor antagonist (ABT-627, 5 mg/kg per day for 10 days) markedly attenuated the increase in MAP observed in the pregnant rats with chronic reductions in uterine perfusion pressure (103.3±5.6 mm Hg, plus endothelin antagonist;
P
<0.05). However, endothelin type A receptor blockade had no significant effect on blood pressure in the normal pregnant animals (96.0±2.7 mm Hg, plus endothelin antagonist). These findings suggest that endothelin plays a major role in mediating the hypertension produced by chronic reductions in uterine perfusion pressure in pregnant rats.
Regression of Renal Vascular Fibrosis by Endothelin Receptor Antagonism
Authors: Boffa Jean-Jacques , Tharaux Pierre-Louis , Dussaule Jean-Claude , Chatziantoniou Christos
Published: June 2012

In previous studies, we have observed that endothelin participates in the progression of renal vascular and glomerular fibrosis during hypertension by activating collagen I gene synthesis. The present study investigated whether administration of endothelin receptor antagonists leads to the regression of renal sclerotic lesions. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-α2 chain promoter. Hypertension was induced by long-term inhibition of nitric oxide synthesis by
N
G
-nitro-
l
-arginine methyl ester (L-NAME); systolic pressure gradually increased, reaching a plateau of 165 mm Hg after 10 weeks of hypertensive treatment. At the same time, collagen I gene expression was increased 2- and 5-fold compared with control animals in afferent arterioles and glomeruli, respectively (
P
<0.01). This increase was accompanied by the appearance of sclerotic lesions within the renal vasculature. When renal vascular lesions had been established (20 weeks of L-NAME), animals were divided into 2 subgroups: the one continued to receive L-NAME, whereas in the other, bosentan, a dual endothelin antagonist, was coadministered with L-NAME for an additional period of 10 weeks. Bosentan coadministration did not alter the increased systolic pressure at 30 weeks; in contrast, collagen I gene activity returned almost to control levels in renal vessels and glomeruli. In this subgroup of animals, renal vascular lesions (collagen and/or extracellular matrix deposition) and mortality rates were substantially reduced compared with untreated mice. These data indicate that endothelin participates in the mechanism(s) of renal vascular fibrosis by activating collagen I gene. Treatment with an endothelin antagonist normalizes expression of collagen I gene and leads to the regression of renal vascular fibrosis and to the improvement of survival, thus providing a complementary curative approach against renal fibrotic complications associated with hypertension.
Superoxide Excess in Hypertension and Aging
Authors: Hamilton Carlene A. , Brosnan M. Julia , McIntyre Martin , Graham Delyth , Dominiczak Anna F.
Published: June 2012

There is evidence in humans that hypertension and aging similarly impair endothelial function, although the mechanism remains unclear. Superoxide anion (O
2
−
) is a major determinant of nitric oxide (NO) bioavailability and thus endothelial function. We sought to determine the relationship between endothelial function, O
2
−
, and age in normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Aortic rings were removed from female WKY and SHRSP at 3 to 4 months (young) and 9 to 12 months (old). O
2
−
generation by aortic rings was measured before and after removal of the endothelium or incubation with
N
G
nitro-
l
-arginine methyl ester, diphenyleneiodonium, or apocynin. Levels of p22phox were studied with immunohistochemistry and used as a marker of NAD(P)H oxidase expression. NO bioavailability was significantly lower in old WKY compared with young WKY (
P
=0.0009) and in old SHRSP compared with young SHRSP (
P
=0.005). O
2
−
generation was significantly greater in old WKY compared with young WKY (
P
=0.0001). Removal of the endothelium and
N
G
nitro-
l
-arginine methyl ester treatment resulted in a significant reduction in O
2
−
generation in old SHRSP (
P
=0.009 and 0.001, respectively). Diphenyleneiodonium significantly reduced O
2
−
generation in 12-month WKY (
P
=0.008) and 12-month SHRSP (
P
=0.009). Apocynin attenuated O
2
−
generation by older WKY (
P
=0.038) and SHRSP (
P
=0.028). p22phox was increased in older animals compared with young. We conclude that NO bioavailability decreases with age in female WKY and SHRSP. O
2
−
generation increases with age in WKY and is higher in SHRSP and may contribute to the reduced NO by scavenging. NAD(P)H oxidase may contribute to the age-related increase in O
2
−
.
Superoxide Inhibits Neuronal Nitric Oxide Synthase Influences on Afferent Arterioles in Spontaneously Hypertensive Rats
Authors: Ichihara Atsuhiro , Hayashi Matsuhiko , Hirota Nobuhisa , Saruta Takao
Published: June 2012

This study was designed to determine the influence of increased superoxide anion in neuronal nitric oxide synthase (nNOS)-dependent regulation of afferent arterioles in spontaneously hypertensive rats (SHR). Afferent arteriolar diameters of male Wistar-Kyoto rats (WKY) and SHR were assessed in vitro with the blood-perfused juxtamedullary nephron technique and averaged 21.6±1.6 (n=6) and 18.8±1.2 (n=7) μm, respectively. The superoxide dismutase mimetic Tempol (1, 10, and 100 μmol/L) did not influence afferent arterioles of WKY but significantly increased afferent arteriolar diameters of SHR by 20.6±5.5%, 25.2±5.4%, and 23.3±4.9%, respectively. In WKY (n=6), the nNOS inhibitor
S
-methyl-
l
-thiocitrulline (L-SMTC; 10 μmol/L) and the NOS inhibitor
N

ω

-nitro-
l
-arginine (L-NNA; 100 μmol/L) significantly decreased afferent arteriolar diameters (19.6±1.6 μm) by 11.9±3.1% and 21.0±3.9%, respectively. In SHR (n=7), L-SMTC did not influence afferent arteriolar diameters (21.0±1.5 μm), but L-NNA exerted an afferent arteriolar constriction (14.8±3.2%) that was similar to the response observed in WKY. Experiments were also performed in the presence of 100 μmol/L Tempol. In afferent arterioles of WKY (n=6), Tempol treatment did not modulate the basal diameters (21.5±1.2 μm) or the constrictor response to L-SMTC (10.6±2.1%) or L-NNA (19.3±3.3%). In SHR (n=8), Tempol significantly increased afferent arteriolar diameters by 22.5±4.3% and enhanced afferent arteriolar constrictor responses to L-SMTC (18.4±2.7%) and L-NNA (31.9±2.6%). However, the nitric oxide donor
S
-nitroso-
N
-acetylpenicillamine (10 μmol/L), which similarly increased afferent arteriolar diameters (17.2±2.3%, n=6), did not affect afferent arteriolar responses to L-SMTC (1.5±2.7%) or L-NNA (18.6±2.3%). These suggest that superoxide anion inhibits the control of afferent arteriolar diameters by nNOS in SHR.
Effect of Estrogen Replacement Therapy on Endothelial Function in Peripheral Resistance Arteries in Normotensive and Hypertensive Postmenopausal Women
Authors: Higashi Yukihito , Sanada Mitsuhiro , Sasaki Shota , Nakagawa Keigo , Goto Chikara , Matsuura Hideo , Ohama Koso , Chayama Kazuaki , Oshima Tetsuya
Published: June 2012

Both menopause and hypertension are associated with endothelial dysfunction and are risk factors for coronary heart disease. We evaluated forearm resistance artery endothelial function in hypertensive postmenopausal women (HPW, n=57) and compared it with endothelial function in normotensive postmenopausal women (NPW, n=67). In addition, we evaluated the effects of long-term estrogen replacement therapy (ERT, conjugated equine estrogen at a dose of 0.625 mg daily for 12 weeks) on endothelial function in HPW (n=10) and NPW (n=35). Forearm blood flow (FBF) was measured by strain-gauge plethysmography during reactive hyperemia to assess endothelium-dependent vasodilation and after sublingual nitroglycerin (NTG) administration to assess endothelium-independent vasodilation. Basal FBF was similar in the NPW and HPW groups. The FBF in the HPW group during reactive hyperemia was significantly lower than that in the NPW group. Increases in FBF after NTG were similar in the 2 groups. ERT decreased the LDL cholesterol concentration and circulating ACE activity and increased estradiol and HDL cholesterol in both groups. Basal blood pressures, heart rate, FBF, and body weight did not change with ERT. After 12 weeks of ERT, the maximal FBF response during reactive hyperemia increased significantly in both groups. The improvement in reactive hyperemia after ERT was significantly greater in the HPW group than in the NPW group (49±8 versus 17±5%,
P
<0.05). Changes in FBF after sublingual NTG administration were similar before and after 12 weeks of ERT. These findings suggest that continued ERT improves forearm resistance artery endothelial function in postmenopausal women and that this beneficial effect is greater in patients that are hypertensive.
Responses to Central Na
+
and Ouabain Are Attenuated in Transgenic Rats Deficient in Brain Angiotensinogen
Authors: Huang Bing S. , Ganten Detlev , Leenen Frans H. H.
Published: June 2012

Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcitation and hypertension. To provide more specific evidence for the involvement of Ang II, locally produced in the brain, transgenic rats were used, which express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by >90%. In freely moving transgenic rats and Sprague-Dawley rats as control animals, blood pressure and heart rate responses to intracerebroventricular infusion (3.8 μL/min for 10 minutes) of artificial cerebrospinal fluid and Na
+
-rich artificial cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na
+
) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 μg/2 μL) were assessed. Central infusion of Na
+
-rich artificial cerebrospinal fluid increased blood pressure and heart rate in a dose-related manner. However, the peak increases by each dose of Na
+
were attenuated by 50% to 70% in the transgenic versus Sprague-Dawley rats. Increases in blood pressure and heart rate in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level was markedly lower (31±9 versus 76±13 pg/g,
P
<0.05) and Ang II level tended to be lower in the transgenic versus Sprague-Dawley rats. These results indicate that the production of angiotensins in the brain is decreased in transgenic rats. The attenuated sympathoexcitatory and pressor responses to ouabain and Na
+
-rich artificial cerebrospinal fluid in transgenic rats support the concept that the local brain renin-angiotensin system, that is, locally produced Ang II, plays an important role in the sympathoexcitatory effects of ouabain and sodium.
Tonic Excitatory Input to the Rostral Ventrolateral Medulla in Dahl Salt-Sensitive Rats
Authors: Ito Satoru , Komatsu Kazutoshi , Tsukamoto Kazuyoshi , Sved Alan F.
Published: June 2012

The goal of the present study was to test the hypothesis that the balance of tonic excitation and inhibition of vasomotor neurons in the rostral ventrolateral medulla (RVLM) driven by excitatory amino acid (EAA)–mediated inputs to the RVLM is shifted toward excitation in Dahl salt-sensitive (DS) rats compared with Dahl salt-resistant (DR) rats. Glutamate and the EAA antagonist kynurenic acid were microinjected into the RVLM of chloralose-anesthetized DS and DR rats maintained on diets containing either 0.3% NaCl or 8.0% NaCl. DS rats had a higher arterial pressure than DR rats, and this difference was greatly exaggerated by high dietary salt intake. Bilateral injection of kynurenic acid (2.7 nmol) into the RVLM decreased mean arterial pressure by 16±2 mm Hg in DS rats fed a diet containing 0.3% NaCl, and this effect was significantly larger in DS rats fed the high-salt diet (40±2 mm Hg). In contrast, injections of kynurenic acid into the RVLM did not significantly decrease arterial pressure in DR rats fed either diet. In DR rats, the pressor response elicited by the injection of glutamate into the RVLM was potentiated in rats fed the high-salt diet. The glutamate-evoked pressor response was greater in DS rats compared with DR rats, and the response in DS rats was not influenced by the salt content of the diet. These data suggest that tonically active EAA inputs to the RVLM may contribute to salt-sensitive hypertension in the Dahl model.
Norepinephrine Reuptake Is Impaired in Skeletal Muscle of Hypertensive Rats In Vivo
Authors: Cabassi Aderville , Vinci Simonetta , Quartieri Fabio , Moschini Luigi , Borghetti Alberico
Published: June 2012

Certain forms of experimental hypertension are characterized by organ-specific alterations of catecholaminergic pathways. The purpose of this study was to evaluate, in the same awake and freely moving normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) before and after the development of arterial hypertension, the norepinephrine (NE) turnover and, in particular, the neuronal NE reuptake activity that ends its effects once released from nerve terminals, in subcutaneous adipose tissue and in skeletal muscle, whose sympathetic efferents are respectively independent or dependent from baroreflexes. Plasma and tissue interstitial NE and 3,4-dihydroxyphenylethylene glycol (DHPG), its major deaminated metabolite, were measured before and after blockade of NE reuptake by tissue perfusion of desipramine through microdialysis probes. Arterial pressure and plasma NE in SHR were similar to those in WKY at 5 weeks of age but increased at 16 weeks of age. In contrast, plasma DHPG was already higher in young SHR. Basal interstitial NE and DHPG were increased in both tissues of young and old SHR compared with age-matched WKY. Desipramine induced a higher rise of interstitial NE in SHR of both ages, with a lesser increase in the skeletal muscle of old compared with young SHR. These results indicate an increased NE turnover in prehypertensive and hypertensive SHR in both baroreflex-dependent and -independent tissues, not shown by plasma NE levels in young SHR. In the skeletal muscle, where sympathetic efferents are baroreflex dependent, the reduced interstitial NE reuptake contributes to the higher availability of interstitial NE for postsynaptic effects in old SHR.
Cardiomyocytes Bind and Activate Native Human Prorenin
Authors: Saris Jasper J. , Derkx Frans H. M. , Lamers Jos M. J. , Saxena Pramod R. , Schalekamp Maarten A. D. H. , Danser A. H. Jan
Published: June 2012

Cardiomyocytes bind, internalize, and activate recombinant human prorenin through mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptors. To investigate whether this also applies to native human prorenin, neonatal rat myocytes were incubated for 4 hours at 37°C with various prorenin-containing human body fluids. Uptake and activation by M6P/IGFII receptors were observed for plasma prorenin from subjects with renal artery stenosis and/or hypertension and for follicular fluid prorenin. The total amount of cellular renin and prorenin (expressed as percentage of the levels of renin and prorenin in the medium) after 4 hours of incubation was 4 to 10 times lower than after incubation with recombinant human prorenin. Although plasma contains alkaline phosphatases capable of inactivating the M6P label as well as soluble M6P/IGFII receptors that block prorenin binding in a competitive manner and proteins (eg, insulin, IGFII) that increase the number of cell-surface M6P/IGFII receptors, these factors were not responsible for the modest uptake of native human prorenin. Uptake did not occur during incubation of myocytes with plasma prorenin from anephric subjects or with amniotic fluid prorenin, and this was not due to the presence of excessively high levels of M6P/IGFII receptors and/or phosphatase activity in these fluids. In conclusion, myocytes are capable of binding, internalizing, and activating native human prorenin of renal and ovarian origin through M6P/IGFII receptors. Differences in prorenin glycosylation and/or phosphorylation as well as the concentration of soluble M6P/IGFII receptors and growth factors affecting cell-surface M6P/IGFII receptor density determine the amount of prorenin entering the heart and thus cardiac angiotensin II production.
A
2B
Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Zacharia Lefteris C. , Mi Zaichuan , Jackson Edwin K.
Published: June 2012

Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng/mL) stimulated DNA synthesis (
3
H-thymidine incorporation), cellular proliferation (cell number), collagen synthesis (
3
H-proline incorporation), and MAP kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5′-N-methylcarboxamidoadenosine, but not N
6
-cyclopentyladenosine, 4-aminobenzyl-5′-N-methylcarboxamidoadenosine, or
CGS21680
, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A
2B
receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-
p
-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5′-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A
2
receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A
2B
receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5′-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A
2B
receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of CF growth by activating A
2B
receptors coupled to inhibition of MAP kinase activity. Thus, A
2B
receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation. Pharmacologic or molecular biological activation of A
2B
receptors may prevent cardiac remodeling associated with hypertension, myocardial infarction, and myocardial reperfusion injury after ischemia.
Workshop:
Endothelial Cell Dysfunction Leading to Diabetic Nephropathy
Authors: Goligorsky Michael S. , Chen Jun , Brodsky Sergey
Published: June 2012

Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications. Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction. Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention.
Dipping Status May Be Determined by Nocturnal Urination
Authors: Perk Gila , Ben-Arie Liora , Mekler Judith , Bursztyn Michael
Published: June 2012

Nondipping, ie, failure to reduce blood pressure by ≥10% during the night, is considered an important prognostic variable of 24-hour ambulatory blood pressure monitoring. However, some people wake up at night to urinate. Usually, 24-hour ambulatory blood pressure monitoring–derived blood pressure includes these rises in the nighttime blood pressure mean. We identified 97 subjects undergoing 24-hour ambulatory blood pressure monitoring who reported waking up at night to urinate. We assessed the 24-hour ambulatory blood pressure monitoring first using total daytime and total nighttime means and then using actual daytime awake and nighttime asleep (as reported by the patient) means. Nocturnal decline in blood pressure was 14.4±8.5/11.8±6.1 mm Hg with the first method and 17.1±8.3/13.8±5.9 mm Hg with the second one (
P
<0.00001). Although the absolute difference between the nocturnal blood pressure declines calculated by the 2 methods was small, the effect on nocturnal dip was profound. Average systolic blood pressure dipping was 10.1% by the total day–total night method and 12.0% by the actual day awake–night asleep method (
P
≤0.00001), and that of diastolic blood pressure was 14.2% and 16.7%, respectively (
P
≤0.00001). The prevalence of systolic blood pressure nondipping decreased from 42.2% by the first method to 31.9% by the second method (
P
≤0.0056), and that of diastolic blood pressure nondipping decreased from 22.6% to 11.3% (
P
≤0.00001). Inclusion of awake blood pressure measurements during the night obscured the normal dipping pattern in people who woke up to urinate. Thus, taking into account people’s actual behavior increases the accuracy of the results.
Long-Term Antioxidant Administration Attenuates Mineralocorticoid Hypertension and Renal Inflammatory Response
Authors: Beswick Richard A. , Zhang Hanfang , Marable Dawnyetta , Catravas John D. , Hill William D. , Webb R. Clinton
Published: June 2012

We previously reported increased monocyte/macrophage infiltration, reactive oxygen species accumulation, and nuclear factor-κB (NF-κB) activation in mineralocorticoid (deoxycorticosterone acetate [DOCA]) hypertensive rats. We tested the hypothesis that prolonged antioxidant administration inhibits superoxide accumulation, lowers blood pressure, and reduces NF-κB activation in DOCA-salt hypertensive rats. DOCA rats exhibited a significant increase in systolic blood pressure compared with sham rats. Aortic rings from DOCA rats exhibited increased superoxide (O
2
−
) production compared with sham rats. In addition, the treatment of DOCA rats with pyrrolidinedithiocarbamate (PDTC) or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol) caused a significant decrease in systolic blood pressure and aortic superoxide accumulation. Monocyte/macrophage infiltration was also significantly decreased in DOCA rats treated with PDTC or Tempol compared with untreated DOCA rats. NF-κB–binding activity was significantly greater in untreated DOCA rats than in either sham rats or PDTC- or Tempol-treated DOCA rats. Also, DOCA rats treated with Tempol exhibited no significant difference in NF-κB–binding activity compared with sham. These results suggest that antioxidants attenuate systolic blood pressure, suppress renal NF-κB–binding activity, and partly alleviate renal monocyte/macrophage infiltration in DOCA-salt hypertension.
Role of Myocytes in Myocardial Collagen Production
Authors: Pathak Manas , Sarkar Sagartirtha , Vellaichamy Elangovan , Sen Subha
Published: June 2012

Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar
1
]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar
1
]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P α
2
r
2
] rat α
2
[I] probe for type I and human skin fibroblast α
1
[III] probe for type III). When [Sar
1
]Ang II was added in vitro to neonatal or adult 28-week-old Wistar-Kyoto rat heart fibroblasts, questionable stimulation in the mRNAs of types I and III occurred. In contrast, when 10
−8
mol/L [Sar
1
]Ang II was added to beating, nonworking Wistar-Kyoto rat heart preparation ex vivo, a 1.5- to 2.5-fold stimulation of collagen mRNAs of phenotypes I and III was observed. When neonatal fibroblasts were cocultured with neonatal myocytes in vitro, with 10
−10
mol/L [Sar
1
]Ang II added, there was no stimulation of either phenotype. However, significant stimulation of both collagen transcripts was recorded when 10
−10
mol/L [Sar
1
]Ang II was added to adult fibroblasts cocultured with either neonatal or adult myocytes. Our data suggest that factors produced by myocytes are necessary for upregulation of collagen genes in vitro and demonstrate that fibroblast-myocyte cross-talk is required for Ang II–induced collagen upregulation.
Therapeutic Actions of a New Synthetic Vasoactive and Natriuretic Peptide, Dendroaspis Natriuretic Peptide, in Experimental Severe Congestive Heart Failure
Authors: Lisy Ondrej , Lainchbury John G. , Leskinen Hanna , Burnett John C.
Published: June 2012

Abstract
—Dendroaspis natriuretic peptide (DNP), a recently discovered peptide, shares structural similarity to the other known natriuretic peptides, ANP, BNP, and CNP. Studies have reported that DNP is present in human and canine plasma and atrial myocardium and increased in plasma of humans with congestive heart failure (CHF). In addition, synthetic DNP is markedly natriuretic and diuretic and is a potent activator of cGMP in normal animals. To date, the ability of synthetic DNP to improve cardiorenal function in experimental CHF is unknown. Synthetic DNP was administered intravenously at 10 and 50 ng · kg
−1
· min
−1
in dogs (n=7) with severe CHF induced by rapid ventricular pacing for 10 days at 245 bpm. In addition, we determined endogenous DNP in normal (n=4) and failing (n=4) canine atrial and ventricular myocardium. We report that administration of synthetic DNP in experimental severe CHF has beneficial cardiovascular, renal, and humoral properties. First, DNP in CHF decreased cardiac filling pressures, specifically right atrial pressure and pulmonary capillary wedge pressure. Second, DNP increased glomerular filtration rate in association with natriuresis and diuresis despite a reduction in mean arterial pressure. Third, DNP increased plasma and urinary cGMP and suppressed plasma renin activity. Fourth and finally, we report that DNP immunoreactivity is present in canine atrial and ventricular myocardium and increased in CHF. These studies report the acute intravenous actions of synthetic DNP in experimental severe CHF and suggest that on the basis of its beneficial properties, DNP may have potential as a new intravenous agent for the treatment of decompensated CHF.
Angiotensin-(1-7) Does Not Affect Vasodilator or TPA Responses to Bradykinin in Human Forearm
Authors: Wilsdorf Terry , Gainer James V. , Murphey Laine J. , Vaughan Douglas E. , Brown Nancy J.
Published: June 2012

Abstract
—Studies in isolated vessels and rat models of hypertension suggest that angiotensin (Ang)-(1-7) potentiates the vasodilator effect of bradykinin, possibly through ACE inhibition. We therefore tested the hypothesis that Ang-(1-7) potentiates the vasodilator or tissue plasminogen activator (TPA) response to bradykinin in the human forearm vasculature. Graded doses of Ang-(1-7) (10, 100, and 300 pmol/min), bradykinin (47, 94, and 189 pmol/min), and Ang I (1, 10, and 30 pmol/min) were administered through the brachial artery to 8 normotensive subjects in random order. Thirty minutes after initiation of a constant infusion of Ang-(1-7) (100 pmol/min), bradykinin and Ang I infusions were repeated. There were no systemic hemodynamic effects of the agonists. Bradykinin significantly increased forearm blood flow (
P
<0.001, from 3.8±0.5 to 13.9±3.1 mL/min per 100 mL at 189 pmol/min) and net TPA release (
P
=0.007, from 1.1±1.0 to 23.6±6.2 ng/min per 100 mL at 189 pmol/min), whereas Ang I caused vasoconstriction (
P
=0.003, from 3.3±0.4 to 2.5±0.3 mL/min per 100 mL at 30-pmol/min dose). There was no effect of Ang-(1-7) on either forearm blood flow (
P
=0.62, 3.3±0.4 to 3.5±0.4 mL/min per 100 mL at 300 pmol/min) or TPA release (
P
=0.52, from 0.7±0.8 to 1.0±0.7 ng/min/100 mL at 300 pmol/min). Moreover, there was no effect of 100 pmol/min Ang-(1-7) on the vasodilator [
P
=0.46 for Ang-(1-7) effect] or TPA [
P
=0.82 for Ang-(1-7) effect] response to bradykinin or the vasoconstrictor response to Ang I [
P
=0.62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis.
β
2
-Adrenergic Receptor Gene Variation and Hypertension in Subjects With Type 2 Diabetes
Authors: Bengtsson Kristina , Orho-Melander Marju , Melander Olle , Lindblad Ulf , Ranstam Jonas , Råstam Lennart , Groop Leif
Published: June 2012

Abstract
—The aim of this study was to investigate whether polymorphisms in the β
2
-adrenergic receptor gene (5′LC-Arg19Cys, Arg16Gly, Gln27Glu) are associated with hypertension in patients with or without type 2 diabetes and with the blood pressure levels in normotensive sib pairs. The association study included 291 hypertensive patients without type 2 diabetes, 124 hypertensive patients with type 2 diabetes, and 265 healthy control subjects from Sweden. In addition, normotensive sib pairs that were discordant for the Arg16Gly (72 pairs) and Gln27Glu (40 pairs) polymorphisms were identified in type 2 diabetes families from Finland. Genotyping was performed using polymerase chain reaction–restriction fragment-length polymorphism analysis. Homozygous carriers of the Arg16 allele had a significantly increased odds ratio (OR) for hypertension in patients with type 2 diabetes (OR 2.14; 95% confidence interval [CI], 1.05 to 4.33), particularly among lean (body mass index<27 kg/m
2
) patients (OR 3.47; 95% CI, 1.06 to 11.33). The Gln27 allele showed a weaker association to hypertension (OR 1.55; 95% CI, 1.00 to 2.41) and was found to be in linkage disequilibrium with the Cys19 allele of the 5′LC-Arg19Cys polymorphism. In the paired-sibling analysis, siblings with at least 1 copy of the Arg16 allele had higher systolic blood pressure (
P
=0.049), and nondiabetic siblings had a higher body mass index (
P
=0.026) than siblings homozygous for the Gly16 allele. These results indicate that the Arg16 allele of the β
2
-adrenergic receptor gene confers an increased risk for hypertension in subjects with type 2 diabetes and is associated with higher blood pressure levels and higher body mass index in sib pairs who are discordant for the polymorphism.