bluuebunny/crossref_metadata_2025 huggingface dataset:
Apoptosis Is Not Increased in Myocardium Overexpressing Type 2 Angiotensin II Receptor in Transgenic Mice
Authors: Sugino Hiroshi , Ozono Ryoji , Kurisu Satoshi , Matsuura Hideo , Ishida Mari , Oshima Tetsuya , Kambe Masayuki , Teranishi Yasuhiro , Masaki Hiroya , Matsubara Hiroaki
Published: June 2012

Abstract
—To determine whether angiotensin type 2 (AT
2
) receptor stimulation induces apoptosis in cardiomyocytes in vivo, we developed transgenic mice overexpressing the AT
2
receptor in a cardiac-specific manner, using the α-myosin heavy-chain promoter. Ten- to 12-week-old male homozygous transgenic mice (n=44) and wild-type mice (n=44) were used. Both transgenic and wild-type mice were given either saline (control), a subpressor dose of angiotensin II (100 ng · kg
−1
· min
−1
), a pressor dose of angiotensin II (1000 ng · kg
−1
· min
−1
) for 14 days, a pressor dose of angiotensin II for 28 days to investigate the effects of stimulation on both angiotensin type 1 (AT
1
) and AT
2
receptors, the AT
1
antagonist
L158809
alone, or a combination of angiotensin II (1000 ng · kg
−1
· min
−1
) and
L158809
for 14 days to investigate the effects of selective AT
2
receptor stimulation. Apoptosis was analyzed in paraffin-embedded ventricular sections by the terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling (TUNEL) technique. In both transgenic and wild-type mice, administration of a subpressor dose of angiotensin II,
L158809
, or a combination of angiotensin II and
L158809
did not significantly affect the tail-cuff blood pressure or heart-to-body weight ratio, whereas administration of a pressor dose of angiotensin II for 14 or 28 days significantly increased blood pressure and the heart-to-body weight ratio. However, there was no statistical difference between the effects of angiotensin II in transgenic and wild-type mice. The number of TUNEL-positive nuclei was ≈0 to 10 per 100 000 cardiomyocytes, with no difference between transgenic and wild-type mice, regardless of saline infusion or any stimulation. In infarcted canine myocardial tissue sections for positive control, the number of TUNEL-positive nuclei was increased by 13.8 to 19.1 times compared with those in the noninfarcted myocardium. In conclusion, angiotensin II infusion for a period of 28 days failed to induce cardiomyocyte apoptosis regardless of the presence or absence of cardiac AT
2
receptor overexpression. It is unlikely that in mice the AT
2
receptor is a strong signal to induce cardiomyocyte apoptosis in vivo.
Polymorphisms in the
hANP (Human Atrial Natriuretic Peptide) Gene, Albuminuria, and Hypertension
Authors: Nannipieri Monica , Manganiello Mascia , Pezzatini Anna , De Bellis Alessandra , Seghieri Giuseppe , Ferrannini Ele
Published: June 2012

Abstract
—Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the
ScaI
and
BstXI
polymorphisms of the human ANP (
hANP)
gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (
P
<0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the
ScaI
mutated allele (
A
1
) was significantly lower in hypertensive than in control subjects (11% versus 19%,
P
=0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%;
P
<0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the
A
1
allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59;
P
=0.003) but not with hypertension. In the same model, the frequency of the
BstXI
mutated allele (
T
708
) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59;
P
<0.001). We conclude that the mutated genotypes of the
ScaI
polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of
BstXI
polymorphism are positively associated with microalbuminuria.
hANP
gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.
Captopril Suppression Versus Salt Loading in Confirming Primary Aldosteronism
Authors: Agharazii Mohsen , Douville Pierre , Grose John H. , Lebel Marcel
Published: June 2012

Abstract
—This prospective study was designed to compare the captopril suppression test with the salt-loading approach to confirm the diagnosis of primary aldosteronism. A total of 49 patients were referred with a presumed diagnosis of primary aldosteronism. The captopril test was performed in the morning with patients in the seated position after overnight fasting. Blood samples for plasma aldosterone were obtained before captopril administration (25 mg PO) and again 2 hours later. Patients were then subjected to a high salt diet (300 mmol sodium per day for 3 days). On the third day, urinary sodium (24 hours) was measured, and plasma aldosterone levels were measured at 8:00
am
(recumbent) and at noon (standing). Of the 49 patients, 44 had nonsuppressible aldosterone concentrations with all the clinical characteristics of primary aldosteronism: 22 patients had surgically confirmed unique adenoma, and 22 patients had presumed bilateral hyperplasia. There was a significant correlation between plasma aldosterone values of salt-loaded patients (mean of 8:00
am
and noon results) and the values 2 hours after captopril administration (
r
=0.8,
P
<0.01). Plasma aldosterone cumulative distribution curves in primary aldosteronism patients (adenoma and hyperplasia) were not significantly different between the 2 suppression tests. Our results showed that the captopril suppression test is as effective as sodium loading in confirming the diagnosis of primary aldosteronism.
Normal Blood Pressure and Renal Function in Mice Lacking the Bradykinin B
2
Receptor
Authors: Milia Anna Franca , Gross Volkmar , Plehm Ralph , De Silva Jose A. , Bader Michael , Luft Friedrich C.
Published: June 2012

Abstract
—Telemetric blood pressure determinations, heart rate measurements, and pressure-natriuresis-diuresis experiments were used to characterize cardiovascular and renal function in bradykinin B
2
receptor knockout mice fed mouse chow containing 0.25% NaCl or mouse chow containing 4% NaCl. In B
2
receptor knockout mice fed usual mouse chow, the mean arterial blood pressure leveled between 108±1 and 110±3 mm Hg, and the heart rate leveled between 520±26 and 525±29 bpm, values that were not different from those measured in B
1
receptor knockout mice or 129Sv/J control mice. Increasing dietary salt intake did not affect mean arterial blood pressure and heart rate. Accordingly, pressure-natriuresis curves, pressure-diuresis curves, renal blood flow, and glomerular filtration rate were not different between B
2
receptor knockout and 129Sv/J mice. Increasing dietary salt intake to 4% increased renal blood flow to levels between 8.41 and 9.50 mL/min per gram kidney wet weight in 129Sv/J mice, whereas in B
2
receptor–deficient mice, renal blood flow was not affected and ranged between 6.85 and 7.88 mL/min per gram kidney wet weight. Other renal function parameters were not affected. Absence of B
2
receptor function was verified in B
2
receptor knockout mice with bradykinin infusion. These data suggest that the absence of B
2
receptor function does not necessarily make B
2
receptor knockout mice hypertensive or induce salt sensitivity. Presumably, differences in the genetic background or an adaptation to the loss of B
2
receptor function may account for these results, in contrast with earlier reports involving B
2
receptor knockout mice. We hold the latter possibility to be more likely and to be a fruitful possibility for future research.
Rho-Kinase Mediates Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression in Rat Vascular Smooth Muscle Cells
Authors: Funakoshi Yuko , Ichiki Toshihiro , Shimokawa Hiroaki , Egashira Kensuke , Takeda Kotaro , Kaibuchi Kozo , Takeya Motohiro , Yoshimura Teizo , Takeshita Akira
Published: June 2012

Recently, it was shown that Rho-kinase plays an important role in blood pressure regulation. However, it is not known whether Rho-kinase is involved in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine that regulates monocyte recruitment and atherogenesis. Therefore, we examined the role of Rho and Rho-kinase in the angiotensin (Ang) II-induced expression of MCP-1. Ang II dose- and time-dependently enhanced the expression of MCP-1 mRNA and the protein production in vascular smooth muscle cells. CV11974, an Ang II type 1 receptor (AT
1
-R) specific antagonist inhibited the enhancement of MCP-1 expression by Ang II, suggesting that the effect of Ang II is mediated by the AT
1
-R. Botulinum C3 exotoxin, a specific inhibitor of Rho, suppressed Ang II-induced MCP-1 production. To examine the role of Rho-kinase in Ang II-induced MCP-1 expression, we used adenovirus-mediated overexpression of the dominant negative mutant of Rho-kinase (AdDNRhoK) or Y-27632, a specific inhibitor of Rho-kinase. Both AdDNRhoK and Y-27632 strongly inhibited Ang II-induced MCP-1 expression. Although inhibition of extracellular signal-regulated protein kinase (ERK) by PD 098,059 also inhibited Ang II-induced MCP-1 expression, Y-27632 did not affect Ang II-induced activation of ERK. These results indicate that Rho-kinase plays a critical role in Ang II-induced MCP-1 production independent of ERK. The Rho-Rho-kinase pathway may be a novel target for the inhibition of Ang II signaling and the treatment of atherosclerosis.
Rescue of Impaired Angiogenesis in Spontaneously Hypertensive Rats by Intramuscular Human Tissue Kallikrein Gene Transfer
Authors: Emanueli Costanza , Salis Maria Bonaria , Stacca Tiziana , Gaspa Leonardo , Chao Julie , Chao Lee , Piana Andrea , Madeddu Paolo
Published: June 2012

Angiogenesis represents a compensatory response targeted to preserve the integrity of tissues subjected to ischemia. The aim of the present study was to examine whether reparative angiogenesis is impaired in spontaneously hypertensive rats (SHR), as a function of progression of hypertension. In addition, the potential of gene therapy with human tissue kallikrein (HK) in revascularization was challenged in SHR and normotensive Wistar-Kyoto rats (WKY) that underwent excision of the left femoral artery. Expression of vascular endothelial growth factor and HK was upregulated in ischemic hindlimb of WKY but not of SHR. Capillary density was increased in ischemic adductor muscle of WKY (from 266±20 to 633±73 capillaries/mm
2
at 28 days,
P
<0.001), whereas it remained unchanged in SHR (from 276±20 to 354±48 capillaries/mm
2
,
P
=NS), thus compromising perfusion recovery as indicated by reduced plantar blood flow ratio (0.61±0.08 versus 0.92±0.07 in WKY at 28 days,
P
<0.05). In separate experiments, saline or 5×10
9
pfu adenovirus containing the HK gene (Ad.CMV-cHK) or the β-galactosidase gene (Ad.CMV-LacZ) was injected intramuscularly at 7 days after the induction of ischemia. Ad.CMV-cHK augmented capillary density and accelerated hemodynamic recovery in both strains, but these effects were more pronounced in SHR (
P
<0.01). Our results indicate that native angiogenic response to ischemia is impaired in SHR, possibly as a result of defective modulation of endothelial cell mitogens. Supplementation with kallikrein, one of the growth factors found to be deficient in SHR, restores physiological angiogenic response utilitarian for tissue healing. Our discoveries may have important implications in vascular medicine for therapeutic benefit.
Perceived Job Stress but not Individual Cardiovascular Reactivity to Stress Is Related to Higher Blood Pressure at Work
Authors: Fauvel Jean Pierre , Quelin Pierre , Ducher Michel , Rakotomalala Hantanirina , Laville Maurice
Published: June 2012

Psychological stress has been reported to be related to higher blood pressure (BP) and unfavorable cardiovascular profile. However, because of the complexity of personal stress management, a multilevel stress measurement strategy is needed. The aim of this cross-sectional study was to analyze the respective influences of the subjective perception of professional strain (high demand and low latitude) and cardiovascular reactivity to a stress test (Stroop stress test) on BP. Worksite BP was measured in 303 healthy normotensive subjects, 18 to 55 years of age, who worked in the same chemical company. In a subset of 70 randomly selected subjects, 24-hour ambulatory BP was performed to assess BP during working hours. The 20% of subjects who reported the highest job strain (high-strain group) or the highest BP stress reactivity (high-responder group) were compared with the remaining subjects (80%) (non-high-strain or low-responder groups). Subjects who submitted to the highest job strain had significantly higher ambulatory diastolic BP (4.5 mm Hg,
P
=0.015) during only working hours, whereas BP was similar during the remaining hours. Worksite BP and stress cardiovascular reactivity were similar between job strain groups. BP stress reactivity did not influence worksite and ambulatory BP. Spontaneous BP variability assessed by standard deviation and spectral analysis was equivalent between complementary groups. Prevalence of microalbuminuria was significantly higher in the high-responder group (8.2% versus 2.5% in low responders) and only slightly higher in the high-strain group (6.2% versus 3.2% in non-high strain). Potential confounding factors, such as age, gender, alcohol consumption, salt intake, body mass index, and occupation, which were equivalent between groups, did not interfere with our results. Our study quantifies high-professional strain effects on BP levels that appear to be higher only during the working period and to be independent from spontaneous BP variability and stress BP reactivity.
Microsatellite DNA Polymorphism of Human Adrenomedullin Gene in Normotensive Subjects and Patients With Essential Hypertension
Authors: Ishimitsu Toshihiko , Hosoya Kazuyoshi , Tsukada Kohju , Minami Junichi , Futoh Yasuo , Ono Hidehiko , Ohrui Masami , Hino Jun , Kangawa Kenji , Matsuoka Hiroaki
Published: June 2012

Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues. We have cloned and sequenced the genomic DNA encoding the human AM gene and have determined that the gene is located in the short arm of chromosome 11. The 3′-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to hypertension. Genomic DNA was obtained from 272 healthy normotensive subjects (NT) age 57±5 years and 266 patients with essential hypertension (EH) age 53±11 years. The DNA was subject to PCR using a fluorescence-labeled primer, and the number of CA repeats were determined by poly-acrylamide gel electrophoresis. The averaged blood pressure was 117±13/73±9 mm Hg in NT and 170±23/104±12 mm Hg in EH. In Japanese, there existed 4 types of alleles with different CA-repeat numbers: 11, 13, 14, and 19. The frequencies of these alleles were significantly different between NT and EH (χ
2
=9.43,
P
=0.024). Namely, 13.5% of EH carried the 19-repeat allele, whereas the frequency was 6.2% in NT (χ
2
=7.62,
P
=0.007). In NT, plasma AM concentrations were not significantly different between the genotypes. In conclusion, microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to EH, although the gene expression is not likely to be affected by the genotypes.
Negative Inotropic and Chronotropic Effects of Oxytocin
Authors: Mukaddam-Daher Suhayla , Yin Ya-Lin , Roy Josée , Gutkowska Jolanta , Cardinal René
Published: June 2012

Abstract—

We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10
−6
mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (−14.7±4.9% of basal levels, n=5,
P
<0.004) and force of contraction (−52.4±9.1% of basal levels, n=5,
P
<0.001). Co-perfusion with 10
−6
mol/L oxytocin receptor antagonist (n=3) completely inhibited the effects of oxytocin on frequency (
P
<0.04) and force of contraction (
P
<0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5×10
−8
mol/L tetrodotoxin (
P
<0.02) or 10
−6
mol/L atropine (
P
<0.03) but not by 10
−6
mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10
−6
mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (−1.85±1.27% versus −14.7±4.9% in oxytocin alone,
P
<0.05) and force of contraction (−24.9±4.4% versus −52.4±9.1% in oxytocin alone, n=4,
P
<0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10
−4
mol/L (−8.1±1.8%,
P
<0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions.
Renal Interstitial cGMP Mediates Natriuresis by Direct Tubule Mechanism
Authors: Jin Xiao-Hong , Siragy Helmy M. , Carey Robert M.
Published: June 2012

The objective of this study was to test the hypothesis that renal interstitial (RI) cGMP is natriuretic in vivo. In conscious rats (n=8), urinary sodium excretion (U
Na
V) was significantly greater on days 3 and 4 of RI infusion of cGMP (1.17±0.14 and 1.61±0.11 mmol/24 h, respectively) than during vehicle infusion (0.56±0.15 and 0.70±0.17 mmol/24 h, respectively) (
P
<0.01). Similarly, U
Na
V was greater on days 3 and 4 of RI infusion of 8-bromo-cGMP (2.15±0.42 and 2.16±0.1 mmol/24 h, respectively). Protein kinase G inhibitor Rp-8-pCPT-cGMPS reduced cGMP-induced and 8-bromo-cGMP-induced U
Na
V to control levels. Acute RI infusion of
l
-arginine (L-Arg, 40 mg · kg
−1
· min
−1
), but not
d
-arginine, caused an increase in U
Na
V from 1.65±0.11 to 4.07±0.1 μmol/30 min (
P
<0.01). This increase was blocked by RI infusion of
N
G
-nitro-
l
-arginine methyl ester (100 ng · kg
−1
· min
−1
) by the phosphodiesterase (PDE II) activator 5,6DMcBIMP (0.01 μmol/μL), by PDE II (0.03 U · kg
−1
· min
−1
) itself, or by the soluble guanylyl cyclase inhibitor 1-
H
-[1,2,4]oxadiazolo-[4,2-α]quinoxalin-1-one (ODQ, 0.12 mg · kg
−1
· min
−1
). The PDE II activator also blocked L-Arg-stimulated cGMP levels. The NO donor
S
-nitroso-
N
-acetylpenicillamine (SNAP, 0.12 μmol · L
−1
· kg
−1
· min
−1
) increased U
Na
V from 1.65±0.11 to 2.93±0.08 μmol/30 min (
P
<0.01), and this response was blocked completely by ODQ. Renal arterial but not RI administration of the heat-stable enterotoxin of
Escherichia coli
induced natriuresis. RA infusion of cGMP (3 μg/min) increased U
Na
V, renal blood flow (RBF), and glomerular filtration rate (GFR). Renal cortical interstitial cGMP infusion increased U
Na
V with no effect on total RBF, renal cortical blood flow, or GFR. Similarly, the natriuretic actions of renal interstitial L-Arg or SNAP were not accompanied by any change in RBF or GFR. Medullary cGMP infusion had no effect on U
Na
V, total RBF, or medullary blood flow. Texas red-labeled cGMP infused via the RI space was distributed exclusively to cortical renal tubular cells. The results demonstrate that RI cGMP inhibits renal tubular sodium absorption via protein kinase G independently of hemodynamic changes. These observations indicate that the cortical interstitial compartment provides a potentially important domain for cell-to-cell signaling within the kidney.
Effect of Salt Intake on Renal Excretion of Water in Humans
Authors: He Feng J. , Markandu Nirmala D. , Sagnella Giuseppe A. , MacGregor Graham A.
Published: June 2012

Two studies were performed to determine the quantitative relationship between salt intake and urinary volume (U
v
) in humans. In study 1, 104 untreated hypertensives were studied on the fifth day of a high- and a low-salt diet. The 24-hour U
v
was 2.2 L (urinary sodium [U
Na
] 277 mmol) on the high-salt diet and decreased to 1.3 L (
P
<0.001) (U
Na
20.8 mmol) on the low-salt diet. The reduction in 24-hour U
v
was significantly related to the decrease in 24-hour U
Na
(
P
<0.001) and predicts that a 100-mmol/d reduction in salt intake would decrease 24-hour U
v
by 367 mL. In study 2, 634 untreated hypertensives were studied on their usual diet. There was a significant relationship between 24-hour U
v
and U
Na
(
P
<0.001). This predicts that a 100-mmol/d reduction in salt intake would decrease 24-hour U
v
by 454 mL. The International Study of Salt and Blood Pressure (INTERSALT) of 1731 hypertensives and 8343 normotensives on their usual diet showed that 24-hour U
v
was significantly related to U
Na
(
P
<0.001) and predicted that a 100-mmol/d reduction in salt intake would decrease 24-hour U
v
by 379 and 399 mL in hypertensives and normotensives, respectively. These findings document the important effect that salt intake has on U
v
. The recommended reduction in salt intake in the general population is from 10 to 5 g/d. This would reduce fluid intake in the population by ≈350 mL/d per person. This would have a large impact on the sales of soft drinks, mineral water, and beer.
Adrenal Response to Angiotensin II in Black Hypertension
Authors: Fisher Naomi D.L. , Hurwitz Shelley , Jeunemaitre Xavier , Price Deborah A. , Williams Gordon H. , Hollenberg Norman K.
Published: June 2012

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na
+
intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (
P
=0.0001). Blacks, on the other hand, showed no gender difference (
P
=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.
Blood Pressure and Inflammation in Apparently Healthy Men
Authors: Chae Claudia U. , Lee Richard T. , Rifai Nader , Ridker Paul M.
Published: June 2012

Inflammation plays an important role in the development of atherosclerosis, but the specific stimuli governing cytokine release in atherogenesis are unknown. We examined the hypothesis that hypertension may increase the risk of atherosclerosis via proinflammatory effects. In a cross-sectional study involving 508 apparently healthy men, we studied the association between blood pressure and baseline plasma concentrations of 2 inflammatory markers, intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6). Increase in systolic blood pressure (SBP) (
P
=0.003), pulse pressure (PP) (
P
=0.019), and mean arterial pressure (
P
=0.014) was significantly associated with levels of sICAM-1. All of these measures of blood pressure, as well as diastolic blood pressure (DBP), were significantly associated with levels of IL-6 (all, P
≤
0.001). In multiple linear regression models controlled for age and other cardiac risk factors, SBP (7.6 ng/mL per 10 mm Hg,
P
=0.016) and PP (8.13 ng/mL per 10 mm Hg,
P
=0.038) were significantly associated with sICAM-1 levels, whereas SBP (0.11 pg/mL per 10 mm Hg,
P
<0.001), DBP (0.11 pg/mL per 10 mm Hg,
P
=0.008), PP (0.10 pg/mL per 10 mm Hg,
P
=0.009), and mean arterial pressure (0.15 pg/mL per 10 mm Hg,
P
<0.001) had similar strong relationships with log-transformed IL-6 levels. Therefore, in apparently healthy men, we observed significant graded relationships between blood pressure and levels of sICAM-1 as well as IL-6. These data suggest that increased blood pressure may be a stimulus for inflammation and that this is a possible mechanism underlying the well-established role of hypertension as a risk factor for atherosclerotic disease.
High-Salt Diet Enhances Vascular Reactivity in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure
Authors: Barron Laura A. , Giardina Jena B. , Granger Joey P. , Khalil Raouf A.
Published: June 2012

Abstract
—

— High-salt (HS) diet is often associated with increased vascular resistance and arterial pressure; however, the effects of HS intake on the vascular control mechanisms of arterial pressure during pregnancy are unclear. We investigated whether a HS diet during pregnancy is associated with increases in vascular reactivity. Active stress was measured in aortic strips of virgin and normal pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced by reduction in uterine perfusion pressure (RUPP), fed either normal-sodium (NS, 1%) or HS diet (8%) for 7 days. In endothelium-intact strips, phenylephrine (Phe) caused a concentration-dependent contraction that was greater in RUPP rats than in normal pregnant or virgin rats and was significantly enhanced in pregnant/HS and RUPP/HS rats compared with pregnant/NS and RUPP/NS rats, respectively. Removal of the endothelium enhanced the Phe-induced stress slightly in virgin rats and significantly in pregnant/NS but not in pregnant/HS, RUPP/NS, or RUPP/HS. In endothelium-intact strips, acetylcholine (ACh) caused a concentration-dependent relaxation that was reduced in RUPP/NS (max, 31%) compared with pregnant/NS rats (max, 75%). ACh relaxation was further reduced in pregnant/HS rats compared with pregnant/NS rats and in RUPP/HS rats compared with RUPP/NS rats. Pretreatment of endothelium-intact strips with N
G
-nitro-
l
-arginine methyl ester (L-NAME, 10
−4
mol/L), to inhibit NO synthase, or with 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10
−6
mol/L), to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced contraction in pregnant/NS rats but not in pregnant/HS, RUPP/NS, or RUPP/HS rats. Basal and ACh-induced nitrite/nitrate production from aortic strips showed significant reduction in pregnant/HS rats compared with pregnant/NS rats but not in RUPP/HS rats compared with RUPP/NS rats. Sodium nitroprusside, an exogenous NO donor, caused relaxation of Phe contraction that was similar in virgin or pregnant rats on an NS or HS diet but was significantly reduced in RUPP/HS rats (ED
50
6×10
−8
mol/L) compared with RUPP/NS rats (ED
50
6×10
−9
mol/L). Thus, a HS diet in normal pregnant and RUPP rats is associated with increases in vascular reactivity. The enhanced vascular reactivity with the HS diet is possibly related to abnormalities in NO synthesis/release from the endothelium in normal pregnant rats and an additional decrease in the sensitivity of the smooth muscle to relaxation by NO in pregnant rats with reduced uterine perfusion pressure.
Hypertension in obese patients: hemodynamic and volume studies.
Authors: Mujais S K , Tarazi R C , Dustan H P , Fouad F M , Bravo E L
Published: June 2012

Distinct hemodynamic and volume characteristics have been suggested for established hypertension in severe obesity, namely, a high cardiac output, and expanded blood volume, and a normal peripheral resistance. To evaluate whether hypertension in moderately obese patients represents a separate entity that can be defined by hemodynamic and volume profiles, we studied these in 50 such patients and compared results with those obtained in 59 nonobese essential hypertensives and 25 normal subjects. Both obese and nonobese hypertensives had a normal cardiac index (men, 2.8 +/- 0.1 vs 2.8 +/- 0.09 liter/min/m2; women, 2.9 +/- 0.1 vs 2.8 +/- 0.1 liter/min/m2, respectively) and similarly elevated total peripheral resistance (men, 47.1 +/- 2.3 vs 46.5 +/- 1.9 U . m2; women, 45.0 +/- 2.4 vs 44.0 +/- 1.3 U . m2, respectively) as compared to normals (cardiac index: men, 2.9 +/- 0.09 liter/min/m2, women, 3.4 +/- 0.2 liter/min/m2; total peripheral resistance: men, 29.4 +/- 1.0 U . m2, women, 28.3 +/- 2.8 U. m2). Volume measurements corrected to body surface area showed that both obese and nonobese hypertensive patients had lower blood volume (men, 2.6 +/- 0.05 vs 2.5 +/- 0.05 liter/m2; women, 2.2 +/- 0.05 vs 2.3 +/- 0.05 liter/m2, respectively) than normals (men, 2.9 +/- 0.08 liter/m2; women, 2.5 +/- 0.08 liter/m2). The results of this study suggest that hypertension in moderately obese subjects is similar in its hemodynamic and volume profiles to hypertension in the nonobese and that the presence of obesity does not alter the hemodynamic characteristics of established essential hypertension.
Renal denervation at weaning retards development of hypertension in New Zealand genetically hypertensive rats.
Authors: Diz D I , Nasjletti A , Baer P G
Published: June 2012

The development of hypertension was studied in 3 to 13-week old New Zealand genetically hypertensive (NZGH) rats subjected to bilateral renal denervation (D) or sham operations (S) at 4 weeks of age. Denervation retarded the development of hypertension and delayed the establishment of stable hypertension; blood pressure of D-NZGH rats was 15-40 mm Hg lower than that of S-NZGH rats from 3 to 7 weeks after surgery, but was similar in the two groups thereafter. D-rat renal catecholamine content was reduced to 17% of control at 1 week after surgery; by the fourth week post surgery, renal catecholamine content had risen to 40% of control, and blood pressure of the D-group had begun to rise, suggesting that spontaneous renal reinnervation prevented the antihypertensive effect of renal denervation from being a permanent one. During the period when blood pressure of the S-rats was greater than that of the D-rats, urinary sodium excretion of the two groups was not significantly different, suggesting that over this interval the relationship between blood pressure and urinary sodium excretion shifted to the right along the pressure axis in the S-rats but not in the renal denervated rats. Throughout the 60-day period of observation, urinary excretion of prostaglandin E2 and kallikrein did not differ between the renal-denervated and sham-operated rats.
Aldosterone infusion into the rat and dose-dependent changes in blood pressure and arterial ionic transport.
Authors: Garwitz E T , Jones A W
Published: June 2012

Induction of hypertension by implantation or injection of deoxycorticosterone acetate (DOCA) requires a dose well above the physiological range. The objective of this study was to produce hypertension in rats by chronic infusion of d-aldosterone, a more potent mineralocorticoid. Aldosterone infused at a dose of 1 microgram/hr for 4 weeks gave maximal rise in systolic blood pressure (132 +/- 3 vs 203 +/- 7 mm Hg). A significant rise in blood pressure was achieved at 0.1 microgram/hr (170 +/- 6 mm Hg) which was associated with a 2.3-fold rise in plasma aldosterone levels (7.6 +/- 0.4 vs 17.7 +/- 2.2 ng/dl). A series of isotope flux studies on the aorta and femoral artery from hypertensive animals demonstrated increases in 42K and 36Cl turnover. In both vessels the largest changes in ion turnover were observed in vessels from animals infused with aldosterone at 0.25 micrograms/hr. Increases in 42K and 36Cl turnover were detected as early as 1 week after the start of aldosterone infusion, well before a significant rise in blood pressure had occurred.
Attenuation of pressor responses to norepinephrine and pitressin and potentiation of pressor response to angiotensin II by captopril in human subjects.
Authors: Imai Y , Abe K , Seino M , Haruyama T , Tajima J , Sato M , Goto T , Hiwatari M , Kasai Y , Yoshinaga K , Sekino H
Published: June 2012

The present study was conducted to investigate the influence of captopril on cardiochemodynamic responses in 38 normal volunteers (20- to 35-year-old men) to exogenously administered vasopressor substances. Norepinephrine (NE), 0.05, 0.1, and 0.2 micrograms/kg min-1; angiotensin II (AII), 5, 10, and 20 ng/kg min-1; and pitressin (2 mU/kg min-1) were infused for 10 minutes. Each infusion was reported twice, and the responses were reproducible. Captopril (50 mg by mouth) significantly attenuated the pressor responses to NE and pitressin, but the decrease in heart rate in response to NE and pitressin was almost the same before and after captopril treatment, suggesting that captopril potentiates reflex slowing of the heart. Captopril significantly potentiated the pressor response to AII. Attenuation of pressor response and potentiation of reflex slowing of the heart, in response to NE and pitressin, disappeared when a subdepressor dose of AII (1 ng/kg min-1) was infused in addition to captopril. Infusion of a subdepressor dose of bradykinin (BK), 0.1 microgram/kg min-1, had no influence on the pressor response to NE. In the subjects treated with indomethacin (225 mg/54 hrs), captopril still attenuated the pressor response to NE. These results suggest that captopril attenuates the pressor responses to NE and pitressin primarily by depletion of endogenous AII; decreased AII may desensitize the contraction of arterial smooth muscle and may potentiate the compensatory reflex mechanism.
Heparin lowers the blood pressure in hypertensive rats.
Authors: Susic D , Mandal A K , Kentera D
Published: June 2012

This study describes the effect of heparin on blood pressure, cardiac output, and total peripheral resistance in spontaneously hypertensive and one-kidney, one clip Goldblatt hypertensive rats. Administration of heparin (200 units/day/rat) for 8 weeks to young (6-week-old) spontaneously hypertensive rats (SHR) resulted in an attenuated rise in blood pressure; mean blood pressure in heparin-treated SHR (180 +/- mm Hg) was significantly lower (p less than 0.05) than that in control SHR (205 +/- 7 mm Hg). Similar heparin treatment started immediately after the induction of one-kidney, one clip (Goldblatt) hypertension reduced the rise in blood pressure. After 4 weeks of treatment, heparin-treated Goldblatt hypertensive rats had much lower blood pressure (150 +/- 4 mm Hg) than did control rats (7178 +/- 8 mm Hg). The difference was highly significant (p less than 0.01). Similarly, heparin treatment also lowered the blood pressure in rats with developed Goldblatt hypertension. After the cessation of heparin treatment, the blood pressure returned to pretreatment level in these rats. When compared to vehicle-treated rats, heparin-treated animals with either spontaneous or Goldblatt hypertension concomitantly exhibited a significant increase in cardiac output, and significant decreases in total peripheral resistance and packed cell volume. Further, the left ventricular weight to body weight ratio was significantly lower (p less than 0.05) in heparin-treated than control animals. Since a relationship seems to exist between an increase in packed cell volume and blood viscosity and the rise in arterial pressure, this blood-pressure-lowering effect of heparin may be attributed to a decrease in packed cell volume.
Biochemical and mechanical properties of resistance arteries from normotensive and hypertensive rats.
Authors: Brayden J E , Halpern W , Brann L R
Published: June 2012

Microchemical techniques were employed to measure the DNA, contractile proteins, and connective tissue protein composition of 150 micrograms samples of mesenteric and cerebral resistance arteries taken from 25-week-old spontaneously hypertensive (SHR) and control Wistar-Kyoto (WKY) rats. The active and passive mechanical properties of intact resistance arteries also were determined. The DNA content of branches of the posterior cerebral and mesenteric arteries (170 micrometers I.D.) were elevated by nearly 30% in the SHR compared to the WKY. The amounts of actin and myosin when normalized to DNA content were unchanged in SHR mesenteric arteries compared to control, whereas these amounts were decreased by 25% and 49%, respectively, in the SHR cerebral arteries vs control. The functional implications of these contractile protein measurements agreed with determinations of active smooth muscle cell stress-generating capabilities, which were found unchanged in the mesenteric arteries and depressed in the SHR cerebral arteries. Neither the absolute amounts and concentrations (relative to tissue mass) of elastin in mesenteric and cerebral arteries, nor the absolute amounts and concentrations of collagen in the mesenteric artery, were changed in the SHR. However, cerebral artery total collagen was elevated by 31% in the SHR, with no change in collagen concentration between the two strains. Under conditions where the smooth muscle cells were fully relaxed, the internal radii of SHR brain and SHR mesenteric arteries were smaller at all pressures with respect to the WKY. However, only the SHR cerebral arteries were actually less distensible than controls. Thus, it is apparent that hypertension-associated changes in the chemical and mechanical properties of the resistance artery wall vary considerably depending upon which vascular bed is examined. The measurements made in this study suggest that these changes are more pronounced in brain arteries. This finding could be of significance regarding the autoregulatory capability of, and blood pressure distribution within, brain vessels of hypertensive animals.
Hypoalgesia in genetically hypertensive rats (SHR) is absent in rats with experimental hypertension.
Authors: Sitsen J M , de Jong W
Published: June 2012

In this study a possible relationship between regulatory mechanisms involved in pain and blood pressure control has been investigated in the rat. Spontaneously hypertensive rats (SHR), their normotensive Wistar-Kyoto (WKY) controls, and two experimental models of hypertension together with their appropriate sham-operated controls were tested for their responsiveness to pain. Two methods for measurement of nociceptive responsiveness (hot plate and electric footshock threshold) were used. A diminished responsiveness was observed in both young (still normotensive) and adult (hypertensive) SHR. Pretreatment with naloxone reduced hot plate response times of adult SHR to the level of WKY, indicating opioid receptor involvement. Despite severe hypertension in rats with a renal artery clip and in DOCA-salt treated rats, no reduction of pain sensitivity as compared to sham-operated controls was evident in the hypertensive rats as assessed by both methods. It is concluded, that the higher pain threshold in SHR is probably determined by genetic factors rather than hypertension.
Synergistic effect of captopril with hydrochlorothiazide for the treatment of low-renin hypertensive black patients.
Authors: Holland O B , von Kuhnert L , Campbell W B , Anderson R J
Published: June 2012

Diuretics have been particularly successful for treatment of low-renin hypertension (LRH), although they may cause metabolic complications such as hypokalemia and hyperglycemia. Since the efficacy of diuretics is largely limited by reactive angiotensin II production, a combination of a converting enzyme inhibitor with a diuretic should be synergistic, particularly in LRH, where heightened aldosterone production in response to angiotensin II has been noted. Eighteen patients with LRH were treated initially with either captopril alone (450 mg/day) or hydrochlorothiazide (HCTZ) (up to 100 mg/day). Captopril alone only reduced average placebo standing blood pressure from 151/100 to 146/96 mm Hg. Combination of HCTZ with captopril reduced average standing blood pressure to 111/76 mm Hg at 3 months and 116/81 mm Hg at 1 year while allowing reductions in average captopril dosage to 100 mg/day and HCTZ dosage to 40 mg/day and reductions in supplemental potassium administration and in HCTZ-induced hyperglycemia. Captopril monotherapy did not increase urinary excretion of kallikrein, prostaglandin E2, or 6-keto prostaglandin F1 alpha, a metabolite of prostacyclin, and did not reduce urinary aldosterone excretion chronically. Thus, a synergism of captopril with HCTZ may be advantageous in certain patients with LRH.
Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.
Authors: Lin M S , McNay J L , Shepherd A M , Musgrave G E , Keeton T K
Published: June 2012

To determine the role of the peripheral sympathetic nervous system in the persistent tachycardia caused by the antihypertensive drug hydralazine, we examined the temporal relationships between the changes in heart rate and plasma norepinephrine concentration and the reduction in blood pressure produced by a range of doses of hydralazine administered intravenously to five hypertensive patients. Significant linear correlations were found between the increases in heart rate and plasma norepinephrine concentration and the reduction in blood pressure at 15 and 30 minutes after injection. However, at 240 minutes after injection, changes in heart rate and plasma norepinephrine were not correlated with changes in blood pressure and were disproportionately elevated relative to the reduction in blood pressure. A significant linear correlation between changes in heart rate and plasma norepinephrine concentration was noted at 15, 30, and 240 minutes after injection. The temporal discordance of the changes of both heart rate and plasma norepinephrine relative to the reduction in blood pressure and the significant linear correlation between the increases in heart rate and plasma norepinephrine concentration suggest that continued activation of the peripheral sympathetic nervous system contributes to the persistent tachycardia seen after the administration of hydralazine.
Simple portable device for sampling a whole day's urine and its application to hypertensive outpatients.
Authors: Tochikubo O , Uneda S , Kaneko Y
Published: June 2012

To simplify 24-hour urine collection for epidemiological and clinical examinations, we devised a portable, semiautomatic urine sampling cup with divided partitions. The cup, 6.6 cm in diameter and 14 cm in height, is double-bottomed and has a pipe-shaped scale and a cock leading to the lower compartment. It is so devised that 1/m of the urine volume excreted into the upper compartment each time remains in the pipe scale, and then comes down into the lower compartment by manipulating the cock. The urine in the lower compartment remains when the urine in the upper compartment is discarded. The cup is carried in a vinyl bag. By repeating this manipulation. 1/m of the total urine excreted during 24 hours can be collected in the small cup (proportional sampling method). When the 24-hour urinary sodium excretion measured by the conventional method and that measured by this method were compared, the correlation coefficient (r) was 0.98, and the average variation was 2.0 +/- 10.8 (SD) mEq (n = 32). Use of this device for outpatients was convenient and enabled counseling on salt intake.
Adrenergic neurotransmission in tail arteries from two-kidney, one clip, renal hypertensive rats.
Authors: Webb R C , Johnson J C , Bohr D F
Published: June 2012

The goal of this study was to determine if increased vascular smooth muscle sensitivity to norepinephrine in two-kidney, one clip (2K1C) hypertensive rats is the result of a decrease in adrenergic nerve function. Vascular sensitivity to norepinephrine was measured in isolated tail artery strips from 2K1C hypertensive and normotensive rats and in various arterial stripe preparations from normotensive rats that exhibit varying degrees of adrenergic innervation. In each case, the characteristic of the vascular smooth muscle response in the vessel with the least amount of adrenergic innervation simulated the response of the vascular smooth muscle from the 2K1C hypertensive rats. Release or displacement of endogenous norepinephrine by electrical stimulation, tyramine, potassium-free solution, and potassium excess, and measurement of tissue content of norepinephrine suggest that the blood vessels of 2K1C hypertensive animals are depleted of catecholamine stores. Based on these observations it is concluded that the increased sensitivity of vascular smooth muscle to norepinephrine in 2K1C hypertensive rats is the result of a diminished adrenergic innervation. This increased sensitivity of the vasculature may be a response of the smooth muscle cells to a decrease in innervation or the consequence of vascular wall hypertrophy leading to an increased number of smooth muscle cells that are remote from their adrenergic supply.
Increase in collateral arterial endothelial cell proliferation induced by captopril after renal artery stenosis in the rat.
Authors: Odori T , Paskins-Hurlburt A , Hollenberg N K
Published: June 2012

Studies to assess the role of blood pressure rise in the growth of the collateral arterial supply following renal artery stenosis were performed in 70 rats. Assessment of the proliferative response was made by coded reading of endothelial cell turnover following tritiated thymidine administration, 5 days after renal artery stenosis. Stenosis induced the anticipated brisk increase in endothelial cell turnover in arterial collaterals and in the ipsilateral renal vein, and ureteric epithelium. Blood pressure elevation did not appear to play the dominant role, as the proliferative response did not parallel blood pressure changes; moreover, neither bilateral renal artery stenosis, designed to enhance the hypertension, nor hydralazine administration, to reduce the blood pressure, influenced endothelial cell turnover. A contribution of elevated blood pressure to the vasoproliferative response, however, was not ruled out definitively in this study. Captopril, also administered to assess the same question, resulted in an enhanced endothelial cell proliferative response, both in frequency and in degree, an observation that became the central thrust of our study. The mechanism by which converting enzyme inhibitor modified endothelial cell turnover is not clear, but may well provide insight into the responsible factors.