bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluvastatin Inhibits Matrix Metalloproteinase-1 Expression in Human Vascular Endothelial Cells
Authors: Ikeda Uichi , Shimpo Masahisa , Ohki Ruri , Inaba Hideko , Takahashi Masafumi , Yamamoto Keiji , Shimada Kazuyuki
Published: June 2012

Abstract
—Matrix metalloproteinase-1 (MMP-1), also called interstitial collagenase, may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effects of fluvastatin on MMP-1 expression in human vascular endothelial cells (ECs). The addition of fluvastatin decreased the basal MMP-1 levels in the culture media of ECs in a time-dependent (0 to 48 hours) and dose-dependent (10
−
8
to 10
−
5
mol/L) manner. On the other hand, fluvastatin did not affect tissue inhibitor of metalloproteinase-1 levels. Collagenolytic activity in conditioned media of ECs was also dose-dependently reduced by fluvastatin. The effect of fluvastatin on MMP-1 expression was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene. Inhibition of Rho by C3 exoenzyme also significantly decreased MMP-1 expression in ECs. Our findings revealed that fluvastatin decreases MMP-1 expression in human vascular ECs through inhibition of Rho.
Bradykinin B
1
Receptor Mediates Inhibition of Neointima Formation in Rat Artery After Balloon Angioplasty
Authors: Agata Jun , Miao Robert Q. , Yayama Katsutoshi , Chao Lee , Chao Julie
Published: June 2012

Abstract
—We evaluated the effects of the kallikrein-kinin system on the proliferation and migration of primary cultured vascular smooth muscle cells (VSMCs) in vitro and neointima formation in balloon-injured rat carotid arteries in vivo. In cultured rat VSMCs, tissue kallikrein inhibited cell proliferation, and this inhibitory effect was blocked by Sar-Tyr-Aca(ε)-Lys [
d
-βNal
7
,Ile
8
]-des-Arg
9
-bradykinin, a bradykinin B
1
receptor antagonist, and by icatibant, a bradykinin B
2
receptor antagonist. Platelet-derived growth factor significantly increased the expression of the B
1
receptor but not the B
2
receptor in VSMCs. Platelet-derived growth factor–induced cell migration was significantly attenuated by des-Arg
9
-bradykinin and to a lesser degree by bradykinin. Endogenous B
1
receptor mRNA increased in rat carotid arteries after balloon angioplasty. After local delivery of adenovirus carrying the human tissue kallikrein gene into the rat carotid artery, we observed a 54% reduction in the intima/media ratio at the injured site compared with the control ratio (n=7,
P
<0.01). Administration of the B
1
receptor antagonist via minipumps blocked the protective effect of kallikrein and partially reversed the intima/media ratio toward the control ratio. Kallikrein gene delivery results in the regeneration of endothelium compared with the control groups, and the B
1
receptor antagonist abolished this effect. Nitrite/nitrate, cGMP, and cAMP levels in balloon-injured arteries significantly increased after kallikrein gene delivery, whereas the B
1
receptor antagonist abolished these increases (n=4 or 5,
P
<0.05). These results indicate that the B
1
receptor contributes to the reduction of neointima formation via the promotion of reendothelialization and inhibition of VSMC proliferation and migration through NO-cGMP and cAMP signaling pathways. This study provides significant implications in treating restenosis after revascularization.
β
2
-Adrenoceptor Polymorphism Determines Vascular Reactivity in Humans
Authors: Cockcroft John R. , Gazis Anastasios G. , Cross Debbie J. , Wheatley Amanda , Dewar Jane , Hall Ian P. , Noon Joseph P.
Published: June 2012

Abstract
—Altered β-adrenergic regulation has been reported in individuals with hypertension. The variability in vascular responsiveness to β-agonists, such as isoproterenol, observed in humans may be explained partially by β
2
-adrenoceptor polymorphism. Individuals with the Gln27 form of the receptor may show reduced vascular reactivity because of downregulation expression of the receptor in the vasculature. We screened 127 normotensive white subjects, 37 of whom were homozygous for these alleles. Thirty-two subjects (17 Gln27 and 15 Glu27) agreed to receive brachial artery infusions of isoproterenol at doses of 1 to 300 ng · min
−
1
; forearm blood flow was measured by using venous occlusion plethysmography. Of these subjects, 25 (12 Glu27 and 13 Gln27) received local doses of isoproterenol (0.3 to 30.0 ng · min
−
1
) via a dorsal hand vein preconstricted with norepinephrine. Compared with subjects homozygous for the Glu27 allele, subjects with the Gln27 substitution had lower baseline blood flow and, in response to isoproterenol, had a significantly attenuated increase in forearm blood flow. This pattern was more marked in veins. We also studied the relationship between the position 16 polymorphism and vascular reactivity. Homozygotes for Arg16 had significantly lower basal blood flow and attenuated increases in forearm blood flow compared with the Gly16 homozygotes. This was significant in veins but not in arteries. Thus, β
2
-adrenoceptor genotype determines vascular responses to isoproterenol in forearm resistance vessels and in capacitance vessels. Further studies are necessary to establish whether β
2
-adrenoceptor polymorphisms are important in the genesis of hypertension.
Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension
Authors: Melander Olle , Orho-Melander Marju , Bengtsson Kristina , Lindblad Ulf , Råstam Lennart , Groop Leif , Hulthén U. Lennart
Published: June 2012

Abstract
—Gitelman’s syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazide-sensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman’s syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman’s syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264;
P
=0.03). In conclusion, we confirm that Gitelman’s syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension.
Dopamine
1
Receptor, G
sα
, and Na
+
-H
+
Exchanger Interactions in the Kidney in Hypertension
Authors: Xu Jing , Li Xiao Xi , Albrecht Frederick E. , Hopfer Ulrich , Carey Robert M. , Jose Pedro A.
Published: June 2012

Abstract
—The ability of dopamine
1
(D
1
) receptors to inhibit luminal Na
+
-H
+
exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D
1
receptor, G
sα
, or effector proteins. The coupling of the D
1
receptor to G
sα
and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D
1
receptor, G
sα
, and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5′-
O
-(3-thiotriphosphate) (GTPγS) decreased NHE activity and increased NHE3 linked with G
sα
similarly in WKY and SHR, indicating normal G
sα
and NHE3 regulation in SHR. However, D
1
agonists increased NHE3 linked with G
sα
in WKY but not in SHR, and the inhibitory effects of D
1
agonists on NHE activity were less in SHR than in WKY. Moreover, GTPγS enhanced the inhibitory effect of D
1
agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D
1
receptor from G
sα
/NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR. We conclude that the defective D
1
receptor function in renal proximal tubules in SHR is proximal to G
sα
/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D
1
receptor from G proteins remains to be determined. Because the primary structure of the D
1
receptor is not different between normotensive and hypertensive rats, differences in D
1
receptor posttranslational modification are possible.
Flow-Mediated Vasodilation and Plasma Fibronectin Levels in Preeclampsia
Authors: Yoshida Atsushi , Nakao Shinji , Kobayashi Mitsunao , Kobayashi Hisaaki
Published: June 2012

Abstract
—To clarify the vascular endothelial function in pregnant women with hypertensive disorders, we assessed the flow-mediated vasodilation in the radial artery and compared it with plasma fibronectin levels. We determined flow-mediated vasodilation by measuring the change in radial artery diameter during hyperemia in 58 normal pregnant women, 22 preeclamptic pregnant women, and 15 pregnant women with chronic hypertension. In 41 of the 95 pregnant women, we measured the plasma fibronectin levels. Flow-mediated vasodilation in preeclamptic women was significantly less than that in normal pregnant women (
P
<0.001). In chronic hypertensive women, flow-mediated vasodilation was significantly less than that in normal pregnant women (
P
<0.001) but more than that in preeclamptic women (
P
<0.001). Flow-mediated vasodilation showed significant negative correlation with plasma fibronectin levels (
P
<0.001,
r
=0.73). Our results indicate that the endothelial function can be noninvasively assessed in pregnant women with hypertensive disorders by measuring the flow-mediated vasodilation of the radial artery with high-resolution ultrasound.
Angiotensin II Sensitivity Is Associated With the Angiotensin II Type 1 Receptor A
1166
C Polymorphism in Essential Hypertensives on a High Sodium Diet
Authors: Spiering Wilko , Kroon Abraham A. , Fuss-Lejeune Monique M. J. J. , Daemen Mat J. A. P. , de Leeuw Peter W.
Published: June 2012

Abstract
—Several investigations have shown heterogeneity in the functional responses to angiotensin II (Ang II) in patients with essential hypertension. The present study was initiated to evaluate whether the A
1166
C polymorphism of the Ang II type 1 receptor (AT
1
R) gene contributes to this variability in Ang II responses. After 7 days of a high-sodium diet (220 mmol Na
+
per day), we measured in 42 essential hypertensive patients blood pressure, heart rate, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), active plasma renin concentration, aldosterone, and atrial natriuretic peptide (ANP) before and during Ang II infusion (increasing doses of 0.3, 1.0, and 3.0 ng/kg per minute). Calculated variables were filtration fraction and renal vascular resistance (RVR). Patients in the 3 genotype groups (
AA
: n=14;
AC
: n=17;
CC
: n=11) were matched for gender, age, and body mass index. At baseline,
CC
patients had decreased GFR (
P
=0.06) and aldosterone (
P
<0.05) and increased ANP (
P
<0.05) compared with
AA
patients. Moreover, responses of ERPF, GFR, and RVR to the lowest concentration of Ang II (0.3 ng/kg per minute) were more pronounced in
CC
patients than in
AA
patients (ERPF/GFR:
P
<0.05; RVR:
P
=0.07), whereas maximal responses were all comparable between the groups. Heart rate was decreased at all levels of Ang II infusion in
CC
patients, while it did not change in
AA
or
AC
patients. There were no differences in responses of active plasma renin concentration, aldosterone, and ANP to Ang II between the 3 groups. From these data, we conclude that the C allele of the AT
1
R A
1166
C polymorphism is associated with increased sensitivity but not reactivity to Ang II. An augmented response to Ang II may well be responsible for the increased incidence of cardiovascular abnormalities found in patients with 1 or 2 C alleles.
Troglitazone Reduces Reactive Oxygen Species Generation by Leukocytes and Lipid Peroxidation and Improves Flow-Mediated Vasodilatation in Obese Subjects
Authors: Garg Rajesh , Kumbkarni Yuvraj , Aljada Ahmad , Mohanty Priya , Ghanim Husam , Hamouda Wael , Dandona Paresh
Published: June 2012

Abstract
—Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter. Insulin concentrations fell significantly at week 1 and remained low at weeks 2 and 4 (
P
<0.001). ROS generation by PMNLs fell to 77.6±25.1% of the basal at week 1 and 47.9±41.1% at week 4 (
P
<0.001). ROS generation by MNCs fell to 59.8±15.7% of the basal at week 1 and 35.1±17.6% at week 4 (
P
<0.001). 9-HODE and 13-HODE concentrations fell significantly from 787.4±52.4 and 713.1±44.7 pg/mL to 720.4±66.7 (
P
<0.004) and 675.2±65.0 pg/mL (
P
<0.01) after 4 weeks, respectively. Postischemic dilatation of the brachial artery was measured by ultrasonography. The mean percent dilatation after forearm ischemia before and after troglitazone was 5.5±3.01% and 8.75±3.37% (
P
<0.02), respectively. The percent increase in diameter after nitroglycerin was 17.08±1.18% before troglitazone, whereas it was 18.9±1.91% (
P
<0.02) after troglitazone. We conclude that troglitazone has a potent and rapid biological inhibitory effect on ROS generation by PMNLs and MNCs and that it inhibits lipid peroxidation significantly. These changes are associated with a significant improvement in postischemic flow-mediated vasodilation in the brachial artery over a relatively short period of 4 weeks.
Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase Cε During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade
Authors: Xu Yi , Clanachan Alexander S. , Jugdutt Bodh I.
Published: June 2012

Abstract
—We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT
2
R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT
2
R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP
3
R) and protein kinase Cε (PKCε) proteins. We assessed AT
2
R, angiotensin II type 1 receptor (AT
1
R), IP
3
R, and PKCε protein expression (Western blots) and AT
2
R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (n=6) were exposed to no IR, no IR+PD (0.3 μmol/L), IR, and IR+PD. Compared with no IR and no IR+PD, IR decreased (
P
<0.05) functional recovery and AT
2
R mRNA and protein, as well as AT
1
R mRNA (not protein) and IP
3
R and PKCε proteins. Compared with IR, PD+IR improved LV functional recovery (
P
<0.05) and markedly increased AT
2
R mRNA and protein (
P
<0.001). However, PD did not change AT
1
R mRNA or protein. More importantly, PD+IR markedly increased IP
3
R and PKCε proteins. The downregulation of AT
2
R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT
2
R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT
2
R blockade and is associated with enhanced downstream IP
3
R and PKCε signaling.
Angiotensin-Converting Enzyme Inhibitor Prevents Age-Related Endothelial Dysfunction
Authors: Goto Kenichi , Fujii Koji , Onaka Uran , Abe Isao , Fujishima Masatoshi
Published: June 2012

Abstract
—Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg · kg
−1
· d
−1
enalapril (WKY-E group) or a combination of 50 mg · kg
−1
· d
−1
hydralazine and 7.5 mg · kg
−1
· d
−1
hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10
−
5
mol/L ACh in the presence of norepinephrine: WKY-O, −14±2 mV; WKY-E, −22±3 mV; WKY-H, −15±2 mV; and WKY-Y, −28±0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45±6%; WKY-E, 63±8%; WKY-H, 43±4%; and WKY-Y, 72±4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K
+
channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.
Quantification of the Contribution of Cardiac and Arterial Remodeling to Hypertension
Authors: Segers Patrick , Stergiopulos Nikos , Westerhof Nico
Published: June 2012

Abstract
—The study aim was to quantify the individual and combined contributions of both the arterial system and the heart to systolic blood pressure in hypertension. We assessed the parameters of a heart–arterial model for normotensive control subjects and hypertensive patients with left ventricular adaptation patterns classified as normal, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy. The present simulations show that vascular stiffening alone increases the pulse pressure without increasing systolic blood pressure. It is only in combination with an increased peripheral resistance that arterial stiffening leads to systolic hypertension in concentric remodeling and concentric hypertrophy. The contribution of cardiac pump function to the increase in blood pressure depends on cardiac remodeling, hypertrophy, or both. In hypertensive patients with a normal left ventricle, the heart is responsible for 55% of the increase in systolic blood pressure. In concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, the cardiac contribution to the increase in systolic blood pressure is 21%, 65%, and 108%, respectively. We conclude that along with arterial changes, cardiac remodeling and hypertrophy contribute to hypertension.
Renin-Angiotensin System Polymorphisms and Coronary Events in Familial Hypercholesterolemia
Authors: Wierzbicki Anthony S. , Lambert-Hammill Michelle , Lumb Peter J. , Crook Martin A.
Published: June 2012

Abstract
—The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I–converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72;
P
=0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24;
P
=0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97;
P
=0.02), plasma glucose (OR=3.31; 95% CI, 3.10 to 3.52;
P
=0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72;
P
=0.06) and increased to 3.10 (95% CI, 1.20 to 7.52;
P
=0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.
Docosahexaenoic Acid, a Peroxisome Proliferator–Activated Receptor-α Ligand, Induces Apoptosis in Vascular Smooth Muscle Cells by Stimulation of p38 Mitogen-Activated Protein Kinase
Authors: Diep Quy N. , Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Omega-3 fatty acids (n-3 FAs) have been shown to exert a blood pressure–lowering effect in hypertension, possibly in part by influencing vascular structure. We previously demonstrated that n-3 FAs induce vascular smooth muscle cell (VSMC) apoptosis, which could exert an effect on the structure of blood vessels. In the present study, we investigated signaling pathways through which n-3 FAs mediate apoptosis in VSMCs. Cultured mesenteric VSMCs from Sprague-Dawley rats were stimulated with docosahexaenoic acid (DHA), a representative n-3 FAs. Morphological changes in apoptosis and DNA fragmentation were examined with phase-contrast microscopy and fluorescence microscopy with Hoechst 33342 staining. To clarify possible pathways of apoptosis, we evaluated the expression of phosphorylated p38 mitogen-activated protein kinases, bax, bcl-2, cytochrome
c
, and peroxisome proliferator-activated receptor-α (PPAR-α) with Western blot analysis. DHA treatment induced cell shrinkage, cell membrane blebbing, and apoptotic bodies in VSMCs. DHA time-dependently activated p38 mitogen-activated protein kinases, bax, PPAR-α, and cytochrome
c
, with maximal effects obtained after 5 and 30 minutes and 1 and 3 hours, respectively. SB-203580 and SB-202190, selective p38 inhibitors, reduced DHA-elicited apoptosis and expression of PPAR-α but had no effect on the expression of bax or cytochrome
c
. The present results indicate that DHA induces apoptosis in VSMCs through ≥2 distinct mechanisms: (1) a p38-dependent pathway that regulates PPAR-α and (2) a p38-independent pathway via dissipation of mitochondrial membrane potential and cytochrome
c
release. The death-signaling pathway stimulated by DHA may involve an integration of these multiple pathways. By triggering VSMC apoptosis, DHA may play a pathophysiological role in vascular remodeling in cardiovascular disease.
Endothelin and Prostaglandin H
2
/Thromboxane A
2
Enhance Myogenic Constriction in Hypertension by Increasing Ca
2+
Sensitivity of Arteriolar Smooth Muscle
Authors: Ungvari Zoltan , Koller Akos
Published: June 2012

Abstract
—The myogenic response of skeletal muscle arterioles is enhanced in hypertension because of the release of endothelin (ET) and prostaglandin H
2
(PGH
2
)/thromboxane A
2
(TxA
2
) from the endothelium. We hypothesized that ET and PGH
2
/TxA
2
modulate Ca
2+
signaling in arteriolar smooth muscle and thereby enhance myogenic constriction. Thus, simultaneous changes in intracellular Ca
2+
concentration in smooth muscle ([Ca
2+
]
i
), measured by fura 2 microfluorometry (expressed as Ca
2+
fluorescence ratio [R
Ca
]), and diameter were obtained as a function of intraluminal pressure (P
i
) in isolated cannulated gracilis muscle arterioles (diameter ≈120 μm) of normotensive Wistar rats (WR) and spontaneously hypertensive rats (SHR). In the absence of extracellular Ca
2+
, increases in P
i
from 20 to 160 mm Hg increased the passive diameter of arterioles without changes in R
Ca
. In the presence of extracellular Ca
2+
and endothelium, increases in P
i
elicited similar increases in R
Ca
(30±7% for control and 33±8% for SHR at 160 mm Hg) but a significantly (
P
<0.05) greater constriction of SHR arterioles compared with WR arterioles (at 160 mm Hg, 55±4% versus 38±2%, respectively, of passive diameter). In the absence of the endothelium, P
i
-induced changes in the R
Ca
and diameter of SHR and WR arterioles did not differ significantly. Also, a step increase in P
i
(from 80 to 140 mm Hg) elicited a similar increase in R
Ca
but greater constrictions in SHR versus WR arterioles. In the presence of the TxA
2
receptor inhibitor SQ29,548 and the ET
A
receptor inhibitor BQ123, there was no difference between responses of SHR and WR arterioles. In WR arterioles, increasing concentrations of KCl elicited a significant increase in R
Ca
(38±7% at 80 mmol/L) and completely constricted the arterioles. In contrast, constrictions to ET (52±7% at 3×10
−
12
mol/L) and the TxA
2
agonist U46619 (40±8% at 3×10
−
9
mol/L) were not accompanied by increases in R
Ca
at submaximal concentrations. Collectively, these findings suggest that in hypertension, endothelium-derived ET and PGH
2
/TxA
2
increase the Ca
2+
sensitivity of the contractile apparatus of arteriolar smooth muscle; thus, the similar increases in [Ca
2+
]
i
in response to the elevation of intraluminal pressure elicit greater myogenic constriction.
Functional Adrenocorticotropic Hormone Receptor in Cultured Human Vascular Endothelial Cells
Authors: Hatakeyama Haruhiko , Inaba Satoru , Taniguchi Naomi , Miyamori Isamu
Published: June 2012

Abstract
—Hypertension is a prominent feature of patients with Cushing’s disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11β-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11β-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11β-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension.
Implications of Pulse Pressure as a Predictor of Cardiac Risk in Patients With Hypertension
Authors: Millar J. Alasdair , Lever Anthony F.
Published: June 2012

Previously we demonstrated that pulse pressure is a strong risk factor for coronary events in male hypertensive subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. In this study, we have assessed the implications of this finding in the treatment of mild essential hypertension. We examined the relationship between diastolic blood pressure and both coronary disease risk and stroke when these events were predicted by the above blood pressure measures using an empirical linear model and multivariate logistic regression models that contained data from the MRC trial. Under these circumstances, the predicted stroke risk increased progressively with increasing values of diastolic blood pressure, but in both empirical and formal statistical models, the predicted risk of a coronary event exhibited a J-shaped relationship with diastolic blood pressure. These results suggest that if coronary event risk in mild essential hypertension is predicted by pulse pressure then it may increase at low values of diastolic blood pressure, in contrast to stroke risk, which declines continuously as diastolic blood pressure falls within the physiological range. This raises the possibility that different sequelae of hypertension are best predicted by different measures of blood pressure and that the effect of treatment on stroke and coronary events in some circumstances may be discordant.
Exercise Training Increases Baroreceptor Gain Sensitivity in Normal and Hypertensive Rats
Authors: Brum Patricia Chakur , Da Silva Gustavo José Justo , Moreira Edson Dias , Ida Fumio , Negrão Carlos Eduardo , Krieger Eduardo Moacyr
Published: June 2012

Abstract
—Exercise training attenuates arterial hypertension and increases baroreflex sensitivity in spontaneous hypertension. However, no information exists regarding the portion of the baroreflex arch in which this attenuation takes place. We tested the hypothesis that exercise training increases the afferent pathway sensitivity of baroreflex control in both normotensive and spontaneously hypertensive rats (SHR). Arterial pressure and whole-nerve activity of the aortic baroreceptor (multifiber preparation) were evaluated in 30 male rats assigned to 4 groups: sedentary and exercise-trained normotensive rats and sedentary and exercise-trained SHR. Exercise training was performed on a motor treadmill, 5 d/wk for 60 minutes, gradually progressing toward a speed of 26.8 m/min. Exercise training reduced mean arterial pressure in conscious exercise-trained SHR (183±4 versus 165±7 mm Hg). The relation between changes in aortic baroreceptor discharge and changes in systolic arterial pressure increased significantly in exercise-trained normotensive rats (2.09±0.1 versus 1.44±0.1%/mm Hg) and exercise-trained SHR (0.92±0.1 versus 0.71±0.1%/mm Hg) compared with their respective sedentary rats. Likewise, the average aortic baroreceptor gain sensitivity (calculated by logistic equation) was significantly higher in exercise-trained normotensive rats (2.25±0.19 versus 1.77±0.03%/mm Hg) and exercise-trained SHR (1.07±0.04 versus 0.82±0.05%/mm Hg) compared with their respective sedentary control rats. In conclusion, exercise training increases aortic baroreceptor gain sensitivity in normotensive and SHR, thus improving baroreceptor sensitivity, which may result in a more efficient arterial pressure regulation by the baroreflexes.
Overexpression of eNOS in NTS Causes Hypotension and Bradycardia In Vivo
Authors: Sakai Koji , Hirooka Yoshitaka , Matsuo Isamu , Eshima Kenichi , Shigematsu Hideaki , Shimokawa Hiroaki , Takeshita Akira
Published: June 2012

Abstract
—The role of nitric oxide (NO) in the brain in the control of blood pressure and the sympathetic nervous system is debated. This study examined the effect of overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarii (NTS) on blood pressure in conscious rats. Adenovirus vectors encoding either eNOS (AdeNOS) or β-galactosidase were transfected into the NTS in vivo. In the AdeNOS-treated rats, the local expression of eNOS in the NTS was confirmed by immunohistochemical staining and Western blot analysis for the eNOS protein and by increased production of nitrite/nitrate in the NTS measured by in vivo microdialysis. Blood pressure and heart rate, monitored by the use of a radiotelemetry system in a conscious state, were significantly decreased in the AdeNOS-treated group at day 5 to day 10 after the gene transfer. Urinary norepinephrine excretion also was decreased at day 7 after the gene transfer in the AdeNOS-treated group. Our results indicate that overexpression of eNOS in the NTS decreases blood pressure, heart rate, and sympathetic nerve activity in conscious rats.
Central Cardiovascular Action of Neuropeptide Y in Conscious Rabbits
Authors: Matsumura Kiyoshi , Tsuchihashi Takuya , Abe Isao
Published: June 2012

Abstract
—We determined the central interactions of neuropeptide Y and leptin on cardiovascular and sympathetic responses in conscious rabbits. Intracerebroventricular injections of neuropeptide Y (0.1 and 1 nmol/40 μL) elicited dose-related decreases in arterial pressure and renal sympathetic nerve activity without a significant change in heart rate. Peak depressor or sympathoinhibitory responses of mean arterial pressure and renal sympathetic nerve activity (−13.0±1.5 mm Hg and −27.6±4.9%) were observed at 25 and 20 minutes after intracerebroventricular injection of 1 nmol of neuropeptide Y, respectively. Pretreatment with intracerebroventricular injection of leptin (3 nmol) prevented the depressor and sympathoinhibitory responses elicited by intracerebroventricular neuropeptide Y. Intravenous injection of the same dose of neuropeptide Y (1 nmol) as that used in the intracerebroventricular experiment failed to cause any cardiovascular and renal sympathetic nerve responses. On the other hand, a subdepressor dose of intracerebroventricular infusion of neuropeptide Y (1 nmol/300 μL per hour) significantly attenuated the baroreflex sensitivities assessed by renal sympathetic nerve activity and heart rate compared with vehicle infusion (G
max
; −7.4±0.7 versus −13.7±0.9%/mm Hg,
P
<0.01, and −4.0±0.3 versus −6.7±0.8 bpm/mm Hg,
P
<0.05, respectively). These results suggest that central neuropeptide Y participates in the regulations of the sympathetic nerve activity to kidney and the baroreceptor reflex and that the depressor response induced by intracerebroventricular neuropeptide Y is modulated, at least in part, by central leptin in conscious rabbits.
Serum Levels of Vascular Endothelial Growth Factor in Preeclamptic and Normotensive Pregnancy
Authors: Hunter Alyson , Aitkenhead Mark , Caldwell Carolyn , McCracken Geoffrey , Wilson David , McClure Neil
Published: June 2012

Abstract
—The purpose of these studies was first to determine if vascular endothelial growth factor (VEGF), a vascular permeability agent, is increased in the serum of women with preclinical and clinical preclampsia (PE), and second to determine how these levels change after delivery. Twenty preeclamptic and 25 normotensive women at term consented to have blood taken pre- and post-delivery. Ten preeclamptic, 10 gestational hypertensive, and 28 normotensive women had blood collected respectively at 12, 20, and 30 weeks gestation and predelivery. Serum was extracted from all samples, and VEGF concentrations were determined by radioimmunoassay. Predelivery, the median serum VEGF concentration in the preeclamptic group was 51.7 ng/mL, and in the control group the concentration was 13.9 ng/mL (
P
<0.0001). Serum VEGF concentrations fell within 24 hours of delivery in both groups, which resulted in median values of 3.8 ng/mL and 3.2 ng/mL respectively (
P
<0.3). At 12 and 20 weeks, there was no significant difference between the serum VEGF concentrations in the 3 groups (
P
<0.3, 0.052 respectively). At 30 weeks, prior to the onset of clinical PE, the serum VEGF levels in the eventual preeclamptic group were elevated significantly compared with the gestational hypertensive and normotensive groups (
P
<0.001). Predelivery serum VEGF concentrations were significantly elevated in the preeclamptic group and were similar to those in the first study (
P
<0.0001). These findings suggest that VEGF may be important in the pathophysiology of PE and has the potential to act as a preclinical marker for the condition.
Estrogen Replacement Reduces Age-Associated Remodeling in Rat Mesenteric Arteries
Authors: Zhang Yunlong , Stewart Ken G. , Davidge Sandra T.
Published: June 2012

Abstract
—Estrogen replacement therapy significantly decreases the incidence of cardiovascular disease in postmenopausal women. In aging, there is an increase in vascular stiffness along with a decrease in matrix metalloproteinase (MMP) activity. Our hypothesis was that estrogen replacement would increase MMPs and therefore reduce the vascular stiffness that is associated with aging. Female Sprague-Dawley rats were implanted with a placebo or 17β-estradiol–containing pellet (0.5 mg/pellet, 60-day release) at 10 months of age (n=6, each). Six young rats (3 months old) were also studied. After a 2-month exposure to the pellet, mesenteric arteries were studied on a pressurized arteriograph system. Distensibility and wall thickness were measured in response to stepwise increases in intraluminal pressure in Ca
2+
-free physiological saline solution buffer with papaverine (10
−
4
mol/L). In response to increasing pressure, aged placebo rats exhibited a significant decrease in distensibility compared with young rats (
P
<0.05) that was accompanied by an increase in wall thickness (
P
<0.05). Conversely, estrogen replacement increased distensibility and decreased wall thickness in aged rats (old estrogen-replaced versus old placebo,
P
<0.05). Zymography data indicated that MMP-2 activity decreased in aging but was increased by estrogen replacement. In summary, estrogen replacement in aging female rats reduces age-associated vascular remodeling.
Fluid Shear Stress Reduces 11β-Hydroxysteroid Dehydrogenase Type 2
Authors: Lanz C.-Bettina , Causevic Maja , Heiniger Christian , Frey Felix J. , Frey Brigitte M. , Mohaupt Markus G.
Published: June 2012

Abstract
—In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11β-hydroxysteroid dehydrogenases (11β-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11β-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11β-HSD1; however, 11β-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11β-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11β-HSD2 activity yet did not prevent the ss response. The ss response was completely protein kinase C independent. The mitogen-activated protein kinase kinase inhibitor PD-098059 enhanced 11β-HSD2 activity in static conditions yet only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (FA)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphorylation of FA kinase dose-dependently, thus maintaining 11β-HSD2 activity. The 11β-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11β-HSD2 activity. In conclusion, JEG-3 cells express 11β-HSD2, which is downregulated by ss. Regulatory mechanisms involve transcriptional control and require intact FA-cytoskeleton signaling and phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response.
Vascular Effects of ACE Inhibition Independent of the Renin-Angiotensin System in Hypertensive Renovascular Disease
Authors: van Ampting Jacobine M. A. , Hijmering Michel L. , Beutler Jaap J. , van Etten Ronald E. , Koomans Hein A. , Rabelink Ton J. , Stroes Erik S. G.
Published: June 2012

Abstract
—To evaluate whether ACE inhibition and angiotensin II type 1 blockade exert beneficial effects on NO availability independent of their blood pressure–lowering effect, we used a double-blind crossover design to study vascular function in 18 patients with hypertensive renovascular disease during 6 weeks of therapy with enalapril (Ena) and valsartan (Val) compared with non–renin-angiotensin system–mediated treatment with the α
1
-blocker doxazosin (Dox). Control measurements were performed in 13 age-matched volunteers. Forearm blood flow was assessed with venous occlusion plethysmography, and serotonin and nitroprusside were used as endothelium-dependent and -independent vasodilators, respectively. Blood pressure was similar during all treatment periods. Serotonin-induced vasodilation was decreased in patients during Dox treatment (n=12) compared with control subjects (n=13) (increase 42±20% versus 107±65%,
P
<0.05). Crossover from Dox to Val (n=6) had no effect on serotonin response (increase 50±14%), but crossover to Ena (n=6) caused a significant improvement (increase 79±39%,
P
<0.05 versus Dox). In an assessment of all patients, serotonin-induced vasodilation during Ena (n=12, increase 75±31%) was increased compared with both Val and Dox (43±14% and 42±20%, respectively; both
P
<0.05 versus Ena). The nitroprusside response remained unaltered during all treatment periods. In conclusion, ACE inhibition improves the impaired endothelium-dependent vascular function in patients with hypertensive renovascular disease. This effect is unrelated to blood pressure–lowering or angiotensin II–mediated effects.
Effects of Blood Pressure, Smoking, and Their Interaction on Carotid Artery Structure and Function
Authors: Liang Yu-Lu , Shiel Louise M. , Teede Helena , Kotsopoulos Dimitra , McNeil John , Cameron James D. , McGrath Barry P.
Published: June 2012

Abstract
—In the present study, we examined the relationships among carotid blood pressure, arterial geometry, and wall stress and determined the impact of hypertension, smoking status, and their interaction on these relationships. The study involved 679 subjects aged 49 to 82 years: 372 smokers (190 men and 182 women) and 307 nonsmokers (110 men and 197 women). Blood samples were taken to determine total cholesterol levels. Central pulse pressure was derived from measured brachial artery pressure with a linear regression equation from data obtained in a subgroup of 276 subjects that related brachial and carotid pulse pressures; the latter was measured with applanation tonometry. Carotid intima-media thickness (IMT), lumen diameter (D), and stiffness index (SI) were determined with high-resolution B-mode ultrasound. Mean and pulsatile circumferential stress (ς
C
) was calculated according to the Laplace relationship. Indexes of arterial geometry and function were adjusted for age, height, and heart rate. Hypertension (treated and/or screening blood pressure of >140/90 mm Hg) was present in 71 nonsmokers and 186 smokers. Nonsmokers and smokers did not differ in blood pressure and cholesterol levels. Hypertension and smoking individually and interactively significantly increased adjusted IMT, D, and SI. The radius-to–wall thickness ratio (R/IMT) (where R=D/2) and ς
C
were increased in hypertensives. SI was correlated with IMT (
r
=0.56,
P
<0.001); radius-to–wall thickness ratio was inversely correlated with central pulse pressure (
r
=−0.38,
P
<0.001). Smoking did not influence these relationships. In conclusion, carotid artery wall remodeling appears to follow Laplace’s law but is insufficient to prevent an increase in circumferential stress in hypertensive subjects. Unlike hypertension, smoking does not influence the lumen-to-wall ratio but has a significant effect on wall stiffness.
Systemic and Regional Hemodynamic Responses to Tempol in Angiotensin II–Infused Hypertensive Rats
Authors: Nishiyama Akira , Fukui Toshiki , Fujisawa Yoshihide , Rahman Matlubur , Tian Run-Xia , Kimura Shoji , Abe Youichi
Published: June 2012

Abstract
—Recent studies have indicated that angiotensin II (Ang II) can stimulate oxidative stress. The present study was conducted to assess the contribution of oxygen radicals to hypertension and regional circulation during Ang II–induced hypertension. With radioactive microspheres, the responses of systemic and regional hemodynamics to the membrane-permeable, metal-independent superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) were assessed in conscious Ang II–infused hypertensive rats. Ang II–infused rats (80 ng/min SC for 12 days: n=25) showed higher mean arterial pressure (MAP: 161±4 mm Hg) and total peripheral resistance (TPR: 1.59±0.08 mm Hg · min
−1
· mL
−1
) than vehicle-infused normotensive rats (116±3 mm Hg and 0.95±0.04 mm Hg · min
−1
· mL
−1
, respectively; n=23). The blood flow rates in the brain, spleen, large intestine, and skin were significantly reduced in Ang II–infused rats compared with vehicle-infused rats, whereas rates in the lung, heart, liver, kidney, stomach, small intestine, mesenterium, skeletal muscle, and testis were similar. Vascular resistance was significantly increased in every organ studied except the lung, in which the resistance was similar. Tempol (216 μmol/kg IV) significantly reduced MAP by 30±4% from 158±7 to 114±5 mm Hg and TPR by 35±6% from 1.57±0.17 to 0.95±0.04 mm Hg · min
−1
· g
−1
in Ang II–infused rats (n=9) but had no effect on these parameters in vehicle-infused rats (n=8). In Ang II–infused rats, tempol did not affect regional blood flow but significantly decreased vascular resistance in the brain (29±6%), heart (31±6%), liver (37±7%), kidney (30±7%), small intestine (38±6%), and large intestine (47±7%). Ang II–infused hypertensive rats showed doubled vascular superoxide production (assessed with lucigenin chemiluminescence), which was normalized by treatment with tempol (3 mmol/L, n=7). Further studies showed that the NO synthase inhibitor,
N
ω
-nitro-
l
-arginine methyl ester (11 μmol · kg
−1
· min
−1
IV, n=11) markedly attenuated the systemic and regional hemodynamic responses of tempol in Ang II–infused rats. These results suggest that in this model of hypertension, oxidative stress may have contributed to the alterations in systemic blood pressure and regional vascular resistance through inactivation of NO.
Association Between Smoking and Blood Pressure
Authors: Primatesta Paola , Falaschetti Emanuela , Gupta Sunjai , Marmot Michael G. , Poulter Neil R.
Published: June 2012

Cigarette smoking causes acute blood pressure (BP) elevation, although some studies have found similar or lower BPs in smokers compared with nonsmokers. Cross-sectional data from 3 years (1994 to 1996) of the annual Health Survey for England were used to investigate any difference in BP between smokers and nonsmokers in a nationally representative sample of adults (≥16 years old). Randomly selected adults (33 860; 47% men) with valid body mass index (BMI) and BP measurements provided data on smoking status (never, past, or current) and were stratified into younger (16 to 44 years old) and older (≥45 years old) age groups. Analyses provided between 89% and 94% power to detect a difference of 2 mm Hg systolic BP between smokers and nonsmokers in the 4 age/gender strata (α=0.05). Older male smokers had higher systolic BP adjusted for age, BMI, social class, and alcohol intake than did nonsmoking men. No such differences were seen among younger men or for diastolic blood pressure in either age group. Among women, light smokers (1 to 9 cigarettes/d) tended to have lower BPs than heavier smokers and never smokers, significantly so for diastolic BP. Among men, a significant interaction between BMI and the BP-smoking association was observed. In women, BP differences between nonsmokers and light smokers were most marked in those who did not drink alcohol. These data show that any independent chronic effect of smoking on BP is small. Differences between men and women in this association are likely to be due to complex interrelations among smoking, alcohol intake, and BMI.