bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Calcium Antagonists on Glomerular Arterioles in Spontaneously Hypertensive Rats
Authors: Sabbatini Maurizio , Leonardi Amedeo , Testa Rodolfo , Vitaioli Lucia , Amenta Francesco
Published: June 2012

Abstract
—Through the use of microanatomic techniques, we investigated the effects of treatment with some dihydropyridine-type calcium antagonists (CAs) (ie, lercanidipine, manidipine, and nicardipine) and with the nondihydropyridine-type vasodilator hydralazine on hypertension-dependent glomerular injury and on the morphology of afferent and efferent arterioles in spontaneously hypertensive rats (SHR). Fourteen-week-old male SHR and age-matched normotensive Wistar-Kyoto rats were left untreated (control groups). Four additional groups of 14-week-old SHR were treated for 12 weeks with daily oral doses of 2.5 mg/kg lercanidipine, 5 mg/kg manidipine, 3 mg/kg nicardipine, or 10 mg/kg hydralazine. These treatments decreased systolic blood pressure values to a similar extent in SHR. Signs of glomerular injury, as characterized by glomerulosclerosis, hypertrophy, and an increased number of mesangial cells, were observed in control SHR. The treatment with CAs improved glomerular morphology and decreased the number of mesangial cells. Lercanidipine and manidipine were more effective than nicardipine in countering glomerular injury. In the SHR, both afferent and efferent arterioles revealed luminal narrowing, accompanied by increased wall thickness in efferent arterioles. The dihydropyridine-type derivatives that were tested decreased the luminal narrowing of afferent arterioles. Lercanidipine and manidipine countered the luminal narrowing of efferent arterioles. Hydralazine had no effect on hypertension-dependent glomerular injury or vascular changes. The present data indicate that lercanidipine and manidipine vasodilate afferent and efferent arterioles in SHR. A vasodilatory activity on efferent arteriole, which is not induced by the majority of CAs, may represent an useful property in the treatment of hypertension complicated by renal disease.
Glomerular Hyperfiltration in Hypertensive African Americans
Authors: Kotchen Theodore A. , Piering Andrew W. , Cowley Allen W. , Grim Clarence E. , Gaudet Daniel , Hamet Pavel , Kaldunski Mary L. , Kotchen Jane M. , Roman Richard J.
Published: June 2012

Abstract
—The incidence of end-stage renal disease attributable to hypertension is 5-fold greater in African Americans than in whites. To determine whether glomerular hyperfiltration is an antecedent to renal failure, we compared responses of renal blood flow and glomerular filtration rate to graded infusions of norepinephrine (0.01, 0.025, and 0.05 μg · kg
−1
· min
−1
for 30 minutes each) in 29 African Americans and 33 age-matched French Canadian whites with essential hypertension. Renal blood flow and glomerular filtration rate were measured by using a constant-infusion technique of PAH and inulin, respectively. Studies were conducted on an inpatient clinical research center, and antihypertensive medications had been discontinued for at least 1 week. Based on 24-hour blood pressure monitoring, nighttime blood pressures decreased (
P
<0.01) in the French Canadians but not in the African Americans. Baseline renal blood flow was higher (
P
<0.05) in the African Americans (1310±127 mL · min
−1
per 1.73 m
2
) than in the French Canadians (1024±42 mL · min
−1
per 1.73 m
2
); baseline glomerular filtration rate was also higher (
P
<0.01) in the African Americans (140±4 versus 121±4 mL · min
−1
per 1.73 m
2
). In response to norepinephrine-induced blood pressure increases, renal blood flow was autoregulated and did not change in either patient group. In the African Americans, glomerular filtration rate increased (
P
<0.01) to 167 mL · min
−1
per 1.73 m
2
during the first norepinephrine infusion, without subsequent change. In contrast, glomerular filtration rate did not change with norepinephrine-induced increases of blood pressure in the French Canadians. In the African Americans, the elevation of baseline glomerular filtration rate, with a further increase in response to norepinephrine, may be indicative of glomerular hyperfiltration. Glomerular hyperfiltration and lack of nocturnal blood pressure decline may contribute to the higher incidence of end-stage renal disease in hypertensive African Americans.
Prognostic Value of Ambulatory Blood Pressure
Authors: Verdecchia Paolo
Published: June 2012

Abstract
—This article is a critical review of the available evidence on the prognostic value of ambulatory blood pressure (ABP). Several event-based cohort studies have shown that ABP improves cardiovascular risk stratification over and beyond traditional risk factors, including office BP. Most of these studies have been conducted in subjects with essential hypertension who were untreated at the time of execution of ABP monitoring; other studies have been conducted in subjects who were poorly controlled with treatment or in the general population. In these studies, ABP was examined as a continuous variable or with operational risk categories. Cardiovascular risk showed a direct and independent association with the observed ABP (systolic, diastolic, and pulse) and an inverse association with the degree of BP reduction from day to night. Cardiovascular risk was also directly associated with the difference between the observed value of ABP and that predicted from the office BP. White-coat hypertension versus ambulatory hypertension and dippers versus nondippers are 2 classifications based on arbitrary operational risk categories. A blunted or absent BP reduction from day to night, defined with ABP as a continuous variable or with operational thresholds, was also associated with a worse outcome regardless of the average value of ABP during the 24 hours. Overall, these studies indicate that ABP monitoring is particularly valuable to refine cardiovascular risk stratification in untreated subjects with office hypertension and in those with resistant hypertension. Intervention studies targeted at ABP are now needed.
Development of Hypertension in a Rat Model of Diet-Induced Obesity
Authors: Dobrian Anca D. , Davies Michael J. , Prewitt Russell L. , Lauterio Thomas J.
Published: June 2012

Abstract
—Although obesity is a risk factor for hypertension, the relationship between these 2 conditions is not well understood. Therefore, we examined some parameters of hypertension and cardiovascular disease in a dietary model of obesity. Male Sprague-Dawley rats were provided either a control diet (C) or a diet containing 32% kcal as fat (similar to a Western diet) for 1, 3, or 10 weeks. Rats in the latter group diverged based on body weight gain into obesity-prone (OP) and obesity-resistant (OR) groups. Systolic blood pressure in OP rats was significantly higher after 10 weeks of the diet (149±4.8 mm Hg) compared with both OR and C groups (131±3.7 and 129±4.5 mm Hg, respectively). The aortic wall area of OP rats was significantly increased, indicating arterial hypertrophy, and a 2-fold increase in plasma renin activity was found in OP rats compared with OR and C rats. The lipid profile showed a significant increase in plasma and VLDL triglycerides of OP versus OR and C groups as early as 3 weeks on the diet. Plasma and LDL-cholesterol levels were increased in the OP group versus the OR and C groups after 3 weeks of the diet, but the difference was blunted after 10 weeks. Lipid peroxidation (thiobarbituric acid–reactive substances) in OP rats was increased 2-fold in LDL and 1.5-fold in aortic wall compared with OR rats, suggesting an increased oxidative stress in these animals. Periodic acid–Schiff staining of the kidney showed mesangial expansion and focal sclerosis that were more prominent in OP rats than in OR rats. The results suggest that hypercholesterolemia, but not hypertriglyceridemia, is linked to the diet; that hypertension and renin-angiotensin system activation are associated with obesity; and that lipid peroxidation and renal damage are the results of both factors.
Platelet-Derived Nitric Oxide and Coronary Risk Factors
Authors: Ikeda Hisao , Takajo Yoshinori , Murohara Toyoaki , Ichiki Kazuya , Adachi Hisashi , Haramaki Nobuya , Katoh Atsushi , Imaizumi Tsutomu
Published: June 2012

Abstract
—Platelet aggregation is inhibited through a negative feedback mechanism by the
l
-arginine/nitric oxide (NO) pathway found in platelets themselves. We have shown that long-term smoking impairs the bioactivity of platelet-derived NO (PDNO), resulting in an increased platelet aggregability. However, little is known about the relation between other coronary risk factors and PDNO release. Accordingly, this study was undertaken to examine whether other coronary risk factors are related to the impairment of PDNO bioactivity. We measured collagen-induced PDNO release with an NO-selective electrode in 61 subjects (mean age 47 years, range 24 to 74 years) who underwent complete physical and laboratory examinations. There was a significant inverse correlation between PDNO release and the number of coronary risk factors (
r
=−0.61,
P
<0.001). Univariate analysis showed a significant inverse correlation between PDNO release and age (
r
=−0.33,
P
<0.01), mean arterial pressure (
r
=−0.40,
P
<0.002), total cholesterol level (
r
=−0.31,
P
<0.02), and LDL-cholesterol level (
r
=−0.33,
P
<0.02). PDNO release was significantly lower in long-term smokers than in nonsmokers (
P
<0.001). With multiple stepwise regression analysis, PDNO release correlated significantly and independently (
r
2
=0.51), with smoking (
F
=37.8), age (
F
=7.1), and mean arterial pressure (
F
=5.1). Thus, we demonstrated that coronary risk factors are associated with an impairment of PDNO release by human platelets. Our findings may contribute to the understanding of the pathophysiological link between coronary risk factors and atherothrombotic disease.
Physical Exercise, Aortic Blood Pressure, and Aortic Wall Elasticity and Composition in Rats
Authors: Niederhoffer Nathalie , Kieffer Pascal , Desplanches Dominique , Lartaud-Idjouadiene Isabelle , Sornay Marie-Hélène , Atkinson Jeffrey
Published: June 2012

Abstract
—With a training schedule (8 weeks’ treadmill running at 30 m/min up a 10% incline 5 d/wk for 90 min/day), we investigated whether exercise modifies aortic wall dimensions, composition (calcium and elastin content), or stiffness in normotensive 6-month-old male Wistar WAG/Rij rats. Maximal oxygen uptake was measured in half of the rats (n=10 per group). Wall stiffness was evaluated in the other half (9 trained and 10 untrained) on the basis of changes in thoracoabdominal pressure pulse wave velocity and differences in amplitude between the peripheral and central aortic pressure signals. Experiments were performed in nonanesthetized, unrestrained rats and then after pithing. The impact of exercise on the oxidative capacity of the plantaris muscles was evaluated with the measurement of citrate synthase activity. Training increased maximal oxygen uptake by 34% and citrate synthase activity by 40%. Mean peripheral aortic pressure increased by 6% and 19% in trained rats, under awake and pithed conditions, whereas mean central aortic pressure increased by 16%, after pithing only. All indexes of aortic stiffness were similar in trained and control rats, as were aortic wall dimensions, composition, cardiac mass, and heart rate. In conclusion, physical exercise in young rats appears to have no effect on aortic stiffness.
Inhibition of Vascular Smooth Muscle Cell Migration by Elevation of Extracellular Potassium Concentration
Authors: Ma Ge , Mason David P. , Young David B.
Published: June 2012

Abstract
—The effect of potassium on the migration of vascular smooth muscle cells was analyzed in media made with extracellular potassium concentrations of 3, 4, 5, and 6 mmol/L. The migration of cultured porcine coronary artery cells was stimulated with platelet-derived growth factor (PDGF)-BB. In the first study, cells were exposed to PDGF-BB at concentrations of 0, 10, or 20 ng/mL for 5 hours with the use of a Boyden chamber. Cells were quiescent overnight in 0.5% fetal bovine serum in Dulbecco’s modified Eagle’s medium with an extracellular potassium concentration of 4 mmol/L. With increasing potassium concentration, migration was significantly inhibited (
P
<0.02, 2-way ANOVA). In the cells exposed to 10 ng/mL PDGF-BB, migration ranged from 500±86% to 294±44% (value in wells with 0 ng/mL PDGF-BB and 4 mmol/L potassium concentration=100%) in medium containing 3 to 6 mmol/L extracellular potassium concentration (
P
<0.03). Long-term potassium exposure was investigated in cells grown in 5% serum in Dulbecco’s modified Eagle’s medium with an extracellular potassium concentration of 3, 4, 5, or 6 mmol/L for 3 to 4 weeks. Migration was assessed with 0 or 20 ng/mL PDGF-BB. Migration was significantly inhibited by the elevation of extracellular potassium concentration (
P
<0.01, 2-way ANOVA). With 20 ng/mL PDGF-BB, the migration rates ranged from 152±11% in medium with 3 mmol/L potassium to 69±5% in 6 mmol/L potassium (
P
<0.01). Increases in extracellular potassium concentration within the physiological range significantly and directly inhibit vascular smooth muscle cell migration.
Effects of Renal Medullary and Intravenous Norepinephrine on Renal Antihypertensive Function
Authors: Correia Anabela G. , Madden Anna C. , Bergström Göran , Evans Roger G.
Published: June 2012

Abstract
—Increasing renal arterial pressure activates at least 3 antihypertensive mechanisms: reduced renin release, pressure natriuresis, and release of a putative renal medullary depressor hormone. To examine the role of renal medullary perfusion in these mechanisms, we tested the effects of the infusion of norepinephrine, either infusion into the renal medullary interstitium or intravenous infusion, on responses to increased renal arterial pressure in pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which allows renal arterial pressure to be set to any level above or below systemic arterial pressure. With renal arterial pressure initially set at 65 mm Hg, intravenous and medullary interstitial norepinephrine (300 ng · kg
−1
· min
−1
) similarly increased mean arterial pressure (by 12% to 17% of baseline) and reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to 19%), but only medullary norepinephrine reduced medullary perfusion (by 28%). When renal arterial pressure was increased to ≈160 mm Hg, in steps of ≈65 mm Hg, urine output and sodium excretion increased exponentially, and plasma renin activity and mean arterial pressure fell. Medullary interstitial but not intravenous norepinephrine attenuated the increased diuresis and natriuresis and the depressor response to increased renal arterial pressure. This suggests that norepinephrine can act within the renal medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing medullary perfusion. These observations support the concept that medullary perfusion plays a critical role in the long-term control of arterial pressure by its influence on pressure diuresis/natriuresis mechanisms and also by affecting the release of the putative renal medullary depressor hormone.
Insulin-Induced Decrease in Large Artery Stiffness Is Impaired in Uncomplicated Type 1 Diabetes Mellitus
Authors: Westerbacka Jukka , Uosukainen Antti , Mäkimattila Sari , Schlenzka Anna , Yki-Järvinen Hannele
Published: June 2012

Abstract
—Normal insulin action in vivo involves a decrease in stiffness of large arteries (a decrease in aortic pressure augmentation). We determined whether the ability of insulin to decrease arterial stiffness is altered in uncomplicated type 1 diabetes. Nine type 1 diabetic men (age 28±2 years, body mass index 24±1 kg/m
2
) and 9 matched normal men were studied under normoglycemic hyperinsulinemic (sequential 2-hour insulin infusions of 1 [step 1] and 2 [step 2] mU · kg
−1
· min
−1
) conditions. Central aortic pressure waveforms were synthesized from those recorded in periphery with applanation tonometry on the radial artery and a validated reverse transfer function to construct the central aortic pressure wave every 30 minutes. This allowed the determination of aortic augmentation (the pressure difference between the first and the second systolic peaks) and the augmentation index (augmentation divided by pulse pressure), as the measure of stiffness of large arteries. Whole-body glucose uptake was 44% (step 1) and 37% (step 2) lower (
P
<0.001) in the diabetic patients than in the normal subjects. At baseline, before the insulin infusion, augmentation averaged 0±1 and 2±1 mm Hg (NS) and the augmentation index was −1.5±4.5% and 4.0±3.7% (NS) in the normal and diabetic subjects, respectively. After 1 hour of hyperinsulinemia, the augmentation index had decreased significantly (
P
<0.01) to −9.5±4.8% in the normal subjects but remained at 4.4±4.2% in the diabetic patients. A significant decrease was not observed in the diabetic patients until 150 minutes (−1.2±4.1%,
P
<0.05 versus baseline). Whole-body glucose uptake was significantly inversely correlated with the change in the augmentation index during step 1 (
r
=−0.61,
P
<0.01). Insulin resistance in type 1 diabetes involves a defect in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to premature stiffening of large arteries.
Role of 11β-Hydroxysteroid Dehydrogenase in Nongenomic Aldosterone Effects in Human Arteries
Authors: Alzamora Rodrigo , Michea Luis , Marusic Elisa T.
Published: June 2012

Abstract
—The aim of the present study was to demonstrate rapid effects of aldosterone on the Na
+
-H
+
exchanger in strips of human vascular vessels and to determine whether 11β-hydroxysteroid dehydrogenase enzyme (11β-HSD) could play a protective role in this response, such as that described for the classic type I mineralocorticoid receptor (MR). The activity of 11β-HSD isoforms 1 and 2 were measured in fetal and adult arteries. Both isoforms are present in adult and fetal vessels. However, a significant difference in the proportion of each isoform was found. Isoform 1 activity (in pmol · min
−1
· 100 mg
−1
protein) was 42±5 in fetal vessels and 29±2 in adult arteries, and isoform 2 activity was 78±7 in fetal and 12±2 in adult tissue. The nongenomic effect of aldosterone on Na
+
-H
+
exchanger activity was measured in strips of chorionic and radial uterine arteries loaded with the pH-sensitive dye 2′,7′-bis(2-carboxyethyl)-5,6-carboxyfluorescein. Recordings of intracellular pH (pH
i
) were made by videofluorescence microscopy. Aldosterone (0.5 nmol/L) rapidly increased pH
i
, with a half-maximal effect between 2 and 3 nmol/L in both fetal and adult vessels. Ethylisopropylamiloride, a specific inhibitor of the Na
+
-H
+
exchanger, inhibited this effect. The hormone-mediated increase in pH
i
was unaffected by spironolactone, a classic antagonist of MR, but was completely blocked by RU28318. Cortisol (up to 1 μmol/L) had no effect on pH
i
, but when applied in the presence of carbenoxolone, a dramatic increase in Na
+
-H
+
exchanger activity was evident. The increments on pH
i
for each cortisol concentration were similar to those observed for aldosterone. These findings suggest that vascular 11β-HSD plays an active role in maintaining the specificity of the rapid effects of aldosterone.
Nitric Oxide Deficiency Contributes to Large Cerebral Infarct Size
Authors: Kidd G. A. , Dobrucki L. W. , Brovkovych V. , Bohr D. F. , Malinski T.
Published: June 2012

Abstract
—The purpose of this study was to examine the role played by a deficit in nitric oxide (NO) in contributing to the large cerebral infarcts seen in hypertension. Cerebral infarction was produced in rats by occlusion of the middle cerebral artery (MCA). Studies were performed in Sprague-Dawley (SD) rats subjected to NO synthase blockade (
N
G
-nitro-
l
-arginine [L-NNA], 20 mg · kg
−1
· d
−1
in drinking water) and in spontaneously hypertensive stroke-prone rats (SHRSP). NO released in the brain in response to MCA occlusion was monitored with a porphyrinic microsensor in Wistar-Kyoto rats. The increment in NO released with MCA occlusion was 1.31±0.05 μmol/L in L-NNA–treated rats, 1.25±0.04 μmol/L in SHRSP, 2.24±0.07 μmol/L in control SD rats, and 2.25±0.06 μmol/L in Wistar-Kyoto rats (
P
<0.0001 for control versus the other groups). Infarct sizes in the L-NNA–treated and control SD rats were 8.50±0.8% and 5.22±0.7% of the brain weights, respectively (
P
<0.05). The basilar arterial wall was significantly thicker in L-NNA–treated rats compared with their controls. We conclude that both the deficit in NO and the greater wall thickness contribute to the larger infarct size resulting from MCA occlusion in SHRSP and in L-NNA–treated rats compared with their respective controls.
Effects of Sleep Deprivation on Neural Circulatory Control
Authors: Kato Masahiko , Phillips Bradley G. , Sigurdsson Gardar , Narkiewicz Krzysztof , Pesek Catherine A. , Somers Virend K.
Published: June 2012

Abstract
—Effects of sleep deprivation on neural cardiovascular control may have important clinical implications. We tested the hypothesis that sleep deprivation increases heart rate, blood pressure, and sympathetic activity and potentiates their responses to stressful stimuli. We studied 8 healthy subjects (aged 40±5 years, 6 men and 2 women). Blood pressure, heart rate, forearm vascular resistance, and muscle sympathetic nerve activity were measured at rest and during 4 stressors (sustained handgrip, maximal forearm ischemia, mental stress, and cold pressor test). Measurements were obtained twice, once after normal sleep and once after a night of sleep deprivation. All measurements were obtained in a blinded, randomized manner. In comparison with normal sleep, sleep deprivation resulted in an increase in blood pressure (normal sleep versus sleep deprivation=82±8 versus 86±7 mm Hg, mean±SEM,
P
=0.012) and a decrease in muscle sympathetic nerve activity (normal sleep versus sleep deprivation=28±6 versus 22±6 bursts/min,
P
=0.017). Heart rate, forearm vascular resistance, and plasma catecholamines were not significantly changed by sleep deprivation, nor did sleep deprivation affect autonomic and hemodynamic responses to stressful stimuli. Sleep deprivation results in increased resting blood pressure, decreased muscle sympathetic nerve activity, and no change in heart rate. Thus, the pressor response to sleep deprivation is not mediated by muscle sympathetic vasoconstriction or tachycardia.
Angiotensin I–Converting Enzyme Isoforms (High and Low Molecular Weight) in Urine of Premature and Full-Term Infants
Authors: Hattori Monica A. , Del Ben Graziela L. , Carmona Adriana K. , Casarini Dulce E.
Published: June 2012

Abstract
—Angiotensin I–converting enzyme (ACE) isoforms in urine from healthy and mildly hypertensive untreated patients have been described in the literature. Healthy subjects have high- and low-molecular-weight ACEs (170 and 65 kDa), whereas mildly hypertensive untreated patients have only low-molecular-weight ACEs (90 and 65 kDa), both of which resemble ACE from the N-terminal domain. Previous studies have shown that ACE is regulated during development, and renal tubules of premature human infants are not completely mature, given that nephrogenesis is not complete until the 36th week of gestation. The aim of the present study was to purify and characterize ACE isoforms from urine of premature and full-term infants and to detect the presence of the N-domain form of ACE during prenatal development. Urine from premature and full-term infants was concentrated in an Amicon concentrator, dialyzed in the same equipment against 50 mmol/L Tris-HCl buffer (pH 8.0) that contained 150 mmol/L NaCl, and submitted to gel filtration on an AcA-34 column equilibrated with the buffer described above. Two peaks (P1 and P2 for premature infants; TP1 and TP2 for full-term infants) with ACE activity on hippuryl-His-Leu (
K
m
, 3 mmol/L) were detected. All enzymes were Cl
−
dependent and inhibited by captopril and EDTA. The peptides angiotensin-(1-7) and
N
-acetyl-Ser-Asp-Lys-Pro, described as specific for N-domain ACE, were hydrolyzed by P2 and TP2, which suggests that both enzymes are N-domain ACE. In premature infants, P1 activity with hippuryl-His-Leu was 12-fold lower than P2 activity, but in full-term infants, the difference between TP1 and TP2 was 1.6-fold. Chromatography profiles of urine from premature infants were analyzed on days 1, 3, 7, 14, 21, and 30 after birth. The P1 of ACE was detected around the 21st and 30th days, whereas P2 was detected from day 1. These results suggest that ACE activity is related to renal development and that N-domain ACE as well as full-length ACE is present in urine from premature infants. This may indicate that healthy subjects produce and secrete the N-domain form of ACE even before term development.
Bradykinin-Induced Vasodilation of Human Forearm Resistance Vessels Is Primarily Mediated by Endothelium-Dependent Hyperpolarization
Authors: Honing Marina L. H. , Smits Paul , Morrison Paul J. , Rabelink Ton J.
Published: June 2012

Abstract
—Bradykinin (BK) stimulates endothelial cells to release a number of relaxing factors, such as NO, prostanoids (PGs), and an endothelium-derived hyperpolarizing factor (EDHF). However, the contributions of NO, PG, and EDHF in the vascular relaxation to BK vary with species and anatomic origin of blood vessels used. Therefore, the present study was designed to investigate the contributions of NO, PG, and EDHF in vasodilation caused by BK in human forearm resistance vessels. Forearm blood flow (FBF) was recorded with venous occlusion plethysmography in healthy nonsmoking subjects. At first, studies were performed to validate the NO clamp technique for its ability to inhibit endogenous NO generation. Brachial artery infusion of serotonin (0.6, 1.8, and 6 ng · 100 mL forearm volume [FAV]
−1
· min
−1
) caused significant forearm vasodilation (2.6 to 4.6 mL · 100 mL FAV
−1
· min
−1
), which is known to be NO mediated. Indeed, during the NO clamp, cumulative doses of serotonin caused no vasodilation (2.4 to 2.6 mL · 100 mL FAV
−1
· min
−1
), indicating that the generation of endogenous NO was completely blocked. Thereafter, the vasodilative actions of BK were investigated. Brachial artery infusion of BK (50, 100, and 200 ng · 100 mL FAV
−1
· min
−1
) caused significant forearm vasodilation in all studies (from 3.1 to 20.4 mL · 100 mL FAV
−1
· min
−1
). After the inhibition of cyclooxygenase and NO synthase activity through the use of aspirin and the NO-clamp technique, BK increased FBF in a similar manner (3.9 to 18.9 mL · 100 mL FAV
−1
· min
−1
), indicating that the vasodilative actions of BK are independent of NO and PG generation. However, vasodilation caused by the 2 lower doses of BK were significantly attenuated after K
Ca
channel activity was blocked with tetraethylammonium chloride (0.1 mg · 100 mL FAV
−1
· min
−1
), suggesting that in the lower dose range, BK mediates vasodilation through the opening of vascular potassium channels. In conclusion, BK is a potent vasodilator peptide in human forearm resistance vessels, causing vasodilation through hyperpolarization of the vascular wall independent of NO and PG production. In addition, the NO-clamp technique is a valid instrument to investigate the contribution of NO in the vasodilative response to different agents.
Molecular Plasticity of Vascular Wall During
N
G
-Nitro-
l
-Arginine Methyl Ester–Induced Hypertension
Authors: Gonzalez Walter , Fontaine Vincent , Pueyo Maria E. , Laquay Nathalie , Messika-Zeitoun David , Philippe Monique , Arnal Jean-François , Jacob Marie-Paule , Michel Jean-Baptiste
Published: June 2012

Abstract
—It has previously been reported that hypertension induced by the chronic blockade of NO production is characterized by a proinflammatory phenotype of the arterial wall associated with a periarterial accumulation of inflammatory cells. In the present study, the cellular and molecular mechanisms involved in the luminal and perivascular accumulation of inflammatory cells were evaluated in the aortas of
N
G
-nitro-
l
-arginine methyl ester (L-NAME)–treated rats. Because the medial layer remains intact, putative markers of the resistance of the vascular wall to cell migration and to oxidative stress were also explored. For this purpose, monocyte adhesion, cytokine expression, superoxide anion production, and nuclear factor-κB (NF-κB) activation were assessed in the aortas of L-NAME–treated rats. Expressions of tissue inhibitor of metalloproteinases-1 (TIMP-1) and heme oxygenase-1 (HO-1) in the aortic wall were also studied as possible markers of such resistance. Chronic blockade of NO production increased ex vivo monocyte adhesion to the endothelium, increased the production of superoxide anions, and activated the NF-κB system. In concert with this modification of the redox state of the vascular wall in L-NAME–treated rats, the expression of proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, and macrophage colony–stimulating factor was increased. In parallel, expressions of both TIMP-1 and HO-1 were increased. All these changes were prevented by treatment with an angiotensin-converting enzyme inhibitor (Zofenopril). Hypertension associated with a proinflammatory phenotype of the vascular wall induced by blockade of NO production could be due to an increase in oxidative stress, which, in turn, activates the NF-κB system and increases gene expression. In parallel, the arterial wall overexpresses factors such as TIMP-1 and HO-1, which could participate in the resistance to cell migration and oxidative stress.
Induction of Oxidative Stress by Glutathione Depletion Causes Severe Hypertension in Normal Rats
Authors: Vaziri Nosratola D. , Wang Xiu Q. , Oveisi Fariba , Rad Behdad
Published: June 2012

Abstract
—Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with those types of hypertension respond favorably to antioxidant therapy. We hypothesize that oxidative stress may cause hypertension via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for 2 weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E–fortified chow and vitamin C–supplemented drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability. These characteristics were associated with a significant accumulation in various tissues of nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species. Administration of vitamin E plus vitamin C ameliorated hypertension, improved urinary nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in the control group. In conclusion, GSH depletion resulted in perturbation of the NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, which supports the notion that oxidative stress was involved in the pathogenesis of hypertension in this model.
Combinations of Variations in Multiple Genes Are Associated With Hypertension
Authors: Williams Scott M. , Addy Jonathan H. , Phillips John A. , Dai Min , Kpodonu John , Afful James , Jackson Harold , Joseph Karen , Eason Felicia , Murray Mark M. , Epperson Pamela , Aduonum Adwoa , Wong Lee-Jun , Jose Pedro A. , Felder Robin A.
Published: June 2012

Abstract
—The genetic analysis of hypertension has revealed complex and inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific genes on blood pressure regulation in diverse human populations. Some of the confusion from previous studies is probably due to undetected gene-gene interactions. Instead of focusing on the effects of single genes on hypertension, we examined the effects of interactions of alleles at 4 candidate loci. Three of the loci are in the renin-angiotensin-system, angiotensinogen, ACE, and angiotensin II type 1 receptor, and they have been associated with hypertension in at least 1 previous study. The fourth locus studied is a previously undescribed locus, named FJ. In total, 7 polymorphic sites at these loci were analyzed for their association with hypertension in 51 normotensive and 126 hypertensive age-matched individuals. There were no significant differences between the 2 phenotypic classes with respect to either allele or genotype frequencies. However, when we tested for nonallelic associations (linkage disequilibrium), we found that of the 120 multilocus comparisons, 16 deviated significantly from random in the hypertensive class, but there were no significant deviations in the normotensive group. These findings suggest that genetic interactions between multiple loci rather than variants of a single gene underlie the genetic basis of hypertension in our study subjects. We hypothesize that such interactions may account for the inconsistent findings in previous studies because, unlike our study, prior studies almost always examined single-locus effects and did not consider the effects of variation at other potentially interacting loci.
Increase in G
iα
Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy
Authors: Kouchi Ichiro , Zolk Oliver , Jockenhövel Friedrich , Itter Gabi , Linz Wolfgang , Cremers Bodo , Böhm Michael
Published: June 2012

Abstract
—Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in β-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to β-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G
sα
protein and β-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G
iα
was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G
iα
and the extent of post-MI remodeling in WKY. A similar correlation between G
iα
and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G
iα
could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.
Blood Pressure Patterns in Normal Pregnancy, Gestational Hypertension, and Preeclampsia
Authors: Hermida Ramón C. , Ayala Diana E. , Mojón Artemio , Fernández José R. , Alonso Ignacio , Silva Inés , Ucieda Rafael , Iglesias Manuel
Published: June 2012

Abstract
—With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (
P
<0.001 in all cases). The differences in circadian rhythm–adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always
P
<0.001). There is also a statistically significant difference in circadian amplitude (extent of daily change) of blood pressure between healthy and complicated pregnancies in all trimesters (always
P
<0.004). Results further indicate similar circadian characteristics between women who later developed gestational hypertension or preeclampsia in the first trimester of pregnancy. The difference between these 2 groups in circadian mean is statistically significant in the second trimester for systolic (
P
=0.022) but not for diastolic blood pressure (
P
=0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables (
P
<0.001). The differences in blood pressure between healthy and complicated pregnancies can be observed as early as in the first trimester of pregnancy. Those highly significant differences are found when both systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability. These differing changes in the circadian pattern of blood pressure with advancing gestational age between healthy and complicated pregnancies offer new end points that may lead to an early identification of hypertensive complications in pregnancy as well as to the establishment of prophylactic intervention.
Effect of Bosentan on NF-κB, Inflammation, and Tissue Factor in Angiotensin II–Induced End-Organ Damage
Authors: Muller Dominik N. , Mervaala Eero M. A. , Schmidt Folke , Park Joon-Keun , Dechend Ralf , Genersch Elke , Breu Volker , Löffler Bernd-Michael , Ganten Detlev , Schneider Wolfgang , Haller Hermann , Luft Friedrich C.
Published: June 2012

Abstract
—Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II–induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)
A/B
receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Untreated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawley controls, both systolic blood pressure and 24-hour albuminuria were increased in untreated dTGR (203±8 versus 111±2 mm Hg and 67.1±8.6 versus 0.3±0.06 mg/d at week 7, respectively). Bosentan and hydralazine both reduced blood pressure and cardiac hypertrophy. Mortality rate was markedly reduced by bosentan (1/15) and partially by hydralazine (4/15). However, only bosentan decreased albuminuria and renal injury. Untreated and hydralazine-treated dTGR showed increased nuclear factor (NF)-κB and AP-1 expression in the kidney and heart; the p65 NF-κB subunit was increased in the endothelium, vascular smooth muscles cells, infiltrating cells, glomeruli, and tubules. In the heart and kidney, ET
A/B
receptor blockade inhibited NF-κB and AP-1 activation compared with hydralazine treatment. Macrophage infiltration, ICAM-1 expression, and the integrin expression on infiltrating cells were markedly reduced. Renal vasculopathy was accompanied by increased tissue factor expression on macrophages and vessels of untreated and hydralazine-treated dTGR, which was markedly reduced by bosentan. Thus, ET
A/B
receptor blockade inhibits NF-κB and AP-1 activation and the NF-κB– and/or AP-1–regulated genes
ICAM-1, VCAM-1,
and
TF,
independent of blood pressure–related effects. We conclude that Ang II–induced NF-κB and AP-1 activation and subsequent inflammation and coagulation involve at least in part the ET
A/B
receptors.
Structure and Mechanical Properties of Resistance Arteries in Hypertension
Authors: Intengan Hope D. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Abnormalities of resistance arteries may play a role in the pathogenesis and pathophysiology of hypertension in experimental animals and humans. Vessels that, when relaxed, measure <400 μm in lumen diameter act as the major site of vascular resistance and include a network of small arteries (lumen ≈100 to 400 μm) and arterioles (<100 μm). Because increased peripheral resistance is generated by a narrowed lumen diameter, significant effort has been focused on determining the mechanisms that reduce lumen size. Three important vascular components are clearly involved, including alterations of vascular structure, mechanics (stiffness), and function. Structural abnormalities comprise a reduced lumen diameter and thickening of the vascular media, resulting in an increased media-lumen ratio. Changes in the mechanical properties of an artery, particularly increased stiffness, may also result in a reduced lumen diameter. These vascular abnormalities may be caused or influenced by the expression and/or topographic localization of extracellular matrix components, such as collagen and elastin, and by changes in cell-extracellular fibrillar attachment sites, such as adhesion molecules like integrins. This article discusses the abnormalities of resistance arteries in hypertension and reviews the evidence suggesting an important role for adhesive and extracellular matrix determinants.
β-Adrenoceptor Dysfunction After Inhibition of NO Synthesis
Authors: Whalen Erin J. , Johnson Alan Kim , Lewis Stephen J.
Published: June 2012

Abstract
—G
s
protein–coupled β-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to β-adrenoceptor–mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of β-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the β-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 μg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 100 μmol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME–treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8×10 μg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 μmol/kg IV) but not in rats treated with saline. Injections of
l
-
S
-nitrosocysteine (1200 nmol/kg IV), a lipophobic
S
-nitrosothiol, before each injection of ISO (10 μg/kg IV) prevented tachyphylaxis to ISO in L-NAME–treated rats. The vasodilator effects of ISO (0.1 to 10 μg/kg IV) in L-NAME–treated rats that received 8 injections of ISO (10 μg/kg IV) were markedly smaller than in L-NAME–treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME–treated rats, and (3) tachyphylaxis to ISO is prevented by
l
-
S
-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of β-adrenoceptors in vivo.
Contribution of Angiotensin-(1–7) to Blood Pressure Regulation in Salt-Depleted Hypertensive Rats
Authors: Iyer Shridhar N. , Averill David B. , Chappell Mark C. , Yamada Kazuo , Allred Alicia J. , Ferrario Carlos M.
Published: June 2012

Abstract
—We exposed 63 adult spontaneously hypertensive rats (SHR) and 10 (mRen-2)27 transgenic hypertensive rats to a 12-day regimen of either a normal diet (0.5%) or a low-salt diet (0.05%) to evaluate the hypothesis that the vasodepressor heptapeptide, angiotensin-(1–7) [Ang-(1–7)], buffers the pressor effects of angiotensin II during endogenous stimulation of the renin-angiotensin system. Catheters were inserted into a carotid artery and jugular vein under light anesthesia the day before the experiment. Separate groups of conscious instrumented SHR were given short-term infusions of an affinity-purified monoclonal Ang-(1–7) antibody or the neprilysin inhibitor SCH 39370. In addition, SHR and (mRen-2)27 rats were given the Ang-(1–7) receptor antagonist [
d
-Ala
7
]Ang-(1–7). Exposure to the low-salt diet increased plasma renin activity and elevated plasma levels of angiotensin I and angiotensin II in SHR by 81% and 68%, respectively, above values determined in SHR fed a normal salt diet. Concentrations of angiotensin I and angiotensin II were also higher in the kidney of salt-depleted SHR, whereas plasma and renal tissue levels of Ang-(1–7) were unchanged. Infusion of the Ang-(1–7) antibody produced dose-dependent pressor and tachycardic responses in salt-depleted SHR but no effect in SHR maintained on a normal-salt diet. A comparable cardiovascular response was produced in salt-depleted SHR given either SCH 39370 or [
d
-Ala
7
]Ang-(1–7). These agents had negligible effects on SHR fed a normal-salt diet. Blockade of Ang-(1–7) receptors produced a similar cardiovascular response in (mRen-2)27 transgenic hypertensive rats fed a low-salt diet. Injections of the heat-inactivated antibody or the subsequent infusion of the antibody to rats given [
d
-Ala
7
]Ang-(1–7) produced no additional effects. The data support the hypothesis that the hemodynamic effects of neurohormonal activation after salt restriction stimulate a tonic depressor action of Ang-(1–7).