bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal Regulation of Transforming Growth Factor-β Receptors on Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats by Angiotensin II
Authors: Fukuda Noboru , Hu Wen-Yang , Kubo Atsushi , Endoh Morito , Kishioka Hirobumi , Satoh Chikara , Soma Masayoshi , Izumi Yoichi , Kanmatsuse Katsuo
Published: June 2012

Abstract
—The effects of angiotensin II (Ang II) on the expression and characteristics of transforming growth factor-β (TGF-β) receptors on vascular smooth muscle cells (VSMC) from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were investigated. TGF-β–induced stimulation of DNA synthesis by VSMC from WKY rats was abolished with Ang II, whereas basal and TGF-β–stimulated DNA synthesis by VSMC from SHR was increased with Ang II. Ang II stimulated DNA synthesis by VSMC from WKY rats in the presence but not in the absence of neutralizing antibody to TGF-β
1
. Antibody to TGF-β
1
enhanced the stimulatory effect of Ang II on DNA synthesis by VSMC from SHR. Ang II increased the specific binding of TGF-β to VSMC from WKY rats by increasing both the expression of the lower-affinity of TGF-β receptors as well as the total number of TGF-β binding sites. In contrast, VSMC from SHR showed a higher affinity and number of TGF-β receptors in the absence of Ang II than did cells from WKY rats, and these parameters were not affected by Ang II. Ang II increased the expression of TGF-β type I receptor mRNA in VSMC from WKY rats but had no effect of TGF-β receptor type I or II mRNA in VSMC from SHR, which predominantly express the type II receptor. These results indicate that an increase in the expression of the TGF-β type I receptor by Ang II may facilitate the ability of endogenous TGF-β to counteract the stimulatory effect of Ang II on growth in VSMC from WKY rats, whereas endogenous TGF-β induced by Ang II cannot counteract the growth-promoting action of Ang II in VSMC from SHR. The abnormal regulation of TGF-β receptors by Ang II may be associated with the exaggerated growth of VSMC from SHR.
Evaluation of the Angiotensinogen Locus in Human Essential Hypertension
Authors: Brand Eva , Chatelain Nathalie , Keavney Bernard , Caulfield Mark , Citterio Lorena , Connell John , Grobbee Diederick , Schmidt Susanne , Schunkert Heribert , Schuster Herbert , Sharma Arya M. , Soubrier Florent
Published: June 2012

Abstract
—Different family and case-control studies support genetic linkage and association at the human angiotensinogen (
AGT
) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The
AGT
locus was studied using a highly polymorphic dinucleotide repeat in the 3′-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the
AGT
gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.
Lack of Association Between the α-Adducin Locus and Essential Hypertension in the Japanese Population
Authors: Kato Norihiro , Sugiyama Takao , Nabika Toru , Morita Hiroyuki , Kurihara Hiroki , Yazaki Yoshio , Yamori Yukio
Published: June 2012

Abstract
—Significant linkage and association of α-adducin, a cytoskeleton protein involved in transmembrane ion transport, with essential hypertension were recently shown in Caucasian populations, especially in relation to salt sensitivity. The present study investigated the relevance of this candidate gene to hypertension in a well-characterized Japanese population. A total number of 507 individuals were selected from clinic outpatients. Hypertensive subjects were defined on the basis of the individual’s blood pressure readings before starting medications; the criteria included systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥95 mm Hg. Patients with diabetes mellitus, renal failure, and secondary forms of hypertension had been excluded. Control subjects had blood pressure values <130/85 mm Hg. The allele frequency of a genetic variant at amino acid residue 460 of α-adducin (460Trp) was compared between cases and control subjects with χ
2
statistics; in addition, the association was tested with blood pressure as a continuous variable. No significant association was found in either of the statistics tested. The 460Trp variant appeared to be relatively common in the Japanese (54% to 60%) compared with a reported prevalence of 13% to 23% in Caucasians. The present study brought up an important issue concerning the pathophysiological role of α-adducin in non-Caucasian populations, given the likely ethnic variation in the nature of genetic susceptibility loci. The 460Trp variant of the α-adducin gene is unlikely to have a major effect on susceptibility to hypertension in the Japanese population studied, although the present study does not exclude the involvement of α-adducin in the pathogenesis of hypertension.
Renoprotective Effects of Felodipine and/or Enalapril in Spontaneously Hypertensive Rats With and Without L-NAME
Authors: Francischetti Aloisio , Ono Hidehiko , Frohlich Edward D.
Published: June 2012

Abstract
—To determine the renoprotective effects of a calcium antagonist (felodipine) and an angiotensin-converting enzyme (ACE) inhibitor (enalapril), alone or in combination, 10 groups of 19-week-old spontaneously hypertensive rats (SHR) (with or without
N
G
-nitro-
l
-arginine methyl ester [L-NAME]) were studied using renal micropuncture techniques. Group 1 (control), group 2 (felodipine, 30 mg · kg
−1
· d
−1
), group 3 (enalapril, 30 mg · kg
−1
· d
−1
), and group 4 (felodipine plus enalapril, 15 mg · kg
−1
· d
−1
each agent) were studied after 3 weeks of treatment without L-NAME. L-NAME (50 mg/L) cotreatment was administered in drinking water to groups 6 through 10 using the same doses of each agent as in groups 1 through 4: group 5 (only L-NAME), group 6 (felodipine), group 7 (enalapril), and group 8 (felodipine plus enalapril). Groups 9 and 10 received L-NAME initially for 3 weeks followed by felodipine or felodipine plus enalapril, respectively, for the subsequent 3 weeks. All three treatments resulted in reductions in mean arterial pressure and total peripheral vascular resistance (
P
<.001) that were associated with important structural and functional renal microcirculatory improvements. Thus, the pathological nephrosclerosis (subcapsular and juxtamedullary) glomerular and arteriolar injury scores were improved (
P
<.05 at least) in association with normalization of afferent and efferent arteriolar resistances, and single-nephron glomerular filtration rate, plasma flow, and blood flow were significantly improved, as well as the ultrafiltration coefficient (compared with group 5, L-NAME). Thus, the calcium antagonist felodipine, alone or in combination with an ACE inhibitor, not only prevented but also reversed L-NAME–exacerbated hypertensive nephrosclerosis in SHR.
Renal Substance P–Containing Neurons and Substance P Receptors Impaired in Hypertension
Authors: Kopp Ulla C. , Cicha Michael Z. , Farley Donna M. , Smith Lori A. , Dixon Bradley S.
Published: June 2012

Abstract
—In normotensive rats, increased renal pelvic pressure stimulates the release of prostaglandin E and substance P, which in turn leads to an increase in afferent renal nerve activity (ARNA) and a contralateral natriuresis, a contralateral inhibitory renorenal reflex. In spontaneously hypertensive rats (SHR), increasing renal pelvic pressure failed to increase afferent renal nerve activity. The inhibitory nature of renorenal reflexes indicates that impaired renorenal reflexes could contribute to increased sodium retention in SHR. Phorbol esters, known to activate protein kinase C, increase afferent renal nerve activity in Wistar-Kyoto rats (WKY) but not in SHR. We examined the mechanisms involved in the impaired responses to renal sensory receptor activation in SHR. The phorbol ester 4β-phorbol 12,13-dibutyrate increased renal pelvic protein kinase C activity similarly in SHR and WKY. Increasing renal pelvic pressure increased afferent renal nerve activity in WKY (27±2%) but not in SHR. Renal pelvic release of prostaglandin E increased similarly in WKY and SHR, from 0.8±0.1 to 2.0±0.4 ng/min and 0.7±0.1 to 1.4±0.2 ng/min. Renal pelvic release of substance P was greater (
P
<.01) in WKY, from 16.3±3.8 to 41.8±7.4 pg/min, than in SHR, from 9.9±1.7 to 17.0±3.2 pg/min. In WKY, renal pelvic administration of substance P at 0.8, 4, and 20 μg/mL increased ARNA 382±69, 750±233, and 783±124% · second (area under the curve of afferent renal nerve activity versus time). In SHR, substance P at 0.8 to 20 μg/mL failed to increase ARNA. These findings demonstrate that the impaired afferent renal nerve activity response to increased renal pelvic pressure is related to decreased release of substance P and/or impaired activation of substance P receptors.
Mechanisms Responsible for Forskolin-Induced Relaxation of Rat Tail Artery
Authors: Rembold Christopher M. , Chen Xiao-Liang
Published: June 2012

Abstract
—The goal of the present study was to determine the physiologically relevant mechanisms for forskolin-induced relaxation of intact rat tail artery. We stimulated deendothelialized rat tail artery with phenylephrine and then relaxed the tissue with the addition of forskolin, a specific activator of adenylyl cyclase. We measured membrane potential with the use of microelectrodes, estimated intracellular Ca
2+
concentration ([Ca
2+
]
i
) with the use of fura 2, and measured isometric force with a strain-gauge transducer. We found that 0.3 to 1.0 μmol/L forskolin relaxed 0.3 to 1.0 μmol/L phenylephrine-stimulated rat tail artery by decreasing the [Ca
2+
]
i
sensitivity of force as well as through repolarization. There was no evidence for forskolin-induced inhibition of Ca
2+
influx beyond that associated with repolarization. There also was no evidence for forskolin-induced enhancement of Ca
2+
efflux or sequestration. Inhibition of ATP-activated K
+
channels with 10 μmol/L glibenclamide, Ca
2+
-activated K
+
channels with 50 nmol/L iberiotoxin, Ca
2+
-activated K
+
channels with 3 or 10 mmol/L tetraethylammonium ion, inwardly rectified K
+
channels with 20 μmol/L Ba
2+
, and voltage-activated K
+
channels with 0.5 mmol/L 4-aminopyridine did not significantly attenuate forskolin-induced reductions in [Ca
2+
]
i
or force. Forskolin-induced repolarization was not altered by 10 μmol/L glibenclamide or 0.5 mmol/L 4-aminopyridine. These data suggest that these K
+
channels were not individually involved in forskolin-induced relaxation and that other channels and/or multiple channels are involved in forskolin-induced repolarization of intact rat tail artery. Our data also suggest that forskolin-induced relaxation of intact rat tail artery occurred primarily through repolarization and reductions in the [Ca
2+
]
i
sensitivity of force.
Oleic Acid and Angiotensin II Induce a Synergistic Mitogenic Response in Vascular Smooth Muscle Cells
Authors: Lu Gang , Meier Kathryn E. , Jaffa Ayad A. , Rosenzweig Steven A. , Egan Brent M.
Published: June 2012

Abstract
—Oleic acid and angiotensin II (Ang II) are elevated and may interact to accelerate vascular disease in obese hypertensive patients. We studied the effects of oleic acid and Ang II on growth responses of rat aortic smooth muscle cells (VSMCs). Oleic acid (50 μmol/L) raised thymidine incorporation by 50% at 24 hours and cell number by 55% at 6 days (
P
<.05). Ang II (10
−11
to 10
−6
mol/L) did not significantly increase thymidine incorporation or VSMC number. Combining Ang II and 50 μmol/L oleic acid doubled thymidine incorporation and VSMC number. Losartan, an angiotensin type 1 (AT
1
) receptor antagonist, blocked the synergistic interaction between Ang II and oleic acid, whereas the AT
2
receptor antagonist PD 123319 did not. Protein kinase C inhibition and downregulation, as well as inhibition of extracellular signal-regulated kinase (ERK) activation by PD 98059, eliminated the rise of thymidine incorporation in response to oleic acid and the synergistic interaction with Ang II. However, the response to 10% fetal bovine serum was unaffected. An antisense oligodeoxynucleotide to ERK-1 and ERK-2 reduced ERK protein expression and activation by 83% and 75%, respectively. Antisense prevented the rise of thymidine incorporation in response to oleic acid and the synergy with Ang II. Antisense reduced but did not prevent increased thymidine incorporation in response to serum. The data indicate that oleic acid and Ang II exert a synergistic mitogenic effect in VSMCs and suggest an important role for the AT
1
receptor, PKC, and ERK in this synergy. The observations raise the possibility that a synergistic mitogenic interaction between oleic acid and Ang II accelerates vascular remodeling in obese hypertensive patients.
Nephroprotection of an ET
A
-Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats
Authors: Orth Stephan R. , Esslinger Jan P. , Amann Kerstin , Schwarz Ute , Raschack Manfred , Ritz Eberhard
Published: June 2012

Abstract
—The present study was designed to assess whether the orally active and highly specific endothelin A (ET
A
) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET
A
receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.
Influence of Race and Dietary Salt on the Antihypertensive Efficacy of an Angiotensin-Converting Enzyme Inhibitor or a Calcium Channel Antagonist in Salt-Sensitive Hypertensives
Authors: Weir Matthew R. , Chrysant Steven G. , McCarron David A. , Canossa-Terris Maria , Cohen Jerome D. , Gunter Patricia A. , Lewin Andrew J. , Mennella Robert F. , Kirkegaard Lance W. , Hamilton Jennifer H. , Weinberger Myron H. , Weder Alan B.
Published: June 2012

Abstract
—Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (≥5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [≤88 mmol/d Na
+
] and high salt [>190 mmol/d Na
+
] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7±107.5 mmol/d urinary Na
+
) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1±50.8 mmol/d Na
+
); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, −3.6/−1.6 mm Hg; white, −6.2/−3.9 mm Hg; Hispanic, −8.1/−5.3 mm Hg) than did enalapril-treated patients (black, −9.0/−5.3 mm Hg; white, −11.8/−7.0 mm Hg; Hispanic, −11.1/−5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.
Mutations and Variants of the Epithelial Sodium Channel Gene in Liddle’s Syndrome and Primary Hypertension
Authors: Melander Olle , Orho Marju , Fagerudd Johan , Bengtsson Kristina , Groop Per-Henrik , Mattiasson Ingrid , Groop Leif , Hulthén U. Lennart
Published: June 2012

Abstract
—Liddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel β- or γ-subunits. These mutations delete or alter a conserved proline-rich amino acid sequence referred to as the PY-motif. We report here a Liddle’s syndrome family with a βArg564X mutation with a premature stop codon deleting the PY-motif of the β-subunit. This family shows marked phenotypic variation in blood pressure, serum potassium levels, and age of onset of hypertension. Given the similarity with primary hypertension, changes in the C termini of the β- or γ-subunits may contribute to the development of primary hypertension or to hypertension associated with diabetic nephropathy. Accordingly, the coding sequences for the cytoplasmic C termini of the β- and γ-subunits were screened for mutations with the use of polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing in 105 subjects with primary hypertension and 70 subjects with diabetic nephropathy. One frequent polymorphism was identified, but its frequency did not differ among subjects with primary hypertension, subjects with diabetic nephropathy, or control subjects. Two of the 175 subjects with primary hypertension or diabetic nephropathy showed variants that were not present in 186 control subjects. None of the variants changed the PY-motif sequence. In conclusion, a βArg564X mutation is the likely cause of Liddle’s syndrome in this Swedish family, but it is unlikely that mutations in the β- and γ-subunit genes of the epithelial sodium channel play a significant role in the pathogenesis of primary hypertension or diabetic nephropathy.
Three Important Subgroups of Hypertensive Persons at Greater Risk of Intracerebral Hemorrhage
Authors: Thrift Amanda G. , McNeil John J. , Forbes Andrew , Donnan Geoffrey A.
Published: June 2012

Abstract
—Hypertension as a risk factor for intracerebral hemorrhage (ICH) is poorly quantified, particularly in the setting of the use of modern antihypertensive agents. To investigate this, we studied 331 consecutive hospital cases of primary ICH verified by computed tomography or autopsy, occurring during the period 1990 through 1992, and 331 age- and sex-matched community-based control subjects in a city-wide study involving 13 hospitals. Hypertension approximately doubled the risk of ICH (adjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.61 to 3.73). The OR associated with hypertension was significantly greater among those who had ceased taking medications, supervised and unsupervised (OR, 4.98; 95% CI, 2.25 to 11.02), compared with those who had not (OR, 1.95; 95% CI, 1.20 to 3.16), were under the age of 55 years (OR, 7.68; 95% CI, 2.65 to 22.5), or were current smokers (OR, 6.12; 95% CI, 2.29 to 16.35). The presence of hypertension did not influence size or location of the hemorrhage. However, those dying from ICH displayed a greater risk of ICH due to hypertension than survivors, with the ratio of the two ORs being 5.47 (95% CI, 1.23 to 24.44). These findings provide evidence for a greater increase in risk of ICH due to hypertension among younger persons, current smokers, and those discontinuing antihypertensive therapy. This is the first direct evidence for a link between stopping antihypertensive medication use and stroke risk; targeting these individuals for more intensive monitoring and education on the importance of risk factor modification may help to reduce the impact of this form of stroke.
Hypertension Among Siblings of Persons With Premature Coronary Heart Disease
Authors: Yanek Lisa R. , Moy Taryn F. , Blumenthal Roger S. , Raqueño Judith V. , Yook Raphael M. , Hill Martha N. , Becker Lewis C. , Becker Diane M.
Published: June 2012

Abstract
—To determine the extent to which the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) guidelines were implemented in high-risk families with premature coronary heart disease, we examined the prevalence of hypertension and associated coronary risk factors in asymptomatic siblings of persons with documented premature coronary disease (<60 years of age). A total of 859 apparently healthy siblings (51% male, 19% African American) were screened for coronary risk factors. Siblings were classified as normotensive or hypertensive (BP ≥140/90 and/or current antihypertensive pharmacotherapy). The prevalence of hypertension, awareness, treatment, and control among siblings was compared with published national estimates from the third National Health and Nutrition Examination Survey. The prevalence of hypertension in siblings was 44%. Among all hypertensives, only 60% were aware of being hypertensive, 45% were being treated, and 16% were under control. A high prevalence of other coronary risk factors was found among hypertensive siblings: 72% were hypercholesterolemic; 61% were obese; 29% were current smokers; 82% were consuming >30% of calories from fat; and only 14% were participating in vigorous physical activity three or more times per week. Comparisons with the national reference population revealed siblings to have a significantly higher prevalence of hypertension, along with significantly lower levels of awareness, treatment, and control. These findings demonstrate the intersection of multiple risk factors among hypertensive siblings and emphasize the need for more aggressive screening and treatment in this easily identifiable high-risk population.
Genetic Analysis of the β Subunit of the Epithelial Na
+
Channel in Essential Hypertension
Authors: Persu Alexandre , Barbry Pascal , Bassilana Frédéric , Houot Anne-Marie , Mengual Raymond , Lazdunski Michel , Corvol Pierre , Jeunemaitre Xavier
Published: June 2012

Abstract
—Mutations of the last exon of the β subunit of the amiloride-sensitive epithelial Na
+
channel (βENaC) can lead to Liddle’s syndrome, a rare monogenic form of hypertension. The objective of this study was to test whether more subtle changes of βENaC could be implicated in essential hypertension. After determination of the βENaC coding gene organization (12 exons spanning 23.5 kb), a systematic screening of the last exon of the gene was performed in 525 subjects (475 whites, 50 Afro-Caribbeans), all probands of hypertensive families. This search was extended to the remaining 11 exons in a subset of 101 probands with low-renin hypertension. Seven amino acid changes were detected: G589S, T594M, R597H, R624C, E632G (last exon), G442V, and V434M (exon 8). These genetic variants were more frequent in subjects of African origin (44%) than in whites (1%). The functional properties of the variants were analyzed in
Xenopus
oocytes by two independent techniques, ie, electrophysiology and
22
Na
+
uptake. Small but not significant differences were observed between the variants and wild type. The clinical evaluation of the family bearing the G589S variant, which provided the highest relative ENaC activity, did not show a cosegregation between the mutation and hypertension. The present study illustrates the difficulty in establishing a relation of causality between a susceptibility gene and hypertension. Furthermore, it does not favor a substantial role of the βENaC gene in essential hypertension.
Obesity, Salt Intake, and Renal Perfusion in Healthy Humans
Authors: Porter Lisa E. , Hollenberg Norman K.
Published: June 2012

Abstract
—Renal perfusion rises as obesity develops during short-term overfeeding in animal studies. In humans, the assessment is complicated by the need to normalize renal perfusion for body size. We made use of the fact that radioactive xenon washout measures renal perfusion per unit of tissue mass to address this issue by comparing 45 moderately obese and 147 lean healthy potential kidney donors. All were disease free. The rationale for involving kidney donors reflects the fact that the xenon method for measuring renal perfusion demands injection of the xenon directly into the renal artery, which can be accomplished during the arteriogram that is a necessary part of potential kidney donor evaluation. In 21 obese subjects (body mass index [BMI], 29.1±0.9) in balance on a 10-mmol sodium intake, renal perfusion (352±16 mL · 100 g
−1
· min
−1
) was significantly higher than predicted from findings in the 95 lean control subjects (313±3 mL · 100 g
−1
· min
−1
;
P
=0.035) after adjustment for age. With a high sodium intake (200 mmol), however, renal perfusion was not significantly different in 24 obese subjects (BMI, 28.8±0.7; 323±13 mL · 100 g
−1
· min
−1
) in comparison to 52 lean controls (341±10 mL · 100 g
−1
· min
−1
) after adjustment for age. Systolic and diastolic blood pressures were similar in obese and age- and gender-matched lean control subjects. Renal vasodilation was seen in association with sustained obesity in humans. While the mechanisms of obesity-related vasodilation are unclear, the dependence on sodium intake in this study is consistent with a role for the renin-angiotensin system. The findings are not in accordance with a reduction in renal perfusion reported in healthy obese humans in whom measured renal perfusion was indexed for body size.
Genetic Mapping of Soluble Guanylyl Cyclase Genes
Authors: Azam Mohammad , Gupta Gopa , Chen Wei , Wellington Sandra , Warburton Dorothy , Danziger Robert S.
Published: June 2012

Abstract
—The nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (α/β). The α1/β1 isoform has greater NO sensitivity than the α1/β2. It has recently been shown that expression of the β subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the β1 subunit is decreased and the β2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. α1 and β1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the β2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5. Genes for α1 and β1 were closely linked by two-point analysis to Na
+
,K
+
-ATPase α1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-δ loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The α1 and β1 genes were closely linked (LOD of 11.3; θ, 0.4). The β2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, α1, β1, and β2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.
Mechanical Interactions Among Cytoskeletal Filaments
Authors: Wang Ning
Published: June 2012

Abstract
—Mechanical properties of the cells are important in controlling cell shape, cell migration, and other functions. To understand how cytoskeletal (CSK) filaments interact with one another mechanically, mechanical properties of adherent endothelial cells were analyzed after treatment with CSK-disrupting drugs. CSK stiffness (the ratio of applied stress to strain, a measure of cell resistance to shape deformation), viscosity (an index of intracellular structural damping), and permanent deformation (a measure of “plasticity”) were measured with magnetic twisting cytometry, by which rotational stress was applied directly to integrin receptors with ferromagnetic beads coated with RGD-containing peptide. Treatment with cytochalasin D, which disrupts actin microfilaments inhibited stiffness by 50% and decreased permanent deformation from 70% to 50% but had almost no effect on viscosity. In contrast, nocodazole, a microtubule disrupter, had very little effect on inhibition of CSK stiffness, decreased viscosity by 25%, and had no effects on permanent deformation. Acrylamide, an intermediate filament disrupter, had little effect on inhibition of CSK stiffness, little effect on viscosity, and no effect on permanent deformation. Taxol, a drug that facilitates microtubule polymerization, increased stiffness by 10%, increased viscosity by 10%, and decreased permanent deformation from 70% to 50%. Combinations of cytochalasin D and nocodazole, cytochalasin D and acrylamide, or all three drugs resulted in a synergistic effect on inhibition of CSK stiffness and viscosity but not in permanent deformation. Inhibition of oxidative metabolism with potassium cyanide had no effects on stress-induced stiffening response. Inhibition of tyrosine phosphatase with phenylarsine oxide had no effect on stress-induced stiffening response. We conclude that higher order mechanical interactions of CSK filaments are important in determining the mechanical properties of the cell.
Estimation of Blood Pressure Variability From 24-Hour Ambulatory Finger Blood Pressure
Authors: Omboni Stefano , Parati Gianfranco , Castiglioni Paolo , Di Rienzo Marco , Imholz Ben P. M. , Langewouters Gerard J. , Wesseling Karel H. , Mancia Giuseppe
Published: June 2012

Abstract
—Portapres is a noninvasive, beat-to-beat finger blood pressure (BP) monitor that has been shown to accurately estimate 24-hour intra-arterial BP at normal and high BPs. However, no information is available on the ability of this device to accurately track ambulatory BP variability. In 20 ambulatory normotensive and hypertensive subjects, we measured 24-hour BP by Portapres and through a brachial artery catheter. BP and pulse interval variabilities were quantified by (1) the SDs of the mean values (overall variability) and (2) spectral power, computed either by fast Fourier transform and autoregressive modeling of segments of 120-second duration for spectral components from 0.025 to 0.50 Hz or in a very low frequency range (between 0.00003 and 0.01 Hz) by broadband spectral analysis. The 24-hour SD of systolic BP obtained from Portapres (24±2 mm Hg) was greater than that obtained intra-arterially (17±1 mm Hg,
P
<0.01), but the overestimation was less evident for diastolic (3±1 mm Hg,
P
<0.01) and mean (3±1 mm Hg,
P
<0.01) BP. The BP spectral power <0.15 Hz was also overestimated by Portapres more for systolic than for diastolic and mean BPs; similar findings were obtained by the fast Fourier transform, the autoregressive approach, and focusing on the broadband spectral analysis. BP spectral power >0.15 Hz obtained by the Portapres was similar during the day but lower during the night when compared with those obtained by intra-arterial recordings (
P
<0.01). No differences were observed between Portapres and intra-arterial recordings for any estimation of pulse interval variabilities. The overestimation of BP variability by Portapres remained constant over virtually the entire 24-hour recording period. Thus, although clinical studies are still needed to demonstrate the clinical relevance of finger BP variability, our study shows that Portapres can be used with little error to estimate 24-hour BP variabilities if diastolic and mean BPs are used. For systolic BP, the greater error can be minimized by using correction factors.
Stimulatory Interaction Between Vascular Endothelial Growth Factor and Endothelin-1 on Each Gene Expression
Authors: Matsuura Akira , Yamochi Wataru , Hirata Ken-ichi , Kawashima Seinosuke , Yokoyama Mitsuhiro
Published: June 2012

Abstract
—The precise regulation of cell growth in the vascular wall maintains vascular integrity, and its disruption leads to cardiovascular disorders including atherosclerosis and restenosis. Vascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells, and endothelin-1 (ET-1) is known to stimulate the proliferation of smooth muscle cells. The aim of this study was to explore a potential interaction between VEGF and ET-1 on each expression in vascular cells. VEGF enhanced preproET-1 mRNA expression and ET-1 secretion in bovine aortic endothelial cells (BAECs). Similarly, in rat vascular smooth muscle cells (VSMCs), ET-1 enhanced VEGF mRNA expression and stimulated VEGF secretion. ET-1–induced VEGF mRNA expression was abolished by a selective ET
A
receptor antagonist, BQ-485, but not by an ET
B
-selective blocker, BQ-788. It was also inhibited by pretreatment with actinomycin D but not by pretreatment with cycloheximide. Furthermore, the actinomycin D chase experiment revealed that ET-1 did not alter VEGF mRNA stability. Coculture of BAECs and VSMCs enhanced both ET-1 and VEGF gene expression in these cells, and the conditioned media from BAECs and VSMCs reproduced the augmentation of each gene expression, which was partially inhibited by BQ-485 or an antibody specific to VEGF. Our results indicate that VEGF and ET-1 have stimulatory interactions on each expression, which may play an important role in concomitant proliferation of endothelial and smooth muscle cells in the vascular wall.
Intrarenal Nitric Oxide Activity and Pressure Natriuresis in Anesthetized Dogs
Authors: Majid Dewan S. A. , Omoro Sophia A. , Chin So Yeon , Navar L. Gabriel
Published: June 2012

Abstract
—Recent studies have indicated that changes in intrarenal nitric oxide (NO) production participate in mediating arterial pressure–induced changes in urinary sodium excretion. Until recently, however, the means to measure changes in intrarenal NO activity in vivo have not been available. For the present study, changes in renal tissue NO activities were assessed directly using an NO-selective microelectrode inserted into the cortical tissue of anesthetized dogs. Control studies demonstrated that the electrode was responsive to intrarenal bolus injections of acetylcholine and to the NO donor
S
-nitroso-acetylpenicillamine (SNAP). Intrarenal nitro-
l
-arginine (50 μg · kg
−1
· min
−1
) decreased renal tissue NO concentration by 593±127 nmol/L (
P
<0.05; n=7). Infusions of SNAP (1, 2, and 3 μg · kg
−1
· min
−1
for 25 minutes) in nitro-
l
-arginine–treated dogs (n=5) resulted in dose-dependent increases in renal tissue NO activity, which showed a positive correlation with changes in urinary excretion rates of NO metabolites, nitrates and nitrites, (
r
=0.62,
P
<0.05) and sodium (
r
=0.78,
P
<0.01). During graded reductions of renal arterial pressure within the autoregulatory range (144±3 to 73±2 mm Hg; n=10), there were decreases in tissue NO activity that were positively correlated with changes in renal arterial pressure (
r
=0.45;
P
<0.05), urinary nitrate/nitrite excretion (
r
=0.64,
P
<0.005), and urinary sodium excretion (
r
=0.46;
P
<0.05). These data support the hypothesis that acute changes in renal arterial pressure result in alterations in intrarenal NO activity, which may be responsible for the associated changes in sodium excretion.
Angiotensin II Induces p67
phox
mRNA Expression and NADPH Oxidase Superoxide Generation in Rabbit Aortic Adventitial Fibroblasts
Authors: Pagano Patrick J. , Chanock Stephen J. , Siwik Deborah A. , Colucci Wilson S. , Clark Justin K.
Published: June 2012

Abstract
—Superoxide radical (O
2
−
) is ubiquitously critical to the bioactivity of endothelial nitric oxide. In angiotensin-dependent hypertension, vascular O
2
−
levels rise and impede endothelium/nitric oxide–dependent vascular relaxation. We have reported that the major O
2
−
source in the rabbit aorta is adventitial fibroblast phagocyte-like NADPH oxidase and shown that angiotensin (Ang) II treatment of adventitial fibroblasts causes a concentration-dependent increase in particulate NADPH-dependent O
2
−
. From cultured rabbit aortic adventitial fibroblasts treated or not treated with Ang II, we prepared particulate fractions and measured lucigenin-enhanced chemiluminescence. Because [Sar
1
,Thr
8
]-Ang II, a generalized antagonist of Ang II and plausible inhibitor of the conversion of Ang II, reversed Ang II (10 nmol/L)–induced NADH- and NADPH-dependent O
2
−
to basal levels, we tested the effect of the inhibitor of aminopeptidase N, amastatin (10 μmol/L), and found no effect on Ang II–stimulated O
2
−
. Ang(1-7), Ang III, and Ang IV also were not effective in stimulating O
2
−
levels at concentrations similar to those of Ang II. Kinetic analysis showed a rise in NADPH oxidase O
2
−
production in response to Ang II, which peaks at 3 hours and returns to basal levels by 16 hours. p67
phox
, a cytosolic factor, appears to be affected at both the level of transcription and protein synthesis because actinomycin and cycloheximide individually inhibited the observed effect. A partial sequence of p67
phox
was recovered by reverse transcriptase from mRNA harvested from cultured rabbit aortic adventitial fibroblasts. Furthermore, the p67
phox
mRNA transcript in aortic fibroblasts is induced by Ang II before the peak of NADPH oxidase by Northern analysis and ribonuclease protection assays. These data suggest that Ang II stimulates NAD(P)H oxidase O
2
−
generation in fibroblasts of aortic adventitia via transcriptional activation of p67
phox
. These data also provide preliminary evidence for the regulation of factors of the NADPH oxidase and potentially provide a novel means by which to abrogate the development of O
2
−
-dependent hypertension.
Differences in Tissue Angiotensin II–Forming Pathways by Species and Organs In Vitro
Authors: Akasu Maki , Urata Hidenori , Kinoshita Akio , Sasaguri Manabu , Ideishi Munehito , Arakawa Kikuo
Published: June 2012

Abstract
—Angiotensin (Ang) II plays an important role in cardiovascular homeostasis, not only in the systemic circulation but also at the tissue level, and is involved in the remodeling of the heart and vasculature under pathological conditions. Although alternative Ang II–forming pathways are known to exist in various tissues, the details of such pathways remain unclear. The aim of this study was to examine tissue Ang II–forming activities and to identify the responsible enzyme in several organs (lung, heart, and aorta) in various species (human, hamster, rat, rabbit, dog, pig, and marmoset). Among the organs examined, the lung contained the highest Ang II–forming activity. The responsible enzyme for pulmonary Ang II formation was angiotensin I-converting enzyme (ACE) in all of the species except the human lung, in which a chymaselike enzyme was dominant. In the heart, the highest total Ang II–forming activity was observed in humans, and a chymaselike enzyme was dominant in all of the species except rabbit and pig. Aorta exhibited a relatively high total Ang II–forming activity, with a predominance of chymaselike activity in all of the species except rabbit and pig, in which ACE was dominant. Our results indicate that there were remarkable differences in Ang II–forming pathways among the species and organs we examined. To study the pathophysiological roles of ACE-independent Ang II formation, one should choose species and/or organs that have Ang II–forming pathways similar to those in humans.
Regulation of Angiotensin II Receptor Expression by Nitric Oxide in Rat Adrenal Gland
Authors: Usui Makoto , Ichiki Toshihiro , Katoh Makoto , Egashira Kensuke , Takeshita Akira
Published: June 2012

Abstract
—We recently reported that administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) production, activates the vascular and cardiac renin-angiotensin systems and causes vascular thickening and myocardial hypertrophy in rats with perivascular and myocardial fibrosis. It has been reported that aldosterone may contribute to the development of cardiac fibrosis, but it is not known whether inhibition of NO synthesis affects angiotensin II (Ang II) receptor gene expression and aldosterone secretion. The aim of this study was to investigate the effect of NO inhibition on the expression of Ang II receptors in the adrenal gland and on aldosterone secretion in rats. Wistar King A rats received normal water, L-NAME alone (1 mg/mL in the drinking water), or L-NAME and the α1-adrenergic receptor blocker bunazosin (0.1 mg/mL in the drinking water) for 1 week. After 1 week of treatment with L-NAME, systolic blood pressure, plasma aldosterone concentration (PAC), and mRNA level and number of Ang II type 1 receptor (AT
1
-R) were increased. Plasma renin activity, serum angiotensin-converting enzyme activity, and the number of AT
2
-R were unchanged. Although addition of bunazosin to L-NAME restored systolic blood pressure to the control level, PAC and AT
1
-R numbers remained significantly higher than those of control level. These results suggest that the increased AT
1
-R number and PAC induced by the inhibition of NO synthesis were independent of blood pressure and systemic renin-angiotensin system. Therefore, hypertension and myocardial fibrosis induced by NO blockade may be due in part to an elevation of PAC caused by increased AT
1
-R in the adrenal gland.
Pulse Pressure and Cardiovascular Mortality in Normotensive and Hypertensive Subjects
Authors: Benetos Athanase , Rudnichi Annie , Safar Michel , Guize Louis
Published: June 2012

Abstract
—There is now increasing evidence that high pulse pressure, which is an indicator of large artery stiffness, is an independent risk factor for cardiovascular mortality, especially coronary mortality, in different populations. We have recently shown in a large French population that in male subjects aged 40 to 69 years, increased pulse pressure was a strong predictor of cardiovascular mortality, especially coronary mortality. In the present report, we analyzed the effect of pulse pressure in men and women of the same cohort after classifying them as normotensive (systolic blood pressure [SBP] <140 mm Hg and DBP <90 mm Hg) or hypertensive (SBP ≥160 mm Hg or DBP ≥95 mm Hg). After adjustment for age, mean blood pressure, and other risk factors, the relative risk (95% confidence limits) for cardiovascular mortality for an increase of 10 mm Hg of pulse pressure was 1.20 (1.01 to 1.44) in normotensives and 1.09 (1.03 to 1.14) in hypertensives. Cardiovascular and coronary death rates were similar in the group of normotensive men with a pulse pressure >50 mm Hg and in the group of hypertensive men with a pulse pressure <45 mm Hg. No association between cardiovascular mortality and pulse pressure was observed in either normotensive or hypertensive women (0.85 [0.60 to 1.21] and 1.0 [0.91 to 1.11], respectively). Low mortality rates could explain this observation in normotensive but not in hypertensive women, in whom cardiovascular mortality rates were relatively high. Because a high pulse pressure in men is an independent predictor of cardiovascular mortality in both hypertensives and in those considered as having normal blood pressure, this parameter could aid in evaluating cardiovascular risk.
Effects of Prolonged Immobilization of the Limb on Radial Artery Mechanical Properties
Authors: Giannattasio Cristina , Failla Monica , Grappiolo Alessandra , Bigoni Marco , Carugo Stefano , Denti Matteo , Mancia Giuseppe
Published: June 2012

Abstract
—Physical training is associated with an increase in arterial distensibility. Whether the effect of training on this variable is evident also for ordinary levels of exercise or no exercise is unknown, however. We have addressed this issue by investigating the effect on radial artery distensibility of prolonged monolateral immobilization of the ipsilateral limb versus the following resumption of normal mobility. We studied 7 normotensive subjects (age, 25.4±3.0 years; systolic/diastolic blood pressure, 119±9/68±6 mm Hg, mean±SE) in whom 1 limb had been immobilized for 30 days in plaster because of a fracture of the elbow. At both the day after plaster removal and after 45 days of rehabilitation, radial artery distensibility was evaluated by an echo-tracking device (NIUS-02), which allows arterial diameter to be measured noninvasively and continuously over all pressures from diastole to systole (finger monitoring), with the distensibility values being continuously derived from the Langewouters formula. In both instances, the contralateral arm was used as control. Immediately after removal of the plaster, radial artery distensibility was markedly less in the previously immobilized and fractured limb compared with the contralateral limb (0.4±0.1 versus 0.8±0.1, 1/mm Hg 10
−3
,
P
<0.05). After rehabilitation, the distensibility of the radial artery was markedly increased in the previously fractured limb (0.65±0.1 1/mm Hg 10
−3
,
P
<0.05), whereas no change was seen in the contralateral limb. Thus, complete interruption of physical activity is associated with a marked reduction of arterial distensibility, indicating that even an ordinary level of activity plays a major role in modulation of arterial mechanical properties.