bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms for Inducible Control of Angiotensinogen Gene Transcription
Authors: Brasier Allan R. , Li Junyi
Published: June 2012

Abstract
The intravascular renin-angiotensin system is an endocrine system designed to maintain cardiovascular homeostasis in response to hypotension. Under normal conditions, angiotensinogen concentrations circulating in the plasma are rate limiting for the maximum velocity of angiotensin I formation. In the liver, the major site of circulating angiotensinogen synthesis, angiotensinogen expression is under exquisite hormonal control. We review the mechanisms by which hormones effect transcriptional control of angiotensinogen expression. Adrenal-derived glucocorticoids produce the translocation of the glucocorticoid receptor into the nucleus. It in turn binds to two glucocorticoid response elements and stimulates angiotensinogen gene transcription. Inflammation activates angiotensinogen transcription as a result of the macrophage-derived cytokines interleukin-1 and tumor necrosis factor-α. These cytokines change the abundance of two transcription factor families that bind a single regulatory site in the angiotensinogen promoter, the acute-phase response element. These proteins include the nuclear factor-κB complex and the CCAAT/enhancer binding protein family. Activation of the renin-angiotensin system, through production of angiotensin II, results in feedback stimulation of angiotensinogen synthesis (the “positive feedback loop”). We have discovered that the nuclear factor-κB transcription factor is regulated by angiotensin II, a finding that provides a mechanism for the transcriptional component of angiotensinogen gene synthesis in the positive feedback loop. These studies underscore the concept that induction of the angiotensinogen gene by diverse physiological stimuli is mediated through changes in the nuclear abundance of sequence-specific transcription factors. The intracellular convergence of cytokine- and angiotensin II–induced signaling pathways on the nuclear factor-κB transcription factor provides a point for “cross talk” between angiotensin- and cytokine-activated second messenger pathways.
Functional Analysis of Human Tissue Kallikrein in Transgenic Mouse Models
Authors: Chao Julie , Chao Lee
Published: June 2012

Abstract
Clinical studies show that an inverse correlation exists between blood pressure and urinary kallikrein levels. It has been postulated that the tissue kallikrein-kinin system contributes to the maintenance of normal blood pressure. To test this hypothesis, we have established transgenic mice that overexpress human tissue kallikrein under the promoter control of the mouse metallothionein gene and a liver-targeted albumin gene. These animals secrete human tissue kallikrein in plasma at levels 10- to 40-fold higher than that found in normal human serum, and they are chronically hypotensive. This hypotensive effect can be reversed by the injection of aprotinin, a potent tissue kallikrein inhibitor, or Hoe 140, a specific bradykinin receptor antagonist. Transgenic mice overexpressing human tissue kallikrein show a sustained reduction in blood pressure throughout their life spans, indicating the lack of sufficient compensatory mechanisms to reverse the hypotensive effect of kallikrein. Somatic gene delivery of rat kallikrein-binding protein by muscle injection increases the blood pressure of the hypotensive transgenic mice to levels comparable with those in normotensive control mice. These results indicate that a direct link exists between kallikrein gene expression and alterations in blood pressure. In addition, we have developed normotensive transgenic mice that harbor the human tissue kallikrein gene containing 801 bp of its native promoter. The tissue distribution pattern of human kallikrein in these transgenic mice is similar to that in human tissues, with the highest level in the pancreas and much lower levels in the kidney and salivary gland. These transgenic mice provide new animal models for investigating the tissue-specific regulation of tissue kallikrein and its role in altering blood pressure.
Angiotensin I–Converting Enzyme Gene Polymorphism and Salt Sensitivity in Essential Hypertension
Authors: Hiraga Hiroyuki , Oshima Tetsuya , Watanabe Mitsuaki , Ishida Mari , Ishida Takafumi , Shingu Tetsuji , Kambe Masayuki , Matsuura Hideo , Kajiyama Goro
Published: June 2012

Abstract
We undertook the present study in 66 Japanese patients with essential hypertension to identify genetic factors associated with salt sensitivity. Patients were classified into salt-sensitive or salt-resistant groups on the basis of changes in their mean blood pressures from a week of a low salt diet (50 mmol/d) to a week of a high salt diet (340 mmol/d). Salt sensitivity and resistance were studied in relation to a 287-bp insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme gene detected by a polymerase chain reaction method and the haptoglobin phenotype determined by polyacrylamide gel electrophoresis. Patients with the angiotensin I–converting enzyme gene genotype II were more apt to be salt sensitive than patients with the ID and DD genotypes, although plasma renin activity was similar in each group. The frequency of the I allele in the salt-sensitive group was significantly higher than that in the salt-resistant group (χ
2
=7.4, odds ratio=2.78). However, there was no significant relationship between haptoglobin phenotype and salt sensitivity. These data suggest that an I/D polymorphism of the angiotensin I–converting enzyme gene is a genetic factor associated with salt sensitivity of blood pressure independently of plasma renin activity in Japanese patients with essential hypertension.
Role of Area Postrema in Transgene Hypertension
Authors: Averill David B. , Matsumura Kiyoshi , Ganten Detlev , Ferrario Carlos M.
Published: June 2012

Abstract
Transgenic [Tg(+)] rats carrying the mouse
Ren
-2
d
gene [(m
Ren
-2
d
)27] are a newly established monogenetic form of experimental hypertension. To determine whether the area postrema contributes to the development of hypertension in m
Ren
-2 Tg(+) rats, this circumventricular organ in the fourth ventricle was removed from 5-week-old Tg(+) rats. From weeks 4 through 9, systolic blood pressure was measured weekly by tail-cuff plethysmography in area postrema–lesioned and sham-lesioned Tg(+) rats. Although systolic blood pressure rose markedly in sham-lesioned Tg(+) rats, the increase in systolic blood pressure was significantly attenuated in area postrema–lesioned Tg(+) rats. At 9 weeks of age, a femoral artery was cannulated for the measurement of arterial pressure in awake rats. Mean arterial pressure (MAP) in area postrema–lesioned Tg(+) rats was significantly (
P
<.01) lower than that in sham-lesioned rats: 171±7 and 132±5 mm Hg, respectively. Baroreceptor reflex was evaluated by intravenous infusion of sodium nitroprusside. There was no significant difference in baroreceptor reflex sensitivity between the two groups. Intravenous pentolinium (5 mg/kg), used to produce sympathetic ganglionic block, caused significant decreases in MAP in both groups. However, the reduction of MAP in the sham-lesioned group was significantly (
P
<.05) greater than that in the area postrema–lesioned group: −73±4 and −48±6 mm Hg, respectively. The ratio of left ventricular weight to body weight in sham-lesioned Tg(+) rats was significantly larger than that of area postrema–lesioned rats. These results suggest that ablation of the area postrema markedly attenuates the development of hypertension in m
Ren
-2
d
Tg(+) rats, and this attenuation may be attributed to decrease in sympathetic outflow.
Effects and Interactions of Endothelin-1 and Angiotensin II on Matrix Protein Expression and Synthesis and Mesangial Cell Growth
Authors: Gómez-Garre Dulcenombre , Ruiz-Ortega Marta , Ortego Mónica , Largo Raquel , López-Armada Maria José , Plaza Juan J. , González Eva , Egido Jesús
Published: June 2012

Abstract
Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ET
A
) and angiotensin type 1 (AT
1
) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti–transforming growth factor-β antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT
1
receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1–mediated effects, whereas the ET
A
receptor antagonist BQ-123 diminished the Ang II–induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ET
A
and AT
1
receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-β, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis.
Erythrocyte Sodium Transport, Intraplatelet pH, and Calcium Concentration in Salt-Sensitive Hypertension
Authors: del Mar Lluch María , de la Sierra Alejandro , Poch Esteban , Coca Antonio , Aguilera María Teresa , Compte Montserrat , Urbano-Márquez Alvaro
Published: June 2012

Abstract
We evaluated changes in erythrocyte sodium transport systems, platelet pH, and calcium concentration induced by low and high salt intakes in a group of 50 essential hypertensive patients classified on the basis of their salt sensitivity. Patients received a standard diet with 20 mmol NaCl daily for 2 weeks supplemented in a single-blind fashion by placebo tablets the first 7 days and NaCl tablets the following 7 days. Salt sensitivity, defined as a significant rise (
P
<.05) in 24-hour mean blood pressure obtained by ambulatory blood pressure monitoring, was diagnosed in 22 (44%) patients. The remaining 28 (56%) were considered to have salt-resistant hypertension. In the entire group of hypertensive patients, high salt intake promoted a significant increase (
P
<.05) in the maximal rate of erythrocyte Na
+
-Li
+
countertransport (from 271±19 to 327±18 μmol/(L cells/h) and of the Na
+
-dependent HCO
3
−
-Cl
−
exchanger (from 946±58 to 1237±92 μmol/L cells/h) as well as in platelet pH (from 7.15±0.01 to 7.19±0.02) and calcium concentration (from 49±2 to 57±2 nmol/L). Depending on salt sensitivity, high salt intake promoted opposing changes in some of the sodium transport systems studied. Salt-sensitive patients increased the maximal rate of the erythrocyte Na
+
-K
+
pump (from 7.0±0.4 to 8.8±0.4 mmol/(L cells/h), Na
+
-K
+
-Cl
−
cotransport (from 416±37 to 612±41 μmol/(L cells/h), and Na
+
-Li
+
countertransport (from 248±20 to 389±17 μmol/(L cells/h) at the end of the high salt period. Conversely, salt-resistant patients decreased the Na
+
-K
+
pump (from 8.0±0.4 to 6.9±0.3 mmol/(L cells/h) and Na
+
-K
+
-Cl
−
cotransport (from 578±53 to 481±43 μmol/(L cells/h). We conclude that modulation of erythrocyte sodium transport systems by high salt intake depends on salt sensitivity. The Na
+
-K
+
pump, Na
+
-K
+
-Cl
−
cotransport, and Na
+
-Li
+
countertransport increase in salt-sensitive patients, whereas the activity of these sodium transport systems tends to decrease in salt-resistant patients. Independent of salt sensitivity, high salt intake promotes a significant increase in the erythrocyte Na
+
-dependent HCO
3
−
-Cl
−
exchanger, platelet pH, and calcium concentration in essential hypertensive patients.
α
2
-Adrenergic Agonists Increase Cellular Lactate Efflux
Authors: Lockette Warren , Kirkland Kevin , Farrow Stephen
Published: June 2012

Abstract
We reported previously that genetic polymorphisms of the α
2
-adrenergic receptor are associated with hyperinsulinemia, diabetes mellitus, and hypertension in blacks. The evolutionary driving force for maintaining such deleterious mutations in the black population is unknown. Recognizing that vascular α
2
-adrenergic receptors mediate cold-induced vasoconstriction and that temperature maintenance is a primary thrust of cellular metabolism, we postulated that vascular α
2
-adrenergic receptors contribute significantly to metabolic heat generation in homeotherms such as humans. Using aerobic lactate production as an indicator of thermogenesis, we measured metabolic heat production in HT29 cells that expressed the gene encoding human vascular α
2
-adrenergic receptors. Epinephrine, an α
2
-adrenergic receptor agonist, increased net lactate efflux from 226±20 to 280±20 nmol/min (mean±SE) (
P
=.06). Clonidine, a more specific α
2
-adrenergic agonist, increased lactate efflux from 110±6 to 156±8 nmol/min (
P
<.01). Similarly, in the presence of physiological concentrations of glucose (5.5 mmol/L), insulin increased lactate production from 123±6 to 175±10 nmol/min (
P
<.01). Because differences in aerobic glycolysis may also explain the heat intolerance and abnormal fuel homeostasis found in genetically hypertensive rats, we also measured lactate production in cultured vascular smooth muscle cells isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive control Wistar-Kyoto rats (WKY). Vascular smooth muscle cells from SHRSP had significantly greater lactate efflux compared with cells from normotensive WKY (296±4 versus 172±2 nmol/min,
P
<.001). These differences were not due to abnormalities in glucose uptake, as lactate efflux was greater in SHRSP cells compared with WKY cells when dextrose was replaced with equimolar concentrations of fructose (230±6 versus 138±2 nmol/min,
P
<.001). α
2
-Adrenergic agonists increase lactate efflux in HT29 cells, and abnormalities in vascular smooth muscle lactate metabolism in genetically hypertensive rats is independent of altered glucose uptake. These data provide support for our hypothesis that balanced polymorphisms of the α
2
-adrenergic receptor could offer protection against cold stress by increasing the thermogenic response associated with aerobic lactate production.
Renal Function and Blood Pressure Response to Dietary Salt Restriction in Normotensive Men
Authors: Barba Gianvincenzo , Cappuccio Francesco Paolo , Russo Luigina , Stinga Francesco , Iacone Roberto , Strazzullo Pasquale
Published: June 2012

Abstract
The interindividual variability of the blood pressure response to changes in dietary sodium intake might be traced in part to heterogeneity in renal adaptation. To further explore this possibility, we evaluated glomerular filtration rate and tubular sodium handling in 47 healthy male volunteers from the Olivetti factory in Naples who were studied on their habitual sodium-rich diet (urinary sodium, 184±9 mmol/24 h) and after 3 days of a salt-restricted diet (urinary sodium, 69±5 mmol/24 h). Individual salt sensitivity, defined as the mean blood pressure change recorded after the shift from habitual to low sodium diet, significantly and directly correlated with glomerular filtration rate and absolute proximal sodium reabsorption during the habitual diet. When the entire population was divided into tertiles of salt sensitivity, the group with the highest salt sensitivity showed higher blood pressure, glomerular filtration rate, and absolute proximal sodium reabsorption during the habitual diet compared with the least salt-sensitive group; however, during the low NaCl diet, no differences were detectable between the groups. Twenty-four-hour urinary sodium was similar across the groups. We conclude that relative hyperfiltration and altered tubular sodium handling may occur in salt-sensitive normotensive individuals on a high sodium diet and that NaCl restriction may offset these abnormalities.
Improvement of Insulin Sensitivity Contributes to Blood Pressure Reduction After Weight Loss in Hypertensive Subjects With Obesity
Authors: Ikeda Toshio , Gomi Tomoko , Hirawa Nobuhito , Sakurai Jun , Yoshikawa Nori
Published: June 2012

Abstract
To assess the role of insulin resistance in obesity hypertension, we examined the change of insulin sensitivity after weight loss in 24 obese hypertensive subjects by the euglycemic hyperinsulinemic glucose clamp method. The results of the 4-week calorie-restricted diet were a weight loss of 10.2% (from 74±12 to 67±11 kg,
P
<.01) and a decrease in mean blood pressure of 13.1% (from 124±7 to 107±9 mm Hg,
P
<.01). A decrease in plasma norepinephrine (from 208±74 to 142±52 pg/mL,
P
<.01) was associated with decreases in plasma renin activity (from 1.06±0.98 to 0.62±0.63 ng/mL per hour,
P
<.01) and serum aldosterone (from 70±28 to 57±24 pg/mL,
P
<.05). Glucose infusion rate increased significantly (42.9%), from 809±194 to 1155±251 μmol/m
2
per minute. The insulin sensitivity index, which is a measure of the glucose infusion rate divided by plasma insulin, increased significantly (42.6%), from 10.8±3.5 to 15.4±4.4 (μmol/m
2
per minute)/(μU/mL). Stepwise multiple linear regression analysis showed that changes of plasma norepinephrine, insulin sensitivity index, plasma renin activity, and age were significant predictive factors for the change of mean blood pressure after weight loss. These results indicate a distinct relation between an improvement of insulin sensitivity and a decrease in blood pressure after weight loss in obese hypertensive subjects. The decrease in blood pressure after weight loss is probably related to the suppression of sympathetic nervous activity.
Tissue-Specific Regulation of Angiotensinogen Gene Expression in Spontaneously Hypertensive Rats
Authors: Tamura Kouichi , Umemura Satoshi , Nyui Nobuo , Yamakawa Tadashi , Yamaguchi Satoshi , Ishigami Tomoaki , Tanaka Shun-ichi , Tanimoto Keiji , Takagi Nobuyoshi , Sekihara Hisahiko , Murakami Kazuo , Ishii Masao
Published: June 2012

Abstract
Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.
Multiple Enhancer Elements Mediate Induction of c-
fos
in Vascular Smooth Muscle Cells
Authors: Chen Yan-Qun , Gilliam Debbie M. , Rydzewski Bartosz , Naftilan Allen J.
Published: June 2012

Abstract
Previous work from this and other laboratories has demonstrated that the vasoconstrictor peptide angiotensin II results in hypertrophy of rat aortic smooth muscle cells that is associated with an increase in transcription of the early growth response gene c-
fos
. To explore the molecular mechanism responsible for c-
fos
induction in rat aortic smooth muscle cells, we used a series of reporter constructs linked to the chloramphenicol acetyl transferase gene in transient transfection experiments in rat aortic smooth muscle cells. Constructs containing both the serum response element and cAMP response element exhibited a 20-fold increase in chloramphenicol acetyl transferase activity in response to either serum or angiotensin II, whereas no increase was seen in vehicle-treated cells. Mutations in either the serum response element or cAMP response element alone, which have been demonstrated to inactivate these elements in other cell types, had no effect on chloramphenicol acetyl transferase inducibility. In contrast, if both elements were mutated, inducibility was almost abolished. Electrophoretic mobility shift assays with oligonucleotides corresponding to either serum response element or cAMP response element demonstrated that these oligonucleotides are capable of forming specific complexes with proteins from rat aortic smooth muscle cell nuclear extracts. One of the proteins binding to the serum response element is the previously described serum response factor, since it was supershifted by a monospecific antibody. These studies demonstrate that c-
fos
induction in smooth muscle occurs by a dual mechanism that can activate transcription via the serum response element or cAMP response element. These elements appear to act equally and independently, involving a distinct set of transacting factors.
Impaired Action of Levcromakalim on ATP-Sensitive K
+
Channels in Mesenteric Artery Cells From Spontaneously Hypertensive Rats
Authors: Ohya Yusuke , Setoguchi Motoko , Fujii Koji , Nagao Tetsuhiko , Abe Isao , Fujishima Masatoshi
Published: June 2012

Abstract
The purpose of the present study was to test the hypothesis that properties of ATP-sensitive K
+
channels are altered in arterial smooth muscle cells of hypertensive rats. Using a patch-clamp technique, we compared effects of a K
+
channel opener, levcromakalim, on membrane currents in mesenteric artery cells from adult Wistar Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR) treated or not treated with hydralazine. Blood pressure was significantly higher in SHR than in WKY or hydralazine-treated SHR. Levcromakalim evoked a time-independent and voltage-insensitive current in a dose-dependent manner in the whole-cell clamp configuration. The reversal potential of the evoked current depended on extracellular K
+
concentration. Application of 3 μmol/L glibenclamide, a specific blocker of ATP-sensitive K
+
channels, abolished the levcromakalim-evoked current; however, the current was unaffected by either 1 mmol/L tetraethylammonium or 0.3 μmol/L charybdotoxin. These results suggest that the levcromakalim-evoked current was carried through ATP-sensitive K
+
channels. In SHR cells, the maximal slope conductance of the levcromakalim-evoked current, normalized by cell capacitance, was decreased, and the dose-response curve was shifted to the right compared with WKY cells. The levcromakalim action was not impaired in cells from hydralazine-treated SHR. In conclusion, the action of levcromakalim on ATP-sensitive K
+
channels in SHR mesenteric artery muscle cells was impaired compared with WKY cells. This impairment was corrected by long-term antihypertensive treatment.
Effect of Race and Hypertension on Plasma Amylin Concentrations
Authors: Dimsdale Joel E. , Kolterman Orville , Koda Joy , Nelesen Richard
Published: June 2012

Abstract
Amylin is a recently discovered peptide hormone composed of 37 amino acids that is cosecreted with insulin by pancreatic β cells. Amylin has been reported to be present in increased amounts in insulin-resistant subjects who are hyperinsulinemic. Because blacks and whites differ in the prevalence of both hypertension and diabetes, we examined amylin levels in 77 individuals; 42 were black (11 hypertensive and 31 normotensive) and 35 were white (10 hypertensive and 25 normotensive) individuals who were either healthy control subjects or hypertensive subjects not receiving antihypertensive medication. Plasma amylin concentrations were measured in two separate monoclonal antibody–based immunofluorescent sandwich-type assays. The F002-2 capture antibody binds amylin plus at least two additional amylin-like peptides, and the F024-4 capture antibody detectably binds only the amylin peptide. There was a significant race-by-diagnosis interaction for levels of amylin immunoreactivity during a 2-hour glucose tolerance test (
P
<.005 for F002-2 antibody and
P
<.05 for F024-4 antibody). Highest levels were found in black hypertensive subjects. The results appear to fit with previously observed differences in metabolic status between blacks and whites and with the association between hypertension and alterations in metabolic status.
Lack of Cross Talk Between α
1
-Adrenergic and Angiotensin Type 1 Receptors in Neurons of Spontaneously Hypertensive Rat Brain
Authors: Yang Hong , Lu Di , Raizada Mohan K.
Published: June 2012

Abstract
Norepinephrine causes downregulation of angiotensin II (Ang II) receptors in Wistar-Kyoto rat (WKY) brain neuronal cultures. The aim of this study was to compare the cross talk between Ang II and α
1
-adrenergic receptors in these neuronal cultures. Norepinephrine causes a 66% decrease in
B
max
of Ang II type 1 (AT
1
) receptors in neuronal cultures of WKY brain. This decrease is mediated by the interaction of norepinephrine with the α
1A
-adrenergic receptor subtype. Norepinephrine also causes a decrease in mRNA levels for AT
1
receptors. A maximal decrease of 83% in AT
1
receptor mRNA is observed in 8 hours with 100 μmol/L norepinephrine, is blocked by 5-methyluradipil, and involves inhibition of AT
1
receptor transcription. Furthermore, decreases in the AT
1
receptor and its mRNA are associated with a significant attenuation of AT
1
receptor–mediated stimulation of norepinephrine transporter mRNA in WKY brain neurons. In contrast, norepinephrine does not decrease AT
1
receptors or mRNA and has no effect on Ang II stimulation of norepinephrine transporter mRNA in neuronal cultures of spontaneously hypertensive rat brain. Thus, these data show that norepinephrine-mediated downregulation of AT
1
receptors is associated with a parallel decrease in AT
1
mRNA and Ang II stimulation of norepinephrine transporter mRNA and involves the α
1A
-adrenergic receptor in neurons of WKY brain. This cross talk between the two receptors is lacking in neurons of spontaneously hypertensive rat brain.
Role of γ-Aminobutyric Acid B Receptors in Baroreceptor Reflexes in Hypertensive Rats
Authors: Yin Ming , Sved Alan F.
Published: June 2012

Abstract
Previous studies demonstrated that stimulation of γ-aminobutyric acid B (GABA
B
) receptors in the nucleus tractus solitarius of spontaneously hypertensive rats (SHR) elicited a larger increase in arterial pressure compared with control Wistar-Kyoto rats. Since stimulation of GABA
B
receptors in the nucleus tractus solitarius attenuates cardiovascular responses evoked by electrical stimulation of the aortic depressor nerve in normotensive rats and there is evidence of a central neural attenuation of aortic depressor nerve–evoked responses in SHR, we conducted studies to test the hypothesis that enhanced stimulation of GABA
B
receptors in the nucleus tractus solitarius in SHR is responsible for the attenuation of the aortic depressor nerve–evoked responses. Electrical stimulation of the left aortic depressor nerve resulted in frequency-dependent decreases in arterial pressure, heart rate, and splanchnic sympathetic nerve activity in urethane-anesthetized control rats. These responses were not significantly altered by injection of the GABA
B
receptor antagonist CGP 35348 into the ipsilateral nucleus tractus solitarius. The responses evoked by aortic depressor nerve stimulation were attenuated in SHR. This attenuation was particularly apparent with more prolonged periods (>15 seconds) of high-frequency (25-Hz) stimulation, with the depressor and sympathetic nerve responses diminishing during the course of stimulation. This time- and frequency-dependent attenuation of baroreceptor-evoked depressor responses was reversed by injection of CGP 35348 into the ipsilateral nucleus tractus solitarius. Rats made hypertensive by treatment with deoxycorticosterone plus salt did not have attenuated aortic depressor nerve–evoked responses. These results suggest that alterations in GABA
B
-mediated neural transmission in the nucleus tractus solitarius contribute to the attenuation of the baroreceptor reflex observed in SHR.
Insulin Resistance, Elevated Glomerular Filtration Fraction, and Renal Injury
Authors: Dengel Donald R. , Goldberg Andrew P. , Mayuga Ronaldo S. , Kairis Gretchen M. , Weir Matthew R.
Published: June 2012

The development of insulin resistance may be an early step in the development of hypertension; however, the mechanism for this process is not known. The worsening of insulin resistance and hypertension could increase both systemic and glomerular capillary pressures and predispose an individual to renal injury. The purpose of this study was to examine the relationship of insulin resistance to glomerular hemodynamics and dietary salt intake in 10 older (68±6 years), obese (body mass index, 31±4 kg/m
2
), mildly hypertensive (151±8/82±2 mm Hg), sedentary subjects without clinical evidence of diabetes or renal disease. They were studied on separate days with radioisotopic renal clearances (glomerular filtration rate by
99m
Tc-diethylenetriaminepentaacetic acid urinary clearance; renal plasma flow by
131
I-hippuran serum disappearance) and a two-dose (40 and 100 mU/m
2
per minute) hyperinsulinemic euglycemic clamp for measurement of glucose disposal after 2 weeks of a 3-g and 2 weeks of a 10-g sodium diet. Glomerular filtration rate (68.1±7.7 to 78.0±6.6 mL/min per 1.73 m
2
,
P
=.08) and glomerular filtration fraction (0.21±0.02 to 0.22±0.02,
P
=.5) did not change significantly after dietary salt was increased. During low dietary salt intake, there was an inverse relationship between glomerular filtration fraction and glucose disposal rate (milligrams per kilogram fat-free mass per minute) at both low (
r
=−.70,
P
=.04) and high (
r
=−.83,
P
=.006) insulin levels. However, these relationships were attenuated during salt loading. This suggests that a greater degree of insulin resistance, not increased dietary salt, may predispose older mildly hypertensive subjects to renal injury by worsening renal hemodynamics through the elevation of glomerular filtration fraction and resultant glomerular hyperfiltration.
Activation of Heat Shock Transcription Factor 1 in Rat Aorta in Response to High Blood Pressure
Authors: Xu Qingbo , Fawcett Timothy W. , Udelsman Robert , Holbrook Nikki J.
Published: June 2012

We have previously demonstrated that acute hypertension induces heat shock protein gene expression in rat arterial wall. Here we provide evidence that this induction is mediated through the activation of heat shock transcription factor 1 in response to high blood pressure. Rats subjected to restraint or immobilization stress displayed an acute elevation in systolic pressure accompanied by an increase in heat shock protein 70 mRNA expression. Consistent with the rapid time course of mRNA induction, an increase in binding activity to an oligonucleotide encompassing a consensus heat shock element sequence was seen in protein extracts from aorta of restrained rats as assessed with gel mobility shift assays. A similar increase in DNA binding activity was also observed in aortic extracts from rats treated with various hypertensive agents, including phenylephrine, angiotensin II, and vasopressin. That the DNA binding activity was attributed to heat shock factor 1 was shown through use of antibodies to the transcription factor that retarded the DNA-protein complexes in gel mobility supershift assays. Western blot analysis of heat shock factor 1 protein expression in aortic extracts showed a slower mobility form of the protein in hypertensive rats, indicative of an activated, presumably phosphorylated, form of the transcription factor. These findings support the view that heat shock factor 1 is responsible for induction of heat shock protein 70 in the arterial wall during acute hypertension, a response that is likely to play an important role in protecting arteries during hemodynamic stress.
Role of Prostaglandins in Acetylcholine-Induced Contraction of Aorta From Spontaneously Hypertensive and Wistar-Kyoto Rats
Authors: Rapoport Robert M. , Williams Shannon P.
Published: June 2012

Evidence in support of prostaglandin (PG) H
2
as the endothelium-derived contracting factor released in response to acetylcholine in vessels from adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) is to a large degree indirect. Therefore, the purpose of the present study was to test the hypothesis that a prostaglandin or prostaglandins other than PGH
2
may serve as the endothelium-derived contracting factor that mediates acetylcholine-induced contraction in these vessels. Acetylcholine-induced contraction of endothelium-intact aorta from 7- to 12-month-old SHR and WKY in the presence of the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine was abolished by indomethacin and only partially decreased by the thromboxane (Tx) A
2
/PGH
2
receptor antagonist SQ29548. Contraction induced by the TxA
2
/PGH
2
receptor agonist U46619 was abolished by SQ29548. These findings suggest that in endothelium-intact aorta from SHR and WKY, acetylcholine causes the release of a cyclooxygenase product other than PGH
2
that induces contraction independently of TxA
2
/PGH
2
receptor activation. To investigate which prostaglandin or prostaglandins could be responsible for the TxA
2
/PGH
2
receptor–independent component, we challenged endothelium-denuded aorta from SHR and WKY with various prostaglandins in the presence of SQ29548. In SQ29548-treated aorta from 7- to 12-month-old rats, maximal contractions to PGF
2
α
, PGE
2
, and carbacyclin (a PGI
2
analogue) were greater than the magnitude of acetylcholine-induced contraction. These findings suggest that PGF
2
α
, PGE
2
, and/or PGI
2
could serve as mediators of the TxA
2
receptor–independent component of the acetylcholine-induced contraction. However, in studies with SQ29548-treated aorta from 4- to 6-week-old SHR and WKY (an age at which acetylcholine-induced contraction is known to be absent), maximal contraction to PGF
2
α
and PGE
2
was also greater or equivalent to that of SQ29548-treated aorta from 7- to 12-month-old rats, whereas carbacyclin induced negligible contraction. Thus, unlike PGE
2
and PGF
2
α
, the age-dependent pattern of contraction induced by carbacyclin closely resembles the pattern induced by acetylcholine. We also measured the levels of PGI
2
released in response to acetylcholine and found that they are sufficient to account for the TxA
2
receptor–independent component of the acetylcholine-induced contraction. Thus, we propose that PGI
2
released in response to acetylcholine may serve as the endothelium-derived contracting factor that elicits the TxA
2
/PGH
2
receptor–independent and -dependent components of the acetylcholine-induced contraction.
Possible Involvement of Phospholipase D and Protein Kinase C in Vascular Growth Induced by Elevated Glucose Concentration
Authors: Yasunari Kenichi , Kohno Masakazu , Kano Hiroaki , Yokokawa Koji , Horio Takeshi , Yoshikawa Junichi
Published: June 2012

Hyperglycemia is believed to be a major cause of diabetic vascular complications. To elucidate the effect of hyperglycemia on vascular response, we studied hyperproliferation, hypertrophy, and the natriuretic peptide response of vascular smooth muscle cells under high-glucose conditions. We observed that cells cultured in high glucose (22.2 mmol/L) showed hyperproliferation and hypertrophy and that natriuretic peptide receptor responses were suppressed compared with cells cultured in normal glucose (5.6 mmol/L). We also examined phospholipase D and protein kinase C activities and found that in high-glucose conditions such activities are higher than in cells cultured in normal glucose. The activation of phospholipase D was not prevented by coincubation with 1 μmol/L protein kinase C(19-36), a specific protein kinase C inhibitor, but the activation of protein kinase C was. Protein kinase C(19-36) also markedly attenuated vascular hyperproliferation and hypertrophy as well as glucose-induced suppression of natriuretic peptide receptor response. These results show that hyperglycemia may be linked to vascular hyperproliferation, hypertrophy, and a suppressed natriuretic peptide receptor response, which are caused by increased phospholipase D and protein kinase C activities.
Characterization of the Renal Phenotype of Transgenic Rats Expressing the Human Endothelin-2 Gene
Authors: Hocher Berthold , Liefeldt Lutz , Thöne-Reineke Christa , Orzechowski Hans-Dieter , Distler Armin , Bauer Christian , Paul Martin
Published: June 2012

We have previously established a transgenic rat model termed TGR(hET-2)37 overexpressing the human endothelin-2 (ET-2) gene with high renal transgene expression. This renal overexpression is of pathophysiological interest because a long-term activated paracrine renal endothelin system has been implicated in chronic renal failure due to progressive glomerular injury. Therefore, our aim in the present study was to analyze renal transgene expression in detail and address the question of whether transgene expression causes phenotypic and functional changes in the kidney. We used reverse transcription-polymerase chain reaction and in situ hybridization techniques for transgene expression analysis. Tissue ET-2 concentrations were measured with a specific radioimmunoassay. For histological evaluation of renal tissue, all samples were subjected to hematoxylin-eosin and periodic acid-Schiff staining. Renal tissue ET-2 concentrations were significantly increased in TGR(hET-2)37 rats. Using in situ hybridization, we found that the human ET-2 gene was almost exclusively expressed within the glomeruli. The glomerular transgene expression resulted in a significantly increased glomerular injury score and likewise in a significantly increased protein excretion, whereas glomerular filtration rate was not altered. Blood pressure was similar in TGR(hET-2)37 rats and age-matched controls, suggesting that the local changes in the kidney were correlated with paracrine endothelin actions. In conclusion, our study revealed that the major renal expression site of the human ET-2 transgene in TGR(hET-2)37 rats was within the glomeruli and caused the development of glomerulosclerosis with significantly increased protein excretion that is independent of blood pressure. We suggest that TGR(hET-2)37 rats are a new monogenetic animal model for study of the paracrine renal endothelin system and its involvement in renal pathophysiology.
Hypertension in Adult American Indians
Authors: Howard Barbara V. , Lee Elisa T. , Yeh Jeunliang L. , Go Oscar , Fabsitz Richard R. , Devereux Richard B. , Welty Thomas K.
Published: June 2012

Hypertension is a primary risk factor for cardiovascular disease in the United States. Although cardiovascular disease is the leading cause of death among American Indians, the prevalence of hypertension, its awareness and control, and its association with other cardiovascular disease risk factors and physiological variables have not been well studied in this population. The Strong Heart Study is a longitudinal study of cardiovascular disease and its risk factors in American Indians. Participants (2703 women and 1846 men) were members of 13 tribes in central Arizona, southwestern Oklahoma, and regions of South and North Dakota. At least 1500 individuals between 45 and 74 years of age participated from each center in a baseline clinical examination conducted between July 1989 and January 1992. The examination consisted of a personal interview and physical examination that included an oral glucose tolerance test and three consecutive blood pressure measurements. This study reports data from the baseline examination on the prevalence of hypertension and correlates of blood pressure. Results indicated that despite the high frequency of diabetes and obesity, prevalence rates of hypertension in Arizona and Oklahoma were similar to those in the US population in the Third National Health and Nutrition Examination Survey (NHANES III), and rates among South/North Dakota participants were significantly lower (
P
<.0001). Blood pressure was higher in individuals with diabetes (
P
<.0001) and was significantly correlated with age (
P
<.0001) and albuminuria (
P
<.0001) but only weakly related to obesity. There was no independent relation between blood pressure and insulin. Blood pressure seems to be less affected by obesity and hyperinsulinemia in American Indians compared with other populations. Nevertheless, hypertension should be aggressively treated and controlled in American Indians because it is a known precursor to morbidity and mortality associated with diabetes and cardiovascular disease.
Influence of Obesity on Left Ventricular Midwall Mechanics in Arterial Hypertension
Authors: de Simone Giovanni , Devereux Richard B. , Mureddu Gian Francesco , Roman Mary J. , Ganau Antonello , Alderman Michael H. , Contaldo Franco , Laragh John H.
Published: June 2012

The evaluation of the effect of obesity on left ventricular systolic performance may differ in relation to the method used to measure left ventricular function and to the type of study population. Whether obesity worsens left ventricular midwall mechanics in arterial hypertension has never been investigated. Accordingly, we assessed echocardiographic left ventricular midwall shortening–circumferential end-systolic stress relations in 156 normotensive and normal-weight (reference) adults, 94 normotensive and overweight (1985 National Institutes of Health partition values) to obese (body mass index >30 kg/m
2
) adults, 263 hypertensive and normal-weight adults, and 224 hypertensive and overweight-to-obese adults. There was an inverse relation of midwall shortening to circumferential end-systolic stress in all groups (all
P
<.005). Left ventricular performance as a ratio of observed to predicted midwall shortening fell below the fifth percentile in 4 of 94 (4%) of overweight-to-obese normotensive individuals. Eighty-eight of 487 hypertensive subjects (18.1%) exhibited depressed midwall shortening as a percentage of the value predicted from wall stress, with no difference between normal-weight (50 of 263 [19%]) and overweight (38 of 224 [17%]) subjects. Sixty-one normotensive and 131 hypertensive subjects were frankly obese. After adjustment for sex and age, midwall shortening, as either absolute values or a percentage of predicted, was not statistically different among obese, overweight, and normal-weight subjects in both normotensive and hypertensive groups. For each quartile of observed-to-predicted midwall shortening ratio, obese subjects had greater left ventricular end-diastolic volume than normal-weight subjects among both normotensive and, more evidently, hypertensive subjects. A predicted midwall shortening was generated from both wall stress and left ventricular volume with the use of multiple regression analysis. High body mass index, mean blood pressure, aging, and male sex independently predicted low afterload and left ventricular volume–independent midwall left ventricular performance (multiple
R
=.31,
P
<.0001). Thus, (1) midwall left ventricular systolic performance in asymptomatic overweight or frankly obese individuals is comparable to that in normal-weight individuals in both the presence and absence of arterial hypertension; (2) however, maintenance of normal left ventricular performance in obese individuals is associated with the use of Starling reserve; and (3) this compensatory mechanism is especially evident when arterial hypertension and obesity coexist.
Hypotensive Effect of a Newly Identified Peptide, Proadrenomedullin
N
-Terminal 20 Peptide
Authors: Shimosawa Tatsuo , Fujita Toshiro
Published: June 2012

Proadrenomedullin
N
-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are both derived from proadrenomedullin, exhibit marked hypotensive effects. We recently reported that PAMP but not AM reduced the release of norepinephrine from peripheral sympathetic nerve endings. Our present objective was to clarify the involvement of the sympathetic nervous system in the hypotensive action of PAMP and AM. Intravenous administration of PAMP (10, 20, and 50 nmol/kg) to conscious rats induced less reflex tachycardia (5±5, 10±5, and 14±6 beats per minute [bpm]) than that of AM in 0.1, 0.5, and 1.0 nmol/kg doses (5±8, 20±7, and 38±5 bpm,
P
<.01) although both agents showed similar hypotensive effects. We evaluated the effect of PAMP on blood pressure in pithed rats whose sympathetic nervous systems were abolished. In pithed rats, AM (−2±1, −7±1, and −10±3 mm Hg; NS,
P
<.05, and
P
<.01, respectively) but not PAMP evoked hypotension. In contrast, administration of PAMP (−3±1, −11±2, and −14±4 mm Hg;
P
<.05,
P
<.01, and
P
<.01, respectively) as well as adrenomedullin (−2±2, −10+3, and −15±4 mm Hg; NS,
P
<.01, and
P
<.01) significantly reduced blood pressure in electrically stimulated, pithed rats, which had reached almost the same levels as in conscious rats. In electrically stimulated, pithed rats, plasma norepinephrine level was reduced by PAMP but not by vehicle or AM. These findings suggest that the hypotensive effect of PAMP is mainly due to inhibition of peripheral sympathetic nerve activity.
Cyclic Strain Enhances Adhesion of Monocytes to Endothelial Cells by Increasing Intercellular Adhesion Molecule-1 Expression
Authors: Cheng Jing-Jy , Wung Being-Sun , Chao Yeun-Jen , Wang Danny Ling
Published: June 2012

Since endothelial cells are constantly subjected to pressure-induced strain, we examined how cyclic strain affects the expression of intercellular adhesion molecule-1 (ICAM-1). Endothelial cells grown on a flexible membrane base were deformed by different sinusoidal negative pressures (−10, −15, or −20 kPa) to produce an average strain of 9%, 11%, and 12%, respectively, for various times. The release of the soluble form of ICAM-1 from strained endothelial cells increased in a time- and strain-dependent manner. Using flow cytometric analysis, we showed the induction of ICAM-1 expression on the endothelial cell surface to depend on both time and the amount of strain. Northern blot analysis revealed a sustained, approximately 1.8-fold increase in ICAM-1 mRNA levels in 11% strained cells. Strain-induced expression of ICAM-1 correlated with a strain-dependent increase in adhesion of monocytic cells to strained cells. This increase in monocytic cell adhesion could be partially inhibited by pretreatment of strained cells with antibody to ICAM-1. These results indicate that mechanical strain can stimulate the expression of ICAM-1 by endothelial cells and thus contribute to the increased adhesion of monocytes to strained cells. Such strain-induced expression of ICAM-1 may contribute to the trapping of monocytes on local vascular walls where strain is high and to the initiation of atherogenesis, thus providing a possible link between hypertension and atherogenesis.