bluuebunny/crossref_metadata_2025 huggingface dataset:
Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats
Authors: Matsumura Yasuo , Hashimoto Norio , Taira Shima , Kuro Toshihiko , Kitano Rika , Ohkita Mamoru , Opgenorth Terry J. , Takaoka Masanori
Published: June 2012

Abstract
—We investigated the involvement of actions mediated by endothelin-A (ET
A
) and endothelin-B (ET
B
) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)–salt–induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ET
A
receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ET
B
receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt–induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary
N
-acetyl-β-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621–treated animals. These results strongly support the view that ET
A
receptor–mediated action plays an important role in the pathogenesis of DOCA-salt–induced hypertension. On the other hand, it seems likely that the ET
B
receptor–mediated action protects against vascular and renal injuries in this model of hypertension. A selective ET
A
receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ET
B
-selective antagonism alone is detrimental to such cases.
ACE Inhibitor Versus β-Blocker for the Treatment of Hypertension in Renal Allograft Recipients
Authors: Hausberg Martin , Barenbrock Michael , Hohage Helge , Müller Susanne , Heidenreich Stefan , Rahn Karl-Heinz
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) inhibitors have been shown to slow the progression of chronic renal failure. However, the value of ACE inhibitors for the treatment of hypertension in renal allograft recipients has not been established. ACE inhibitors dilate the efferent glomerular arteriole, an effect that may aggravate the decrease in glomerular filtration rate resulting from cyclosporine-induced vasoconstriction at the afferent glomerular arteriole. Therefore, the goal of this double-blind, randomized study was to compare the antihypertensive and renal effects of the ACE inhibitor quinapril with those of the β-blocker atenolol in renal allograft recipients in whom hypertension developed 6 to 12 weeks after transplantation. All patients received cyclosporine as an immunosuppressant and had stable graft function (serum creatinine concentration, <220 μmol/L) at entry into the study. Twenty-nine patients who received quinapril (daily dose titrated between 2.5 and 20 mg) and 30 patients who received atenolol (daily dose titrated between 12.5 and 100 mg) completed the 24-month study. The two groups did not differ in age, sex ratio, height, and weight before entry into the study. Quinapril decreased diastolic blood pressure from 96±1 to 84±1 mm Hg (average throughout treatment period), and atenolol decreased diastolic blood pressure from 96±1 to 83±1 mm Hg. The serum creatinine concentration did not change significantly in either group after 24 months (129±8 μmol/L at entry and 148±19 μmol/L after 24 months in the quinapril group and 131±6 μmol/L at entry and 152±15 μmol/L after 24 months in the atenolol group;
P
=NS for both groups). After 24 months, the change in urinary albumin excretion from baseline was −10±15 mg/d in the quinapril group and 52±32 mg/d in the atenolol group (
P
=0.03). These results show that quinapril and atenolol are effective antihypertensive drugs when used after renal transplantation. Moreover, compared with atenolol, quinapril has no adverse effects on graft function. The relative reduction in albuminuria observed with quinapril as compared with atenolol could indicate a beneficial effect of quinapril on long-term graft function.
Maximum-Likelihood Generalized Heritability Estimate for Blood Pressure in Nigerian Families
Authors: Rotimi Charles N. , Cooper Richard S. , Cao Guichan , Ogunbiyi Olufemi , Ladipo Modupe , Owoaje Eme , Ward Ryk
Published: June 2012

Abstract
—Elevated blood pressure (BP) is more common in relatives of hypertensives than in relatives of normotensives, indicating familial resemblance of the BP phenotypes. Most published studies have been conducted in westernized societies. To assess the ability to generalize these estimates, we examined familial patterns of BP in a population-based sample of 510 nuclear families, including 1552 individuals (320 fathers, 370 mothers, 475 sons, and 387 daughters) from Ibadan, Nigeria. The prevalence of obesity in this community is low (body mass index: fathers, 21.6; mothers, 23.6; sons, 19.2; and daughters=21.0 kg/m
2
). The BP phenotype used in all analyses was created from the best regression model by standardizing the age–adjusted systolic blood pressure (SBP) and diastolic blood pressure (DBP) to 0 mean and unit variance. Heritability was estimated by use of the computer program SEGPATH from the most parsimonious model of “no spouse and neither gender nor generation difference” as 45% for SBP and 43% for DBP. The lack of a significant spouse correlation is consistent with little or no influence of the common familial environment. However, the heritability estimate of <50% for both SBP and DBPs reinforces the importance of the nonshared environmental effect.
Protection Against Necrosis but Not Apoptosis by Heat-Stress Proteins in Vascular Smooth Muscle Cells
Authors: Champagne Marie-Josée , Dumas Pierre , Orlov Sergei N. , Bennett Martin R. , Hamet Pavel , Tremblay Johanne
Published: June 2012

Abstract
—We have reported previously that cultured vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR) show higher proliferation and cell death than normotensive controls. In addition to protecting cells against death, heat stress proteins (HSPs) appear to play a role in cell proliferation. This investigation examines the involvement of HSP72 and HSP27 in altered SHR VSMC proliferation and death. We have performed detailed discriminatory analysis to characterize which type of VSMC death is induced by heat stress (HS) and serum deprivation. Serum deprivation induced apoptosis (caspase-3 cleavage and DNA laddering) and secondary necrosis, the 2 processes being a continuum of each other. In contrast, acute HS (46°C, 30 minutes), which inhibited BN.lx and SHR VSMC proliferation by 2-fold, increased necrosis (by 5-fold and 2-fold, respectively) but not apoptosis. HSP72 and HSP27 expression evoked in VSMC by mild HS (44°C, 15 minutes) 6 hours before acute HS prevented the inhibition of proliferation and induction of necrosis with no effect on serum deprivation–induced or staurosporine-induced apoptosis. This induced expression of HSP72 and HSP27 did not eliminate the higher basal proliferation, apoptosis, and necrosis of SHR VSMC compared with BN.lx VSMC, suggesting that these HSPs are not involved in altered SHR VSMC proliferation and death. Also, although apoptosis and necrosis may be a continuum, in VSMC the 2 processes may be distinguished by HS, in which only necrosis is prevented by prior HSP accumulation. This observation may be of use in designing strategies for cellular protection.
Cardiovascular Effects of Nociceptin in Unanesthetized Mice
Authors: Madeddu Paolo , Salis Maria Bonaria , Milia Anna Franca , Emanueli Costanza , Guerrini Remo , Regoli Domenico , Calò Girolamo
Published: June 2012

Abstract
—We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe
1
ψ(CH
2
-NH)Gly
2
]NC(1–13)NH
2
([F/G]NC(1–13)NH
2
) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted <10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114±3 to 97±2 mm Hg at 10 minutes,
P
<0.01). The latter dose reduced heart rate from 542±43 to 479±31 beats/min (
P
<0.05) and increased aortic blood flow by 41±5% (
P
<0.05). Hypotension and bradycardia were also evoked by NC(1–17)NH
2
and NC(1–13)NH
2
fragments, whereas NC(1–13)OH and NC(1–9)NH
2
were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1–13)NH
2
and revealed the ability of NC(1–13)OH to decrease mean blood pressure. [F/G]NC(1–13)NH
2
, a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1–13)NH
2
did not alter the hypotension induced by bradykinin or endomorphin-1 (a μ-receptor agonist), and the bradycardia induced by leu-enkephalin (a δ-receptor agonist) or U504885 (a synthetic κ-receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice
,
with the NC(1–13) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1–13)NH
2
is a potent and selective antagonist of the NC receptor in vivo.
Genetic Determination of Cardiac Mass in Normotensive Rats
Authors: Sebkhi Abdelkrim , Zhao Lan , Lu Long , Haley Christopher S. , Nunez Derek J. R. , Wilkins Martin R.
Published: June 2012

Abstract
—Genetic determinants affect adult cardiac mass and the predisposition to develop cardiac hypertrophy. The aim of this study was to identify quantitative trait loci (QTL) that control heart and left ventricular (LV) weight by use of normotensive inbred rat strains that differ in their adult cardiac mass phenotype. We studied 126 male F
2
rats derived from a cross of normotensive Wistar-Kyoto and Fischer 344 rats. At 12 weeks of age, total heart weight and LV weight were measured. Genomic DNA from these animals was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). In this cross, the genetic contribution to total heart weight variation was 56%, and the genetic contribution for LV weight was 55%. Using the Mapmaker/QTL computer package, we identified a significant QTL on chromosome 3 with a log
10
likelihood (LOD) score of 4.8, which accounted for 16.5% of the total variance of LV weight. This QTL was centered close to the marker D3Rat29. The QTL was also found to be significantly linked with total heart weight (LOD=4.4). These data provide the first demonstration of a QTL on chromosome 3 that plays a role in determining the difference in LV mass between normotensive Fischer 344 and Wistar- Kyoto inbred rat strains. The prostaglandin synthase 1 gene is located within the QTL.
Angiotensin II Type 1 Receptor Antagonist Downregulates Nonmuscle Myosin Heavy Chains in Spontaneously Hypertensive Rat Aorta
Authors: Fujii Kozo , Umemoto Seiji , Fujii Akihisa , Yonezawa Takahito , Sakumura Toshihiro , Matsuzaki Masunori
Published: June 2012

Abstract
—The aim of this study was to clarify the differences between the angiotensin II type 1 (AT
1
) receptor antagonist and the angiotensin-converting enzyme (ACE) inhibitor on smooth muscle and nonmuscle myosin heavy chain isoforms in aortic smooth muscle cells of Wistar-Kyoto rats and spontaneously hypertensive rats. All 4 myosin heavy chain isoforms are heterogeneously expressed in the smooth muscle cells of the aortic tunica media in 20-week-old rats, and the contractile-type myosin heavy chains are highly expressed in smooth muscle cells of the aortic tunica media compared with the synthetic-type myosin heavy chains. Both the AT
1
receptor antagonist and the ACE inhibitor had the same effects on hemodynamics, smooth muscle cell hypertrophy and proliferation, fibrosis, and vascular remodeling in spontaneously hypertensive rats. However, the AT
1
receptor antagonist had a more potent effect on the downregulation of the synthetic-type myosin heavy chains than the ACE inhibitor in spontaneously hypertensive rat aortic tunica media. In contrast, these effects of the AT
1
receptor antagonist and the ACE inhibitor on hemodynamics, morphology, fibrosis, and expression of myosin heavy chain isoforms in smooth muscle cells of the aortic tunica media were not observed in Wistar-Kyoto rats. Thus, within 6 weeks, the AT
1
receptor antagonist might modulate the cellular composition of myosin heavy chain isoforms in smooth muscle cells more efficiently than the ACE inhibitor, without morphological changes in the spontaneously hypertensive rat aorta.
Metformin Attenuates Salt-Induced Hypertension in Spontaneously Hypertensive Rats
Authors: Muntzel Martin S. , Hamidou Ibrahima , Barrett Shean
Published: June 2012

Abstract
—Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130±3 mm Hg; metformin, 133±5 mm Hg; mean±SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153±4 mm Hg; metformin, 140±5 mm Hg;
P
<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136±13 mm Hg) than those in the control (98±5 mm Hg,
P
<0.01), metformin (100±7 mm Hg,
P
<0.01), and metformin/high-salt groups (92±3 mm Hg,
P
<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310±3 and 305±4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332±3 and 324±2 bpm,
P
<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.
Ventricular Adrenomedullin Levels Correlate With the Extent of Cardiac Hypertrophy in Rats
Authors: Morimoto Atsushi , Nishikimi Toshio , Yoshihara Fumiki , Horio Takeshi , Nagaya Noritoshi , Matsuo Hisayuki , Dohi Kazuhiro , Kangawa Kenji
Published: June 2012

Abstract
—We investigated the pathophysiological significance of adrenomedullin (AM) in the development of left ventricular hypertrophy (LVH). LVH was produced by aortic banding (AB) in rats. The left ventricular weight/body weight (LV/BW) ratio, ventricular AM peptide and mRNA levels, and hemodynamics were measured at 1, 3, 7, and 21 days after the operation. Both LV/BW ratio and ventricular AM levels showed a significant increase from 1 day after the operation in the AB rats versus the sham-operated rats. Both increased in a time-dependent manner. The ventricular AM levels correlated with the LV/BW ratio (
r
=0.76,
P
<0.01). The AM mRNA levels were highly expressed at 1 day after the operation in the AB rats but showed no difference from 3 to 21 days after the operation between the AB and sham groups. The plasma AM levels showed a peak at 1 day after the operation in both groups. Then, we treated AB rats with an angiotensin-converting enzyme inhibitor (quinapril) in 2 doses (1 and 10 mg · kg
−1
· d
−1
) for 21 days. The quinapril treatment attenuated similarly both the LV/BW ratio and the ventricular AM levels. We also assessed the effects of AM and hydralazine administration for 7 days on the LV/BW ratio and hemodynamics of AB rats. Both AM and hydralazine administration reduced the blood pressure by ≈10% compared with the nontreated AB rats, but a reduction of the LV/BW ratio was observed only in the AM-treated group (
P
<0.05). These results suggest that ventricular AM levels are elevated by chronic pressure overload in a time-dependent manner concomitant with the extent of LVH and that AM may play a pathophysiological role in the development of LVH in chronic pressure overload.
Pressor Response to Compression of the Ventrolateral Medulla Mediated by Glutamate Receptors
Authors: Morimoto Satoshi , Sasaki Susumu , Miki Shigeyuki , Kawa Tetsuyoshi , Nakamura Kazue , Ichida Tatsuya , Itoh Hiroshi , Nakata Tetsuo , Takeda Kazuo , Nakagawa Masao , Yamada Hisao
Published: June 2012

Abstract
—The rostral ventrolateral medulla (RVLM) is considered a major center for the regulation of sympathetic and cardiovascular activities. Several clinical studies have indicated a possible causal relationship between neurovascular contact of the left RVLM and essential hypertension, and some investigators have suggested that the left RVLM is more sensitive to pulsatile compression than the right RVLM. Previously, we reported that pulsatile compression of the RVLM elevates arterial pressure by enhancing sympathetic outflow in rats; however, we have not investigated the laterality of the responses to the compression. In addition, it remains to be elucidated whether RVLM neurons are activated by compression and, if so, how they are activated. Therefore, we performed compression experiments in rats to investigate these issues. Pulsatile compression was performed on the unilateral RVLM with a pulsating probe in anesthetized and artificially ventilated rats. Pulsatile compression of the unilateral RVLM increased arterial pressure, heart rate, and sympathetic nerve activity. The pressor response to compression was inhibited significantly after local microinjection of glutamate receptor antagonists. Pulsatile compression of the RVLM increased Fos immunoreactivitiy, a marker of neuronal activation, within the nuclei of postsynaptic RVLM neurons. All results were observed symmetrically. The data indicate that the responses to pulsatile compression of the unilateral RVLM are similar on both sides. They also suggest that pulsatile compression of the RVLM increases sympathetic and cardiovascular activities by activating postsynaptic RVLM neurons through the stimulation of the local glutamate receptors in rats.
Systemic Administration of Lipopolysaccharide Induces Release of Nitric Oxide and Glutamate and c-
fos
Expression in the Nucleus Tractus Solitarii of Rats
Authors: Lin Hui-Ching , Wan Fang-Jung , Kang Bor-Hwang , Wu Chin-Chen , Tseng Ching-Jiunn
Published: June 2012

Abstract
—There is increasing recognition that communication pathways exist between the immune system and brain, which allows bidirectional regulation of immune and brain responses to infection. The endotoxin lipopolysaccharide (LPS) has been reported to elicit release of cytokines and expression of inducible nitric oxide synthase (iNOS) in peripheral organs. Whereas LPS given systemically causes endotoxic shock, little is known about its central nervous system action, particularly the induction of iNOS. Nitric oxide (NO) and glutamate in the nucleus tractus solitarii (NTS) are important mediators of central cardiovascular regulation. We have previously demonstrated that intravenous injections of LPS increased the NO precursor
l
-arginine–induced depressor effect in the NTS. The present study investigated further the effects of LPS on the release of NO and glutamate in the NTS and the expression of c-
fos
, an immediate early response gene product, in neural substrates for central cardiovascular control. In vivo microdialysis coupled with chemiluminescence and electrochemical detection techniques were used to measure extracellular levels of NO and glutamate in the rat NTS. Immunohistochemistry was used for the examination of c-
fos
protein expression. We found that intravenous infusion of LPS (10 mg/kg) produced a biphasic depressor effect, with an early, sharp hypotension that partially recovered in 15 minutes and a secondary, more prolonged hypotension. In the NTS, a progressive increase of extracellular glutamate and NO levels occurred 3 and 4 hours after LPS was given, respectively. The effects of LPS on the induction of delayed hypotension and NO formation in the NTS were abolished by pretreatment with the iNOS inhibitor aminoguanidine. Finally, c-
fos
protein expression in the NTS and related structures for cardiovascular regulation was observed after LPS challenge. Taken together, these data suggest that an endotoxin given systemically can elicit delayed increases of glutamate release and iNOS-dependent NO production in the NTS and activate the central neural pathway for modulating cardiovascular function.
Superoxide Anion Production Is Increased in a Model of Genetic Hypertension
Authors: Kerr Susanne , Brosnan M. Julia , McIntyre Martin , Reid John L. , Dominiczak Anna F. , Hamilton Carlene A.
Published: June 2012

Abstract
—The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O
2
−
) was examined. O
2
−
generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O
2
−
generation was increased in male and female SHRSP (4.11±0.24 and 3.84±0.28 nmol O
2
−
· min
−1
· mg
−1
respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22±0.08 in males and 0.8±0.08 nmol O
2
−
· min
−1
· mg
−1
respectively) (SHRSP versus WKY
P
<0.0001, 95% CI −3.39, −2.51; male versus female WKY
P
=0.0029, 95% CI −0.67, −0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O
2
−
generation in SHRSP but not WKY. In males, removal of the endothelium reduced O
2
−
generation from 3.86±0.12 to 1.35±0.08 nmol · min
−1
· mg
−1
(
P
<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13±0.17 to 1.32±0.16 nmol · min
−1
· mg
−1
(
P
<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females.
l
-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O
2
−
generation in SHRSP from 4.04±0.11 to 2.36±0.40 nmol · min
−1
· mg
−1
(
P
=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O
2
−
generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O
2
−
appear to be the endothelium and eNOS, respectively. The increase in O
2
−
generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.
Cortisol Effects on Body Mass, Blood Pressure, and Cholesterol in the General Population
Authors: Fraser Robert , Ingram Mary C. , Anderson Niall H. , Morrison Caroline , Davies Eleanor , Connell John M. C.
Published: June 2012

Abstract
—The effects of excess cortisol secretion on blood pressure and fat deposition are well documented, but the importance of this glucocorticoid in controlling these processes in normal individuals is less clear. We studied the relationship between cortisol excretion rate (tetrahydrocortisol [THF]+allo-THF+tetrahydrocortisone [THE]) and a range of important cardiovascular risk factors in 439 normal subjects (238 male) sampled from the North of Glasgow (Scotland) population. There were marked gender differences: female subjects were lighter and had lower blood pressures and cortisol levels, whereas HDL cholesterol was higher. The pattern of cortisol metabolism was also different; the index of 11β-hydroxysteroid dehydrogenase activity (THF+allo-THF/THE) was lower and that of 5α-reductase (allo-THF/THF) was higher. There was a strong correlation of blood pressure (positive), cholesterol (positive), and HDL cholesterol (negative in women, positive in men) with age. Cortisol excretion rate did not correlate with blood pressure but correlated strongly with parameters of body habitus (body mass index and waist and hip measurements [positive]) and HDL cholesterol (negative). With multiple regression analysis, there remained a significant association of cortisol excretion rate with HDL cholesterol in men and women and with body mass index in men. These results suggest that glucocorticoids regulate key components of cardiovascular risk.
Maternal Hypertension and Progeny Blood Pressure
Authors: Gomez-Sanchez Elise P. , Gomez-Sanchez Celso E.
Published: June 2012

Abstract
—Epidemiological and experimental evidence suggests that gestational events modulate the level of blood pressure that will be “normal” for the individual as an adult. Glucocorticoid excess during gestation is associated with low birth weight, a large placenta, and adult hypertension in humans and animals. It has been proposed that the deficiency in placental 11β-hydroxysteroid dehydrogenase activity in humans produces a gestational hormonal milieu, notwithstanding normal circulating levels of glucocorticoids, that predisposes the adult progeny to hypertension. Animal studies indicate that maternal hypertension, excess glucocorticoids, and hydroxysteroid dehydrogenase inhibition program adult blood pressure. Blood pressures of Sprague-Dawley rat dams were manipulated during gestation with continuous intracerebroventricular infusions of vehicle, aldosterone, 11α-hydroxyprogesterone, or carbenoxolone at doses known to produce hypertension with no renal effects or with subcutaneous infusions of larger, equally hypertensinogenic doses that produce systemic effects. Blood pressures of all treated dams were significantly greater (
P
<0.01) during gestation than those of the vehicle ICV control rats but not significantly different from each other. The blood pressures of both male and female progeny (n≥6 per group, comprising representatives from at least 4 litters) were measured after 6 weeks of age. No significant difference was found in the blood pressure of the pups regardless of the maternal gestational blood pressure or treatment with an enzyme inhibitor, even after high-salt diet challenge.
Effect of Ceramide on K
Ca
Channel Activity and Vascular Tone in Coronary Arteries
Authors: Li Pin-Lan , Zhang David X. , Zou Ai-Ping , Campbell William B.
Published: June 2012

Abstract
—A sphingomyelin metabolite, ceramide, serves as a second messenger in a variety of mammalian cells. Little is known regarding the production and actions of this novel intracellular signaling lipid molecule in the vasculature. The present study was designed to test the hypothesis that a ceramide-mediated signaling pathway is present in coronary arterial smooth muscle and that ceramide serves as an inhibitor of the large-conductance Ca
2+
-activated potassium (K
Ca
) channels and mediates vasoconstriction in coronary circulation. We found that C
2
-ceramide produced a concentration-dependent decrease in K
Ca
channel activity in vascular smooth muscle cells from small bovine coronary arteries. The average channel activity of the K
Ca
channels in cell-attached patches decreased from 0.046±0.01 to 0.008±0.001 at a C
2
-ceramide concentration of 10 μmol/L. In inside-out patches, C
2
-ceramide (1 μmol/L) reduced the average channel activity of the K
Ca
channels from 0.06±0.007 to 0.016±0.004. Dithiothreitol, an inhibitor of acidic sphingomyelinase (1 mmol/L), increased the average channel activity of the K
Ca
channels in cell-attached patches from 0.05±0.02 of control to 0.26±0.04, a 5-fold increase that was reversed by addition of 1 μmol/L ceramide. Glutathione, an inhibitor of neutral sphingomyelinase, was without effect. C
2
-ceramide significantly reduced the diameter of isolated perfused small coronary arteries in a concentration-dependent manner. Addition of 1 μmol/L C
2
-ceramide decreased average arterial diameter by 28%. When
14
C-sphingomyelin was incubated with coronary arterial homogenates at pH 7.4 and pH 5.0,
14
C–choline phosphate and ceramide were produced. The conversion rates of
14
C-sphingomyelin into
14
C–choline phosphate and ceramide were 65.1±1.0 fmol/min per milligram protein at pH 7.4 and 114.6±8.3 fmol/min per milligram protein at pH 5.0. We conclude that both acidic and neutral sphingomyelinases are present in the bovine coronary arteries and that ceramide inactivates the K
Ca
channel in arterial smooth muscle cells and hence exerts a tonic vasoconstrictor action in coronary microcirculation.
Preactivated Peripheral Blood Monocytes in Patients With Essential Hypertension
Authors: Dörffel Yvonne , Lätsch Christoph , Stuhlmüller Bruno , Schreiber Stefan , Scholze Susann , Burmester Gerd R. , Scholze Jürgen
Published: June 2012

Abstract
—The purpose of this study was to investigate the possible involvement of human peripheral blood monocytes in the pathology of hypertensive disease. We determined the in vitro secretion patterns of proinflammatory cytokines obtained from isolated peripheral monocytes from normal controls and from hypertensive patients either after in vitro stimulation with angiotensin II (Ang II) with or without preincubation with an Ang II type 1 receptor antagonist (losartan) or after stimulation with lipopolysaccharide. Blood samples were obtained from 22 patients with essential hypertension (before any drug administration or after interruption of antihypertensive therapy) and from 24 normotensive healthy individuals used as a control group. Peripheral blood monocytes were isolated by density gradient centrifugation and plastic adherence. The state of monocyte activity was determined by the capacity to secrete tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6, (IL-6) either spontaneously or after stimulation. Cytokine concentrations were determined in culture supernatants by specific ELISA. Proinflammatory cytokine levels were assessed by semiquantitative reverse transcribed polymerase chain reaction. After stimulation with Ang II, the IL-1β secretion of peripheral blood monocytes was significantly increased in hypertensive patients versus healthy individuals (
P
<0.05). In contrast, in monocytes preincubated with losartan before exposure to Ang II, IL-1β secretion was diminished in both groups to comparable levels. The secretion of IL-1β and TNF-α was significantly increased in peripheral blood monocytes from hypertensive patients versus healthy individuals after stimulation with lipopolysaccharide (TNF-α,
P
<0.02; IL-1β,
P
<0.05). Upregulation of IL-1β and TNF-α secretion in peripheral blood monocytes from hypertensive patients was also seen at the RNA level. Our results indicate preactivated peripheral blood monocytes in hypertensive patients. Ang II may be directly involved in the process of monocyte activation.
Cardiac Consequences of Prolonged Exposure to an Isolated Increase in Aortic Stiffness
Authors: Lartaud-Idjouadiene Isabelle , Lompré Anne-Marie , Kieffer Pascal , Colas Thérèse , Atkinson Jeffrey
Published: June 2012

Abstract
—In elderly patients, aortic stiffness is a major determinant of increased end-systolic stress leading to left ventricular (LV) hypertrophy with impaired cardiac performance. However, in a rat model of aortic elastocalcinosis (induced by vitamin D
3
–nicotine [VDN] treatment), brief exposure (1 month) to increased aortic stiffness modified neither cardiac function nor cardiac structure. Here we report the impact of longer exposure (3 months) to aortic stiffness. Three months after induction of aortic stiffness, aortic characteristic impedance was measured in awake rats, 8 control and 10 VDN. Stroke volume was measured (electromagnetic probe) at baseline and after acute volume overload. LV weight/body weight ratio, collagen, and myosin heavy chain (MHC) contents were determined. Although aortic characteristic impedance increased (controls, 32±2; VDN rats, 50±8 10
3
dyne · s/cm
5
;
P
=0.0248), stroke volume was maintained in VDN rats at baseline (controls, 223±18; VDN, 211±13 μL) and after volume overload (controls, 378±14; VDN, 338±15 μL). However, LV weight/body weight ratio (controls, 1.54±0.07; VDN, 1.73±0.05 g/kg;
P
=0.0397) and LV collagen content (controls, 31±4; VDN, 52±4 μg/g dry wt;
P
=0.0192) increased. A shift from α-MHC (controls, 82±2%; VDN, 69±3%;
P
=0.0056) to β-MHC (controls, 18±2%; VDN, 31±3%;
P
=0.0056) was also observed. Three months’ exposure to increased aortic stiffness in VDN rats induced LV hypertrophy with moderate interstitial fibrosis and a shift in the MHC-isoform pattern. Such structural adaptation maintains LV performance.
Effects of Potassium on Blood Pressure in Salt-Sensitive and Salt-Resistant Black Adolescents
Authors: Wilson Dawn K. , Sica Domenic A. , Miller Sydney B.
Published: June 2012

Abstract
—This study examined the effects of increasing dietary potassium on ambulatory blood pressure nondipping status (<10% decrease in blood pressure from awake to asleep) and cardiovascular reactivity in salt-sensitive and salt-resistant black adolescents. A sample of 58 normotensive (blood pressure, 101/57±9/4 mm Hg) black adolescents (aged 13 to 16 years) participated in a 5-day low sodium diet (50 mmol/24 h) followed by a 10-day high sodium diet (150 mmol/24 h NaCl supplement) to determine salt-sensitivity status. Participants showed a significant increase in urinary sodium excretion (24±19 to 224±65 mmol/24 h) and were identified as salt-sensitive if their mean blood pressure increase was ≥5 mm Hg from the low to high sodium diet. Sixteen salt-sensitive and 42 salt-resistant subjects were then randomly assigned to either a 3-week high potassium diet (80 mmol/24 h) or usual diet control group. Urinary potassium excretion significantly increased in the treatment group (35±7 to 57±21 mmol/24 h). At baseline, a significantly greater percentage of salt-sensitive (44%) compared with salt-resistant (7%) subjects were nondippers on the basis of diastolic blood pressure classifications (
P
<0.04). After the dietary intervention, all of the salt-sensitive subjects in the high potassium group achieved dipper status as a result of a drop in nocturnal diastolic blood pressure (daytime, 69 versus 67 mm Hg; nighttime, 69 versus 57 mm Hg). No significant group differences in cardiovascular reactivity were observed. These results suggest that a positive relationship between dietary potassium intake and blood pressure modulation can still exist even when daytime blood pressure is unchanged by a high potassium diet.
Arterial Stiffness and the Development of Hypertension
Authors: Liao Duanping , Arnett Donna K. , Tyroler Herman A. , Riley Ward A. , Chambless Lloyd E. , Szklo Moyses , Heiss Gerardo
Published: June 2012

Abstract
—Decreased elasticity in large and medium-sized arteries has been postulated to be associated with cardiovascular diseases. We prospectively examined the relation between arterial elasticity and the development of hypertension over 6 years of follow-up in a cohort of 6992 normotensive men and women aged 45 to 64 years at baseline from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Arterial elasticity was measured from high-resolution B-mode ultrasound examination of the left common carotid artery as adjusted arterial diameter change (in micrometers, simultaneously adjusted for diastolic blood pressure, pulse pressure, pulse pressure squared, diastolic arterial diameter, and height), Peterson’s elastic modulus (in kilopascals), Young’s elastic modulus (in kilopascals), and β stiffness index. Incident hypertension (n=551) was defined as systolic blood pressure ≥160 mm Hg, diastolic blood pressure ≥95 mm Hg, or the use of antihypertensive medication at a follow-up examination conducted every 3 years. The age-, ethnicity-, center-, gender-, education-, smoking-, heart rate–
,
and obesity-adjusted means (SE) of baseline adjusted arterial diameter change, Peterson’s elastic modulus, Young’s elastic modulus, and β stiffness index were 397 (5), 148 (2.0), 787 (12.7), and 11.43 (0.16), respectively, in persons who developed hypertension during follow-up, in contrast to 407 (1), 124 (0.6), 681 (3.7), and 10.34 (0.05), respectively, for persons who did not. The similarly adjusted cumulative incident rates of hypertension from the highest to the lowest quartiles of arterial elasticity were 6.7%, 8.0%, 7.3%, and 9.6%, respectively, when measured by adjusted arterial diameter change (
P
<0.01). One standard deviation decrease in arterial elasticity was associated with 15% greater risk of hypertension, independent of established risk factors for hypertension and the level of baseline blood pressure. These results suggest that lower arterial elasticity is related to the development of hypertension.
Differential Effects of T- and L-Type Calcium Antagonists on Glomerular Dynamics in Spontaneously Hypertensive Rats
Authors: Nakamura Yasuyuki , Ono Hidehiko , Frohlich Edward D.
Published: June 2012

Abstract
—To determine whether there is a difference in the effects of T- and L-type calcium antagonists on systemic, renal, and glomerular hemodynamics, the pathological changes of
N
G
-nitro-
l
-arginine methyl ester (L-NAME)–exacerbated nephrosclerosis and clinical alterations were investigated in spontaneously hypertensive rats (SHR). Seven groups of 17-week-old male SHRs were studied: Group 1, control; Group 2, mibefradil, 50 mg · kg
−1
· d
−1
; Group 3, L-NAME in drinking water, 50 mg/L; Group 4, L-NAME (50 mg/L) plus mibefradil (50 mg · kg
−1
· d
−1
); Group 5, L-NAME (50 mg/L) plus amlodipine (10 mg · kg
−1
· d
−1
); Group 6 and 7, L-NAME (50 mg/L) for 3 weeks followed by mibefradil (50 mg · kg
−1
· d
−1
) or amlodipine (10 mg · kg
−1
· d
−1
), respectively, for the subsequent 3 weeks. Both the T- and L-channel calcium antagonists similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances and the ultrafiltration coefficient (
P
<0.01). Furthermore, the histopathological glomerular and arterial injury scores and urinary protein excretion were also significantly improved (
P
<0.01), and left ventricular and aortic masses were significantly diminished in all treated groups. Both drugs, mibefradil and amlodipine, had effects of increasing the single-nephron glomerular filtration ratio (SNGFR), and single-nephron plasma flow (SNPF), and of reducing glomerular afferent arteriolar resistance and urinary protein excretion. Thus, the T-type (mibefradil) and L-type (amlodipine) calcium antagonists each prevented and reversed the pathophysiological alterations of L-NAME–exacerbated hypertensive nephrosclerosis in SHR. The T-type calcium antagonist (mibefradil) seemed to have been more effective than the L-type amlodipine antagonist and it produced a greater reduction in afferent arteriolar resistance while preserving SNGFR.
Activation of the Brain Angiotensin System by In Vivo Human Angiotensin-Converting Enzyme Gene Transfer in Rats
Authors: Nakamura Shigefumi , Moriguchi Atsushi , Morishita Ryuichi , Yamada Kazuo , Nishii Tadahiko , Tomita Naruya , Ohishi Mitsuru , Kaneda Yasufumi , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—The possibility of the brain-specific expression of a component of the renin-angiotensin system was evaluated in the present study. We used the hemagglutinating virus of Japan-liposome complex to transfect human angiotensin-converting enzyme (ACE) cDNA, driven by the cytomegalovirus enhancer and β-actin promoter, into the lateral cerebroventricle of male Sprague-Dawley rats. We evaluated the time course of hemodynamics, the tissue levels of angiotensin (Ang) II and vasopressin, and ACE activity. Intracerebroventricular transfection of the human ACE gene increased both blood pressure and heart rate. Transfected rats exhibited higher concentrations of brain Ang II and increased brain ACE activity. This activation of the brain angiotensin system was accompanied by increased vasopressin production. The increases in blood pressure and heart rate were abolished by intracerebroventricular administration of an ACE inhibitor or Ang II type 1 receptor antagonist. The expression of the transgene was widely distributed in the periventricular cell layer, the cortex, the hypothalamic nuclei, and the brain stem. Expression in the neuronal cells persisted for up to 14 days. Thus, this hemagglutinating virus of Japan-liposome method is a highly efficient system for gene delivery and is extremely useful for functional gene transfection. This novel hypertensive model may enable characterization of the functions of the renin-angiotensin system in the brain and determination of its role in the pathogenesis of hypertension.
Levels of Mineralocorticoids in Whites and Blacks
Authors: Pratt J. Howard , Rebhun John F. , Zhou Lifen , Ambrosius Walter T. , Newman Shirley A. , Gomez-Sanchez Celso E. , Mayes Darrel F.
Published: June 2012

Abstract
—Blacks appear, on average, to retain more Na than whites. A higher production rate of mineralocorticoids could explain the greater Na retention in blacks. Although production of aldosterone has been shown to be lower in blacks, the level of another mineralocorticoid may be increased. Plasma levels of deoxycorticosterone and cortisol were measured in young whites (n=23; age=16.4±3.1[SD] years) and young blacks (n=25; age=13.8±1.3 years). Blacks had lower plasma levels of renin activity and aldosterone and lower urinary aldosterone excretion rates; thus, they appeared to be representative of blacks that retain additional Na. Plasma deoxycorticosterone levels were lower in blacks than in whites both at baseline (247±161 versus 381±270 pmol/L,
P
=0.048) and after stimulation with adrenocorticotropic hormone (822±294 versus 1127±628 pmol/L at 30 minutes,
P
=0.047; 925±366 versus 1440±834 pmol/L at 60 minutes,
P
=0.013). Cortisol levels were also lower in blacks at baseline (
P
=0.014) but were not significantly different from levels in whites after stimulation with adrenocorticotropic hormone. In a larger cohort of 407 whites (age=12.0±2.9 years) and 247 blacks (age=12.9±3.1 years), 18-hydroxycortisol excretion rates were also lower in blacks (
P
=0.021). In conclusion, increased Na retention in blacks does not appear to be secondary to increased production of either aldosterone, deoxycorticosterone, cortisol, or 18-hydroxycortisol. A primary renal mechanism may mediate the increase in Na reabsorption in blacks.
Plasma Saturated and Linoleic Fatty Acids Are Independently Associated With Blood Pressure
Authors: Grimsgaard Sameline , Bønaa Kaare H. , Jacobsen Bjarne K. , Bjerve Kristian S.
Published: June 2012

Abstract
—The role of individual fatty acids in blood pressure regulation is unclear. We studied the cross-sectional relationship of blood pressure, total plasma phospholipid fatty acid concentrations, and proportions of individual fatty acids among participants in a population study. Blood pressure was measured automatically, and plasma phospholipid fatty acids were determined by gas-liquid chromatography in 4033 healthy men 40 to 42 years old. Significant positive linear associations existed between total fatty acids and saturated fatty acids and blood pressure, whereas polyunsaturated linoleic acid was inversely associated with blood pressure. In multiple regression analyses, a 2-SD increase in total fatty acids was associated with an increase of 6.0 (95% CI, 5.1 to 6.8) mm Hg systolic blood pressure. A 2-SD increase in saturated palmitic acid was associated with 1.4 (95% CI, 0.5 to 2.3) mm Hg increase in systolic blood pressure. In contrast, a 2-SD increase in polyunsaturated linoleic acid was associated with a 1.9 (95% CI, 1.0 to 2.8) mm Hg decrease in systolic blood pressure. We conclude that plasma levels of total fatty acids, saturated fatty acids, and polyunsaturated linoleic acid are independently associated with blood pressure. The present study supports the hypothesis that the composition of dietary fat influences blood pressure.
Nitric Oxide–Induced Inhibition of Transport by Thick Ascending Limbs From Dahl Salt-Sensitive Rats
Authors: García Néstor H. , Plato Craig F. , Stoos Barbara A. , Garvin Jeffrey L.
Published: June 2012

Abstract
—The factor responsible for salt sensitivity of blood pressure in Dahl rats is unclear but presumably resides in the kidney. We tested the hypotheses that (1) thick ascending limbs of Dahl salt-sensitive rats (DS) absorb more NaCl than those of Dahl salt-resistant rats (DR) and (2) NO inhibits transport to a lesser extent in thick ascending limbs from DS. We found that basal chloride absorption (J
Cl
) by thick ascending limbs from DR was 105.8±10.0 pmol · mm
−1
· min
−1
(n=6). Ten and 100 μmol/L spermine NONOate, an NO donor, decreased J
Cl
in DR to 65.8±8.5 and 46.8±7.0 pmol · mm
−1
· min
−1
, respectively. Basal J
Cl
in DS was 131.6±13.4 pmol · mm
−1
· min
−1
(n=7). In DS, 10 and 100 μmol/L spermine NONOate decreased J
Cl
to 111.5±12.8 and 46.8±6.2 pmol · mm
−1
· min
−1
, respectively. No difference was observed in basal or NO-inhibited Na absorption by cortical collecting ducts or in basal or NO-inhibited oxygen consumption by inner medullary collecting ducts. Because NO acts via generation of cGMP, we measured cGMP production by thick ascending limbs from DS and DR to see whether a difference in cGMP production could account for the difference in basal or NO-inhibited transport. Basal rates of cGMP production were similar between the 2 strains. Although NO increased cGMP production by thick ascending limbs from both strains, no difference existed between DS and DR. We concluded that the reduced ability of NO to block transport in thick ascending limbs in DS may account for at least part of the salt sensitivity of blood pressure in this strain.