bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Sinoaortic Deafferentation on Renal Wrap Hypertension
Authors: VanNess J. Mark , Hinojosa-Laborde Carmen , Craig Teresa , Haywood Joseph R.
Published: June 2012

Abstract
—The purpose of this study was to determine whether sinoaortic deafferentation (SAD) alters the severity of hypertension or sympathoadrenal contribution to mean blood pressure (MAP) during renal wrap hypertension. Male Sprague-Dawley rats were implanted with radiotelemetry transmitters for 24-hour recording of MAP and heart rate. All rats underwent either SAD or sham SAD (Intact) surgery and were allowed to recover for 10 to 14 days. The rats were then assigned to a normotensive (Sham) group or a hypertensive (Wrap) group in which 1-kidney figure-8 renal wrap was performed. SAD increased the acute MAP response to renal wrap (Intact-Sham=5±1 mm Hg, Intact-Wrap=45±3 mm Hg, SAD-Sham=3±3 mm Hg, SAD-Wrap=58±4 mm Hg) and increased the lability of MAP (SD of MAP; Intact-Sham=3.8±0.2, Intact-Wrap=4.2±0.3, SAD-Sham=9.6±1.4, SAD-Wrap=9.7±1.4). MAP was not different between SAD and Intact rats during 4 weeks after renal wrap or sham surgery; however, induction of hypertension produced additional MAP variability that was independent of SAD (Intact-Sham=4.6±0.4, Intact-Wrap=6.2±0.6, SAD-Sham=6.3±0.5, SAD-Wrap=10.8±1.5). In a separate group of rats, the sympathoadrenal contribution to MAP was assessed by the depressor response to ganglionic blockade and plasma norepinephrine at rest and after neuronal uptake inhibition with desipramine. The depressor response to ganglionic blockade was significantly increased by renal wrap and by SAD (Intact-Sham=−49±2 mm Hg, Intact-Wrap=−73±4 mm Hg, SAD-Sham=−77±5 mm Hg, SAD-Wrap=−96±6 mm Hg). In the 3 groups with enhanced ganglionic blockade responses, desipramine caused a significant increase in plasma norepinephrine. These results indicate that SAD does not alter the development of renal wrap hypertension but does increase the sympathoadrenal contribution to MAP in both normotensive and hypertensive animals.
Selective Inhibition of the Renal Dopamine Subtype D
1A
Receptor Induces Antinatriuresis in Conscious Rats
Authors: Wang Zhi-Qin , Felder Robin A. , Carey Robert M.
Published: June 2012

Abstract
—Both dopamine D
1
-like (D
1A
and D
1B
) and D
2
-like (D
2
, D
3
, and D
4
) receptor subfamilies are present in the kidney. Blockade of the intrarenal D
1
-like receptor family is associated with natriuresis and diuresis. Because the D
1A
and D
1B
receptor subtypes are not distinguishable by currently available dopaminergic agents, their functional role remains undefined. In the present study, the effect of selective inhibition of the renal D
1A
receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) was investigated in conscious uninephrectomized rats. After renal interstitial administration of Texas red–labeled D
1A
receptor AS-ODN, intense fluorescent signal was localized in the renal tubular epithelium and vasculature. In rats on normal salt intake, AS-ODN injected interstitially into the kidney reduced daily urinary sodium excretion (1.4±0.04 versus 0.8±0.2 mEq/d, n=5,
P
<0.05) and urine output (16.9±3.8 versus 12.5±3.6 mL/d, n=5,
P
<0.05). In rats on high sodium intake, continuous renal interstitial administration of D
1A
receptor AS-ODN transiently decreased daily urinary sodium excretion (5.4±0.5 versus 4.2±0.3 mEq/d, n=7,
P
<0.01) and urine output (27.6±4.5 versus 18.1±1.8 mL/d, n=7,
P
<0.01). Neither vehicle nor sense oligodeoxynucleotide had significant effects. Systolic blood pressure remained unchanged. The renal D
1A
receptor protein was significantly decreased by 35% and 46% at the end of the study in AS-ODN–treated rats on normal and high salt intake, respectively, whereas the D
1B
receptor and β-actin were not affected. These results provide the first direct evidence that the renal D
1A
receptor subtype plays an important role in the control of sodium excretion.
Kidney Aminopeptidase A and Hypertension, Part II
Authors: Song Lijun , Healy Dennis P.
Published: June 2012

Abstract
—Aminopeptidase A (APA) is the principal enzyme that metabolizes angiotensin II (Ang II) to angiotensin III. Previously, we showed that kidney APA was elevated in spontaneously hypertensive rats and was reduced after angiotensin-converting enzyme inhibition. In the present study, we sought to determine whether kidney APA expression was altered after chronically elevated Ang II, either exogenously delivered via osmotic minipumps or endogenously produced in two-kidney, one clip (2K1C) hypertensive rats. Ang II (200 ng · kg
−1
· min
−1
) was infused subcutaneously for 1 or 2 weeks by osmotic minipumps, and 2K1C rats were tested 4 weeks after unilateral renal artery clipping. Blood pressure was not significantly elevated in the Ang II–infused animals but was significantly increased at 3 and 4 weeks in the 2K1C animals. APA was significantly elevated approximately 2-fold in kidney cortical membranes from Ang II–infused animals but was decreased 45% in the clipped kidney and 18% in the nonclipped kidneys from 2K1C animals. Isolated glomeruli from Ang II–infused animals and the nonclipped kidneys from 2K1C animals had markedly higher APA activity and immunoreactivity. Likewise, histochemical and immunohistochemical studies indicated that APA levels were increased in glomeruli from angiotensin-infused animals and in both nonclipped and clipped kidneys from 2K1C animals. In contrast, tubular APA was decreased in tubular elements from 2K1C animals, most markedly in the clipped kidneys. Thus, despite the increase in glomerular APA expression in kidneys from 2K1C animals, the decrease in tubular APA expression is more extensive and accounts for the measured reduction in total APA in cortical homogenates. Because clipped kidneys are not exposed to high blood pressure, these results suggest that glomerular APA expression is positively regulated and tubular APA negatively regulated by Ang II. These results further suggest that changes in kidney APA expression could influence the progression of angiotensin-dependent hypertension.
Renal Changes on Hyperglycemia and Angiotensin-Converting Enzyme in Type 1 Diabetes
Authors: Marre Michel , Bouhanick Béatrice , Berrut Gilles , Gallois Yves , Le Jeune Jean-Jacques , Chatellier Gilles , Menard Joël , Alhenc-Gelas François
Published: June 2012

Abstract
—Hyperglycemia causes capillary vasodilation and high glomerular capillary hydraulic pressure, which lead to glomerulosclerosis and hypertension in type 1 diabetic subjects. The insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme (ACE) gene can modulate risk of nephropathy due to hyperglycemia, and the II genotype (producing low plasma ACE concentrations and probably reduced renal angiotensin II generation and kinin inactivation) may protect against diabetic nephropathy. We tested the possible interaction between ACE I/D polymorphism and uncontrolled type 1 diabetes by measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during normoglycemia (≈5 mmol/L) and hyperglycemia (≈15 mmol/L) in 9 normoalbuminuric, normotensive type 1 diabetic subjects with the II genotype and 18 matched controls with the ID or DD genotype. Baseline GFR (145±22 mL/min per 1.73 m
2
) and ERPF (636±69 mL/min per 1.73 m
2
) of II subjects declined by 8±10% and 10±9%, respectively, during hyperglycemia; whereas baseline GFR (138±16 mL/min per 1.73 m
2
) and ERPF (607±93 mL/min per 1.73 m
2
) increased by 4±7% and 6±11%, respectively, in ID and DD subjects (II versus ID or DD subjects:
P
=0.0007 and
P
=0.0005, for GFR and ERPF, respectively). The changes in renal hemodynamics of subjects carrying 1 or 2 D alleles were compatible, with a mainly preglomerular vasodilation induced by hyperglycemia, proportional to plasma ACE concentration (
P
=0.024); this was not observed in subjects with the II genotype. Thus, type 1 diabetic individuals with the II genotype are resistant to glomerular changes induced by hyperglycemia, providing a basis for their reduced risk of nephropathy.
Diastolic Compliance Is Reduced in Obese Rabbits
Authors: Carroll Joan F. , Summers Richard L. , Dzielak David J. , Cockrell Kathy , Montani Jean-Pierre , Mizelle H. Leland
Published: June 2012

Abstract
—Obesity often leads to symptoms of cardiopulmonary congestion associated with normal systolic but abnormal diastolic function. This study analyzed alterations in passive diastolic compliance in obesity using the rabbit model. New Zealand White rabbits were fed a normal (n=8) or 10% added fat diet (n=8). After 12 weeks, rabbits fed the high fat diet developed obesity (5.34±0.11 versus 3.68±0.04 kg,
P
≤0.05) and left ventricular hypertrophy (1.37±0.07 versus 0.98±0.03 g dry weight,
P
≤0.05). Compliance was assessed with the isolated heart preparation by analyzing the passive end-diastolic left ventricular pressure-volume relationship. The pressure-volume relation was fit to an exponential function by regression analysis; results showed that the modulus of stiffness was greater in obese than in lean rabbits (1.21±0.16 versus 0.83±0.05,
P
≤0.05), indicating that diastolic compliance was reduced. Computer simulation analyses suggested that an isolated reduction in diastolic compliance may contribute to elevated cardiac filling pressures and exercise intolerance. These data suggest that diastolic compliance is reduced early in the development of obesity and may be an important component in the reduction of cardiac reserve in obesity.
Human Renin mRNA Stability Is Increased in Response to cAMP in Calu-6 Cells
Authors: Sinn Patrick L. , Sigmund Curt D.
Published: June 2012

Abstract
—The human carcinoma–derived cell line Calu-6 has previously been demonstrated to endogenously express human renin (hREN) mRNA and to markedly increase steady-state hREN mRNA levels (100-fold after 24 hours) in response to analogues of cAMP and postreceptor activators of adenylyl cyclase such as forskolin. However, both transfection analysis using hREN promoter-reporter constructs and nuclear run-on experiments suggest that transcriptional activity alone cannot account for this level of induction. We performed primer extension, reverse transcription–polymerase chain reaction, and 3′ rapid amplification of cDNA ends to compare hREN mRNA between unstimulated and forskolin-stimulated cells. We demonstrate that hREN mRNA is identical under both conditions with respect to (1) utilization of the appropriate transcription start site, (2) processing of renin mRNA, and (3) utilization of the proper polyadenylation site and length of the poly-A tail. To address the mechanism of induction caused by cAMP, we used transcriptional inhibition and measured decay of hREN mRNA before and after forskolin or phorbol ester treatment. Experiments with both actinomycin D and 5,6-dichlororibofuranosylbenzimidazole (DRB) showed that forskolin treatment markedly stabilized hREN mRNA in Calu-6 cells. A 2.3-fold increase in hREN mRNA half-life was also observed after treatment of Calu-6 cells with phorbol ester. Experiments with DRB demonstrated a similar robust stabilization of hREN mRNA after forskolin and phorbol ester treatment. These data demonstrate that the induction in hREN mRNA in response to both cAMP and phorbol ester occurs by a mechanism involving a posttranscriptional component.
Blood Pressure, Sodium Intake, Insulin Resistance, and Urinary Nitrate Excretion
Authors: Facchini Francesco S. , DoNascimento Carlos , Reaven Gerald M. , Yip Jeannie W. , Ni Xi Ping , Humphreys Michael H.
Published: June 2012

Abstract
—The objective of this study was to investigate the relationships among various humoral factors thought to be involved in the regulation of blood pressure during high NaCl intake. Nineteen healthy subjects underwent sequential 5-day periods ingesting a low-sodium (25 mmol/d) or high-sodium (200 mmol/d) diet. Insulin resistance was assessed by the steady-state plasma glucose concentration at the end of a 3-hour insulin suppression test. Insulin resistance correlated inversely with natriuresis (
P
=0.04) and directly with increase in weight (
P
=0.03). The increase in mean arterial pressure associated with the high-sodium diet correlated directly with the gain in weight (
P
<0.05) and inversely with the increase in urinary nitrate excretion (
P
<0.0001). In a multiple regression model, more than 2/3 of the variance in mean arterial pressure was accounted for by the gain in weight and change in urinary nitrate excretion. The steady-state plasma glucose concentrations obtained with the 2 diets were similar, indicating that insulin resistance was unaffected by sodium intake. During high sodium intake, plasma renin activity and aldosterone decreased and plasma atrial natriuretic peptide increased; these changes did not correlate with the change in mean arterial pressure, insulin resistance, or change in urinary nitrate excretion. To the extent that urinary nitrate excretion reflects activity of the endogenous nitric oxide system, these results suggest that the salt sensitivity of mean arterial pressure may be related to blunted generation of endogenous nitric oxide. The results also demonstrate that insulin-resistant individuals have an impaired natriuretic response to high sodium intake.
Epithelial Sodium Channel Activity Is Not Increased in Hypertension in Whites
Authors: Baker Emma H. , Portal A. James , McElvaney Teresa A. , Blackwood Alison M. , Miller Michelle A. , Markandu Nirmala D. , MacGregor Graham A.
Published: June 2012

Abstract
—Abnormal renal sodium transport causing excess reabsorption of sodium may be one mechanism that causes high blood pressure. For example, increased activity of epithelial sodium channels in the distal tubule is the cause of high blood pressure in Liddle’s syndrome, a rare familial form of hypertension. We have shown that the increase in sodium channel activity can be detected in the nose using transepithelial potential difference measurements in 1 family with Liddle’s syndrome. We therefore used nasal potential difference measurements to look for increased sodium channel activity in white patients with essential hypertension. Transnasal potential difference was measured in 42 white hypertensive (HT) subjects and 38 white normotensive (NT) subjects before and after topical application of 10
−4
mol/L of amiloride. There was no difference in maximum potential between HT and NT subjects (HT, −18.8±0.9 mV; NT, −18.2±1.0 mV) (values mean±SEM; lumen-negative with respect to the submucosa). However, the postamiloride potential was significantly higher (HT, −12.6±0.7 mV; NT, −10.5±0.7 mV;
P
=0.015) and the change in potential in response to amiloride significantly lower (HT, 6.2±0.5 mV, 33.1±2.0%; NT, 7.7±0.6 mV, 41.9±2.0%;
P
=0.046 and 0.003, respectively) in HT than in NT subjects. These results suggest that sodium channel activity is not increased in whites with essential hypertension and indicate that sodium channel overactivity similar to that seen in Liddle’s syndrome is unlikely to be the cause of high blood pressure in this group. Increased postamiloride potential may reflect increased activity of chloride channels or amiloride-insensitive sodium channels.
Arterial Baroreflex Control of the Sinus Node During Dobutamine Exercise Stress Testing
Authors: van de Borne Philippe , Heron Shirley , Nguyen Hung , Unger Philippe , Leeman Marc , Vincent Jean Louis , Degaute Jean Paul
Published: June 2012

Abstract
—The contributions of increases in circulating catecholamines, changes in central command, and muscle afferents on baroreflex control of the sinus node during exercise are unclear. We used a dobutamine infusion to induce hemodynamic changes comparable to those of moderate physical exercise in the absence of changes in central command and muscle afferents in 13 healthy subjects. Dobutamine (up to 9 μg/kg body weight per minute) increased systolic blood pressure, shortened the RR interval, increased systolic blood pressure variability, but blunted RR interval variability (
P
<0.05 versus placebo). Consequently, dobutamine decreased the coherence between variations in systolic blood pressure and RR interval and decreased arterial baroreflex sensitivity from 12±2 to 3±1 ms/mm Hg (
P
<0.01). The largest increases in systolic blood pressure with dobutamine were paralleled by the greatest impairments in arterial baroreflex sensitivity (0.50<
r
<0.56,
P
<0.01). The chronotropic effects of dobutamine prevented a reflex bradycardia in response to the blood pressure increase. However, less predominant low-frequency oscillations in systolic blood pressure (
P
<0.0001) suggested preserved sympathetic withdrawal in response to the blood pressure increase induced by dobutamine. In conclusion, this study revealed that a shift in the operating point of the arterial baroreceptors and the chronotropic effects of adrenergic stimulation impair baroreflex control of the sinus node during dobutamine exercise stress testing. Baroreflex control of the sinus node is not reset when hemodynamic characteristics of exercise are reproduced in the absence of modifications in central command and muscles afferents.
Role of Increased Production of Superoxide Anions by NAD(P)H Oxidase and Xanthine Oxidase in Prolonged Endotoxemia
Authors: Brandes Ralf P. , Koddenberg Guido , Gwinner Wilfried , Kim Do-yei , Kruse Hans-Joachim , Busse Rudi , Mügge Andreas
Published: June 2012

Abstract
—Superoxide anions (O
2
−
) are supposedly involved in the pathogenesis of endothelial dysfunction. We investigated whether the enhanced formation of O
2
−
is involved in the attenuation of endothelium-dependent relaxation induced by lipopolysaccharide (LPS). Rats were injected with LPS (10 mg/kg IP), the aorta was removed after 12 or 30 hours, and generation of O
2
−
, H
2
O
2
, and ONOO
−
was measured using chemiluminescence assays. Protein tyrosine nitration and expression of xanthine oxidase (XO), NAD(P)H oxidase, and manganese superoxide dismutase were determined by Western or Northern blotting, and endothelium-dependent relaxation in aortic rings was studied. LPS treatment increased vascular O
2
−
(from 35±2 cpm/ring at baseline to 166±21 cpm/ring at 12 hours and 225±16 cpm/ring at 30 hours) and H
2
O
2
formation, which was partially sensitive to the NAD(P)H oxidase inhibitor diphenylene iodonium at both time points studied and to the XO inhibitor oxypurinol only 30 hours after LPS treatment. Expression of XO and NAD(P)H oxidase (p22phox, p67phox, and gp91phox) were increased by LPS in a time-dependent manner, as were protein tyrosine nitration and ONOO
−
formation. LPS also induced expression of the oxidative stress–sensitive protein manganese superoxide dismutase. Endothelium-dependent relaxation was impaired after LPS treatment and could not be restored by inhibition of inducible NO synthase. Inhibition of O
2
−
with superoxide dismutase, oxypurinol, tiron, or the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride did not restore but further deteriorated the relaxation of LPS-treated rings. In summary, treatment of rats with LPS enhances vascular expression of XO and NAD(P)H oxidase and increases formation of O
2
−
and ONOO
−
. Because removal of O
2
−
compromised rather than restored endothelium-dependent relaxation, a direct role of O
2
−
in the induction of endothelial dysfunction is unlikely. Other mechanisms, such as prolonged protein tyrosine nitration by peroxynitrite (which is formed from NO and O
2
−
) or downregulation of the NO effector pathway, are more likely to be involved.
Therapeutic Angiogenesis Induced by Human Recombinant Hepatocyte Growth Factor in Rabbit Hind Limb Ischemia Model as Cytokine Supplement Therapy
Authors: Morishita Ryuichi , Nakamura Shigefumi , Hayashi Shin-ichiro , Taniyama Yoshiaki , Moriguchi Atsushi , Nagano Tomokazu , Taiji Mutsuo , Noguchi Hiroshi , Takeshita Satoshi , Matsumoto Kunio , Nakamura Toshikazu , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells and acts as a survival factor against endothelial cell death. Therefore we hypothesized that a decrease in local vascular HGF might be related to the pathogenesis of peripheral arterial disease. We initially evaluated vascular HGF concentration in the vessels of patients with arteriosclerosis obliterans. Consistent with in vitro findings that hypoxia downregulated vascular HGF production, vascular HGF concentration in the diseased segments of vessels from patients with arteriosclerosis obliterans was significantly decreased as compared with disease-free segments from the same patients (
P
<0.05), accompanied by a marked reduction in HGF mRNA. On the other hand, a novel therapeutic strategy for ischemic diseases that uses angiogenic growth factors to expedite and/or augment collateral artery development has recently been proposed. Thus in view of the decreased endogenous vascular HGF, rhHGF (500 μg/animal) was intra-arterially administered through the internal iliac artery of rabbits in which the femoral artery was excised to induce unilateral hind limb ischemia, to evaluate the angiogenic activity of HGF, which could potentially have a beneficial effect in hypoxia. Administration of rhHGF twice on days 10 and 12 after surgery produced significant augmentation of collateral vessel development on day 30 in the ischemic model as assessed by angiography (
P
<0.01). Serial angiograms revealed progressive linear extension of collateral arteries from the origin stem artery to the distal point of the reconstituted parent vessel in HGF-treated animals. In addition, we examined the feasibility of intravenous administration of rhHGF in a moderate ischemia model. Importantly, intravenous administration of rhHGF also resulted in a significant increase in angiographic score as compared with vehicle (
P
<0.01). Overall, a decrease in vascular HGF might be related to the pathogenesis of peripheral arterial disease. In the presence of decreased endogenous HGF, administration of rhHGF induced therapeutic angiogenesis in the rabbit ischemic hind limb model, as potential cytokine supplement therapy for peripheral arterial disease.
Altered Pressure-Natriuresis in Obese Zucker Rats
Authors: Fujiwara Keiji , Hayashi Koichi , Matsuda Hiroto , Kubota Eiji , Honda Masanori , Ozawa Yuri , Saruta Takao
Published: June 2012

Abstract
—It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0±4.0×10
−8
, n=9) and blood pressure (119±3 mm Hg) were greater than those in lean Zucker rats (LZ; 7.0±1.9×10
−8
and 103±4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073±0.015 vs 0.217±0.047 μEq/min kidney weight/mm Hg,
P
<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032±0.331 μmol/L; medulla, 4.329±0.515 μmol/L) compared with that in LZ (cortex, 7.315±1.102 μmol/L; medulla: 7.698±0.964 μmol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639±0.286 μmol/L; medulla, 5.978±0.284 μmol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure-natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.
Induction of Interleukin-6 Expression by Angiotensin II in Rat Vascular Smooth Muscle Cells
Authors: Funakoshi Yuko , Ichiki Toshihiro , Ito Kiyoko , Takeshita Akira
Published: June 2012

Abstract
—Recent studies suggest that atherosclerosis is a kind of inflammatory process and that cytokine plays important roles in this process. Although it is generally accepted that angiotensin II (Ang II) plays an important role in atherogenesis, the role of Ang II in cytokine production has not been explored. In this report, we investigated the effect of Ang II on the production of interleukin-6 (IL-6), which is a multifunctional proinflammatory cytokine in rat vascular smooth muscle cells. Ang II significantly increased the expression of IL-6 mRNA and protein in a dose-dependent manner (10
−10
to 10
−6
mol/L). The expression of IL-6 mRNA induced by Ang II showed 2 peaks at 30 minutes and 12 to 24 hours after stimulation. The effect of Ang II on IL-6 release and mRNA expression was completely blocked by an Ang II type 1 receptor antagonist, CV11974; however, an Ang II type 2 receptor antagonist, PD123319, showed no effect. Chelating of intracellular Ca
2+
with BAPTA-AM, inhibition of tyrosine kinase with genistein, and inhibition of mitogen-activated protein kinase kinase with PD98059 completely abolished the effect of Ang II. However, downregulation of protein kinase C by pretreatment with a phorbol ester for 24 hours or a specific protein kinase C inhibitor, calphostin C, did not affect the Ang II–induced expression of IL-6 mRNA. Deletion and mutational analysis of IL-6 gene promoter showed that cAMP-responsive element was important for Ang II–induced IL-6 gene expression. Gel mobility shift assay showed an increase of cAMP-responsive element binding protein by Ang II. These results provide new insights into Ang II signaling and the role of Ang II in the progression of inflammatory changes of blood vessels.
Torasemide Inhibits Angiotensin II–Induced Vasoconstriction and Intracellular Calcium Increase in the Aorta of Spontaneously Hypertensive Rats
Authors: Fortuño Ana , Muñiz Paula , Ravassa Susana , Rodriguez Jose Antonio , Fortuño Ma Antonia , Zalba Guillermo , Díez Javier
Published: June 2012

Abstract
—Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)–induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II–induced increases of intracellular free calcium concentration ([Ca
2+
]
i
) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10
−9
to 10
−6
mol/L) in endothelium-denuded aortic rings (pD
2
=7.5±0.3). Isometric contraction induced by a submaximal concentration of Ang II (10
−7
mol/L) was reduced in a dose-dependent way by torasemide (IC
50
=0.5±0.04 μmol/L). Incubation of VSMCs with different concentrations of Ang II (from 10
−10
to 10
−6
mol/L) resulted in a dose-dependent rise of [Ca
2+
]
i
(pD
2
=7.5±0.3). The stimulatory effect of [Ca
2+
]
i
induced by a submaximal concentration of Ang II (10
−7
mol/L) was blocked by torasemide (IC
50
=0.5±0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca
2+
]
i
induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo.
Exercise Training-Induced Blood Pressure and Plasma Lipid Improvements in Hypertensives May Be Genotype Dependent
Authors: Hagberg James M. , Ferrell Robert E. , Dengel Donald R. , Wilund Kenneth R.
Published: June 2012

Abstract
—Exercise training improves cardiovascular disease risk, but individual responses are highly variable. We hypothesized that common polymorphic gene variations would affect these responses. Sedentary obese hypertensive older men who had undergone exercise training were typed at the apolipoprotein (apo) E, angiotensin-converting enzyme (ACE), and lipoprotein lipase (LPL) loci. Individuals of all genotype subgroups were generally similar before training; they also changed body weight, body composition, and V̇
o
2
max similarly with training. ACE insertion/insertion (II) and insertion/deletion (ID) genotype individuals (n=10) tended to reduce systolic blood pressure more with training than deletion/deletion (DD) individuals (n=8) (−10 versus −5 mm Hg,
P
=0.16). ACE II and ID individuals decreased diastolic blood pressure more with training than DD individuals (−10 versus −1 mm Hg,
P
<0.005). Systolic blood pressure reductions with training were also larger in apoE3 and E4 (n=15) than apoE2 men (n=3) (−10 versus 0 mm Hg,
P
<0.05). The same trend was evident for diastolic blood pressure (−7 versus −3 mm Hg), but the difference was not significant. Systolic (14 versus −6 mm Hg,
P
=0.08) and diastolic (−9 versus −5 mm Hg,
P
=0.10) blood pressure reductions tended to be greater in LPL
Pvu
II +/+ (n=4) than +/− and −/− individuals (n=14). Systolic (−10 versus 3 mm Hg,
P
<0.05) and diastolic (−9 versus 2 mm Hg,
P
<0.05) blood pressure reductions were larger in LPL
Hind
III +/+ and +/− (n=15) than −/− persons (n=3), respectively. LPL
Pvu
II −/− individuals (n=3) had larger increases in HDL cholesterol (11 versus 2 mg/dL,
P
<0.05) and HDL
2
cholesterol (8 versus 0 mg/dL,
P
<0.05) than LPL
Pvu
II +/− and +/+ individuals (n=15). These results are consistent with the possibility that apoE, ACE, and LPL genotypes may identify hypertensives who will improve blood pressure, lipoprotein lipids, and cardiovascular disease risk the most with exercise training.
Angiotensin-Converting Enzyme Inhibition Modifies Angiotensin but Not Kinin Peptide Levels in Human Atrial Tissue
Authors: Campbell Duncan J. , Duncan Ann-Maree , Kladis Athena
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes bradykinin and kallidin peptides. Decreased Ang II levels and increased kinin peptide levels are implicated in the mediation of the therapeutic effects of ACE inhibition. However, alternative non-ACE pathways of Ang II formation have been proposed to predominate in human heart. We investigated the effects of ACE inhibition on cardiac tissue levels of angiotensin and kinin peptides. High-performance liquid chromatography–based radioimmunoassays were used to measure angiotensin peptides and hydroxylated and nonhydroxylated bradykinin and kallidin peptides in right atrial appendages of subjects who had been prepared for cardiopulmonary bypass. Peptide levels in subjects who received ACE inhibitor therapy were compared with those who did not receive ACE inhibitor therapy. ACE inhibition reduced Ang II levels, which was associated with an 80% reduction in the Ang II/Ang I ratio. ACE inhibition did not modify either bradykinin or kallidin peptide levels or the bradykinin-(1-7)/bradykinin-(1-9) ratio. The 80% reduction in the Ang II/Ang I ratio by ACE inhibition indicated a primary role for ACE in the conversion of Ang I to Ang II in atrial tissue. These data support a role for reduced Ang II levels but do not support a role for increased kinin peptide levels in mediating the direct cardiac effects of ACE inhibition.
Inhibition of the p53 Tumor Suppressor Gene Results in Growth of Human Aortic Vascular Smooth Muscle Cells
Authors: Aoki Motokuni , Morishita Ryuichi , Matsushita Hidetsugu , Hayashi Shin-ichiro , Nakagami Hironori , Yamamoto Kei , Moriguchi Atsushi , Kaneda Yasufumi , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—Loss of activity of the p53 tumor suppressor gene product has been postulated in the pathogenesis of human restenosis. Although the antioncogenes p53 and retinoblastoma (Rb) susceptibility gene have been reported to play a pivotal role in cell cycle progression in various cells, the role of p53 and Rb in the growth of human vascular smooth muscle cells (VSMC) has not yet been clarified. We used antisense strategy against p53 and Rb genes by the viral envelope–liposomal method. Transfection of antisense p53 oligodeoxynucleotides (ODN) alone resulted in an increase in DNA synthesis compared with control (
P
<0.01). Similarly, transfection of antisense Rb ODN alone resulted in a higher DNA synthesis rate than control (
P
<0.01). Moreover, increase in VSMC number was only induced by transfection of antisense p53 ODN alone or cotransfection of p53/Rb ODN (
P
<0.01), whereas a single transfection of antisense Rb ODN had little effect on cell number. Therefore, we hypothesized that this discrepancy is due to the induction of apoptosis mediated by p53. Interestingly, apoptotic cells were markedly increased in VSMC transfected with antisense Rb ODN alone, accompanied by the induction of p53 protein. The number of apoptotic cells was attenuated by cotransfection of antisense p53 ODN (
P
<0.01). We finally examined the molecular mechanisms of apoptosis induced by the absence of Rb. In VSMC transfected with antisense Rb ODN, bax, a promoter of apoptosis, was significantly increased in VSMC transfected with antisense Rb ODN (
P
<0.01), whereas bcl-2 and Fas did not play a pivotal role in the induction of apoptosis. Overall, these data first demonstrated that the antioncogenes p53 and Rb negatively regulated the cell cycle in VSMC, suggesting that the modulation of their activity may mediate VSMC growth such as that in restenosis and atherosclerosis. The presence of p53 plays a pivotal role in the regulation of apoptosis in human VSMC growth, probably through the bax pathway. These results provide evidence that p53 is a functional link between cell growth and apoptosis in VSMC.
Effects of Aging and Antihypertensive Treatment on Aortic Internal Diameter in Spontaneously Hypertensive Rats
Authors: Giummelly Philippe , Lartaud-Idjouadiene Isabelle , Marque Valérie , Niederhoffer Nathalie , Chillon Jean-Marc , Capdeville-Atkinson Christine , Atkinson Jeffrey
Published: June 2012

Abstract
—The effect of antihypertensive treatment on the development of large-artery remodeling in young animals has been widely studied, but reversal of established changes in older hypertensive animals has been largely ignored, although the latter represents a better paradigm for the human condition. We studied the effect of treatment with captopril plus hydrochlorothiazide, from 3 months onward, on geometry and wall stress of the thoracic aorta of adult (9 months, maturation) and old (15 months, senescence) spontaneously hypertensive rats; normotensive Wistar-Kyoto rats were used as controls. At 3 months of age, blood pressure, medial cross-sectional area, and internal diameter were higher in spontaneously hypertensive rats than in Wistar-Kyoto rats. In both strains, medial cross-sectional area and lumen diameter increased during maturation; there was little change with senescence. Changes in blood pressure were minor. Because medial hypertrophy failed to compensate for the wider lumen and higher intraluminal pressure in spontaneously hypertensive rats, medial stress was higher in these rats than in Wistar-Kyoto rats. Captopril plus hydrochlorothiazide rapidly lowered blood pressure and medial cross-sectional area. Despite a marked fall in blood pressure, the internal diameter of the thoracic aorta of treated animals was similar to that of untreated animals after 6 months of treatment and started to fall only after the animals had been treated for 1 year. Thus, under treatment with captopril plus hydrochlorothiazide, medial stress remained elevated, even after very-long-term treatment, because medial cross-sectional area was not adapted to internal diameter. We suggest that some changes in large-artery structure associated with hypertension and aging, such as the increase in diameter, take considerable time to regress after blood pressure is lowered, and this may explain why, despite treatment, wall stress remains elevated.
Validity of Echocardiographic Measurement in an Epidemiological Study
Authors: Dai Shifan , Ayres Nancy A. , Harrist Ronald B. , Bricker J. Timothy , Labarthe Darwin R.
Published: June 2012

Abstract
—In Project HeartBeat!, a longitudinal study of cardiovascular disease risk factors in healthy children and adolescents, 3 samples of 40, 80, and 182 echocardiograms, respectively, were randomly selected and reread to evaluate intraobserver and interobserver variabilities and comparability between measurements of field echocardiographic technicians and reference readings at Texas Children’s Hospital. Included in the evaluation were 8 M-mode echocardiographic measurements, ie, aortic root diameter, left atrial diameter, and end-diastolic and end-systolic measurements of interventricular septal thickness, left ventricular (LV) diameter, and LV posterior wall thickness; 8 Doppler measurements; and a calculated LV mass. Means and SDs of the differences of the paired measurements were used to assess the relative bias and random error of the measurements. For the intraobserver comparison, means and SDs of the differences were very small, indicating that the echo measurements were performed consistently by each project echo technician. Interobserver comparison showed statistically but not clinically significant differences between the paired readings of end-diastolic septal thickness, end-systolic LV posterior wall thickness, and 5 Doppler measurements. Comparison with reference readings at Texas Children’s Hospital showed significant differences in diastolic LV diameter, systolic septal thickness, and right ventricular ejection time. These differences, however, were minimal with limited clinical significance. Mean differences in LV mass for the corresponding comparisons were –1.82, 4.50, and 0.0013 g, and the SDs were 18.79, 24.16, and 12.35 g, respectively. We conclude that the echocardiographic measurements taken from healthy children in a longitudinal study can be made accurately with acceptable reproducibility.
Multiple Clinic and Home Blood Pressure Measurements Versus Ambulatory Blood Pressure Monitoring
Authors: Jula Antti , Puukka Pauli , Karanko Hannu
Published: June 2012

Abstract
—To compare multiple clinic and home blood pressure (BP) measurements and ambulatory BP monitoring in the clinical evaluation of hypertension, we studied 239 middle-aged pharmacologically untreated hypertensive men and women who were referred to the study from the primary healthcare provider. Ambulatory BP monitoring was successfully completed for 233 patients. Clinic BP was measured by a trained nurse with a mercury sphygmomanometer and averaged over 4 duplicate measures. Self-recorded home BP was measured with a semiautomatic oscillometric device twice every morning and twice every evening on 7 consecutive days. Ambulatory BP was recorded with an auscultatory device. Two-dimensionally controlled M-mode echocardiography was successfully performed on 232 patients. Twenty-four–hour urinary albumin was determined by nephelometry. Clinic BP was 144.5±12.6/94.5±7.4 mm Hg, home BP (the mean of 14 self-recorded measures) was 138.9±13.1/92.9±8.6 mm Hg, home morning BP (the mean of the first 4 duplicate morning measures) was 137.1±13.7/92.4±9.2 mm Hg, daytime ambulatory BP was 148.3±13.9/91.9±7.8 mm Hg, nighttime ambulatory BP was 125.5±16.4/75.6±8.9 mm Hg, and 24-hour ambulatory BP was 141.7±14.0/87.2±7.6 mm Hg. Pearson correlation coefficients of clinic, home, home morning, and daytime ambulatory BPs to albuminuria and to the characteristics of the left ventricle were nearly equal. In multivariate regression analyses, 36% (
P
<0.0001) of the cross-sectional variation in left ventricular mass index was attributed to gender and home morning systolic BP in models that originally included age, gender, and clinic, self-measured home morning, and ambulatory daytime, nighttime, and 24-hour systolic and diastolic BPs. We concluded that carefully controlled nonphysician-measured clinic and self-measured home BPs, when averaged over 4 duplicate measurements, are as reliable as ambulatory BP monitoring in the clinical evaluation of untreated hypertension.
Elastic Properties and Composition of the Aortic Wall in Old Spontaneously Hypertensive Rats
Authors: Marque Valérie , Kieffer Pascal , Atkinson Jeffrey , Lartaud-Idjouadiene Isabelle
Published: June 2012

Abstract
—We hypothesized that age-linked changes in the composition and elastic properties of the arterial wall occur earlier in hypertensive than in normotensive rats. We evaluated the consequences of hypertension and aging on aortic mechanics, geometry, and composition in 3-, 9-, and 15-month-old awake Wistar-Kyoto rats (WKY) (normotensive) and spontaneously hypertensive rats (SHR) (hypertensive). The elastic modulus of the thoracic aorta, calculated from aortic pulse wave velocity and geometry, was higher in young and adult SHR than in age-matched WKY, as was wall stress; however, isobaric pulse wave velocity and pulse wave velocity–pressure curves were similar. Elastic modulus, isobaric pulse wave velocity, and the slope of the pulse wave velocity–pressure curve dramatically increased in old SHR compared with age-matched WKY; there was no further elevation of blood pressure or wall thickness. Fibrosis did not develop with age in SHR, and the ratio of elastin to collagen decreased in a similar fashion with aging in both strains. In conclusion, although elastic properties of the aortic wall are not intrinsically modified in young and adult SHR in comparison to age-matched WKY, aging is associated with a dramatic stiffening of the aortic wall in old SHR but not in WKY. Changes in blood pressure, aortic wall geometry, or scleroprotein composition do not appear to explain this age-linked aortic stiffening in SHR, suggesting that other mechanisms of disorganization of the media may be involved.
Microalbuminuria and Transcapillary Albumin Leakage in Essential Hypertension
Authors: Pedrinelli Roberto , Penno Giuseppe , Dell’Omo Giulia , Bandinelli Simona , Giorgi Davide , Di Bello Vitantonio , Navalesi Renzo , Mariani Mario
Published: June 2012

Abstract
—Microalbuminuria (an increased urinary albumin excretion that is not detectable by the usual dipstick methods for macroproteinuria) predicts cardiovascular events in essential hypertensive patients. A possible reason for this behavior is that albumin leaks through exaggeratedly permeant glomeruli exposed to the damaging impact of subclinical atherogenesis. To evaluate this possibility, the transcapillary escape rate of albumin (TER
alb
, the 1-hour decline rate of intravenous
125
I-albumin), a parameter that estimates the integrity of systemic capillary permeability, albuminuria, blood pressure, echocardiographic left ventricular mass, lipids, and body mass index were measured in 73 uncomplicated, glucose-tolerant men with essential hypertension and normal renal function; 53 were normoalbuminuric, and 20 were microalbuminuric. Twenty-one normotensive age-matched male subjects were the controls. TER
alb
was higher in hypertensives, a behavior explained in part by a positive correlation with blood pressure values, although body mass index, lipids, and left ventricular mass showed no association. Transcapillary albumin leakage values did not differ between normoalbuminuric and microalbuminuric patients and were unrelated to albuminuria. Blood pressure, particularly systolic, and cardiac mass were higher in microalbuminuric patients in whom albuminuria correlated with both cardiovascular variables and indicated the influence of the hemodynamic load on urinary albumin levels. Thus, TER
alb
, a parameter influenced by the permeability surface area product for macromolecules and the filtration power across the vascular wall, is altered in essential hypertensives. However, this abnormality is dissociated from the amount of albuminuria, which is contrary to the hypothesis that a higher albumin excretion reflects a greater degree of systemic microvascular damage in essential hypertension.
Pathophysiological Roles of Endothelin-1 in Dahl Salt-Sensitive Hypertension
Authors: Ikeda Takanori , Ohta Hisashi , Okada Megumu , Kawai Nobuko , Nakao Rumi , Siegl Peter K. S. , Kobayashi Tsutomu , Maeda Seiji , Miyauchi Takashi , Nishikibe Masaru
Published: June 2012

Abstract
—The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription–polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J-104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET
A
/ET
B
) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for ≥24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET
A
/ET
B
receptor antagonist could be useful in the treatment for salt-sensitive hypertension.
Rat Renal and Plasma Prorenin Are Activated In Vitro by Different Mechanisms
Authors: Vincent Paula A. , De Vito Eduardo
Published: June 2012

Abstract
—The aim of the present study was to purify and identify a plasma protein fraction (PreR-Co) involved in renal prorenin activation and to explore its capacity to process plasma prorenin. PreR-Co was obtained from plasma as a single electrophoretic band by (NH
4
)
2
SO
4
precipitation, Sephacryl S-200 HR gel filtration, anti-rat albumin immunoaffinity, and ion-exchange chromatography. The amidase, esterase, and kallikrein activities of PreR-Co were studied, as was its N-terminal amino acid sequence. Rat kidney extract or plasma (normal or previously treated with acid to pH 2.8) were incubated with PreR-Co for 15 minutes at 37°C. Renin concentration was measured by incubation with homologous angiotensinogen. The same protocol was repeated with samples activated by trypsin. The N-terminal amino acid sequence was IIGGSMDAKGSFP, which had a homology of 90% with the β-chain of haptoglobin, 69% with serine-proteases, and 65% with kallikreins. The renin concentration in rat kidney extract was 34±4 ng of angiotensin I (Ang I) · mg of tissue
−1
· h
−1
. After PreR-Co or trypsin treatments, renin concentrations were 211±7 and 110±11 ng of Ang I · mg of tissue
−1
· h
−1
, respectively. The plasma renin concentration in normal plasma was 67.6±13.3 ng of Ang I · mL
−1
· h
−1
, and no significant difference was observed after PreR-Co treatment. However, a significant increase (202.8±7.8 ng of Ang I · mL
−1
· h
−1
;
P
<0.01) was found after trypsin treatment. The isolated PreR-Co acts on renal prorenin but not on plasma prorenin. These results suggest that active renin is processed in the kidney by a circulating enzyme that may have a role in the regulation of circulating renin.