bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric Oxide Synthase Expression in the Course of Lead-Induced Hypertension
Authors: Vaziri Nosratola D. , Ding Yaoxian , Ni Zhenmin
Published: June 2012

Abstract
—We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E–fortified chow, or a normal control group given either regular food and water or vitamin E–fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension.
Angiotensin II–Stimulated Induction of
sis
-Inducing Factor Is Mediated by Pertussis Toxin–Insensitive G
q
Proteins in Cardiac Myocytes
Authors: Hunt Rachel A. , Bhat G. Jayarama , Baker Kenneth M.
Published: June 2012

Abstract
—The Janus kinase–signal transducers and activators of transcription (JAK-STAT) pathway is stimulated by angiotensin II (Ang II) via the type 1 receptor after acute pressure overload in the heart. The purpose of this study was to determine whether activation of the JAK-STAT pathway by Ang II is dependent on G proteins. Ang II (100 nmol/L for 120 minutes) caused formation of
sis
-inducing factor (SIF) complexes and tyrosine phosphorylation of STAT proteins in neonatal rat ventricular myocytes. The percentage of change in Ang II–stimulated SIF induction was not affected by pertussis toxin (PTX) or GP antagonist-2A, compounds that inhibit activation of G
i
and G
o
proteins. In contrast, GP antagonist-2A, a peptide that selectively inhibits activation of G
q
proteins, completely abolished Ang II–stimulated SIF induction and STAT3 tyrosine phosphorylation. Pretreatment of cardiac myocytes with U73122, an inhibitor of phosphatidylinositol-specific phospholipase C (PLC) activity, decreased Ang II–stimulated SIF induction and STAT3 tyrosine phosphorylation in a dose-dependent manner. Chelation of intracellular Ca
2+
with BAPTA-AM did not alter Ang II–stimulated SIF induction. In contrast, pretreatment of cardiac myocytes with Ro-31-8220, a potent and specific inhibitor of protein kinase C (PKC), decreased Ang II–stimulated SIF induction in a dose-dependent manner. Ang II–stimulated SIF induction was abolished in cardiac myocytes after downregulation of PKC by treatment with PMA. From these data, we conclude that Ang II–stimulated SIF induction and STAT3 tyrosine phosphorylation is mediated by PTX-insensitive G proteins through a G
q
-PLC-PKC–mediated pathway in neonatal rat ventricular myocytes.
Apoptosis, Coronary Arterial Remodeling, and Myocardial Infarction After Nitric Oxide Inhibition in SHR
Authors: Ono Yuko , Ono Hidehiko , Matsuoka Hiroaki , Fujimori Takahiro , Frohlich Edward D.
Published: June 2012

Abstract
—This study was designed to investigate the relationship between apoptosis (programmed cell death) and coronary arterial remodeling in spontaneously hypertensive rats (SHR) following prolonged nitric oxide synthesis inhibition. In addition, we evaluated whether the development of coronary arterial smooth muscular cell apoptosis was related to hemodynamics or to vascular hypertrophy. Three groups of 20-week-old male SHR were investigated: controls, and two groups that received two doses of N
G
-nitro-
l
arginine (L-NAME, 50 mg/L and 80 mg/L) each for 3 weeks. Mean arterial pressure and total peripheral resistance index increased whereas cardiac index diminished with L-NAME. Pathohistological study demonstrated increased pericardiac fibrosis and coronary arterial injury score in the L-NAME group in a dose-dependent manner. The high dose of L-NAME (Group 3) produced myocardial infarction in 78% of the rats. The wall:lumen ratio of epicardial coronary arteries was greater in L-NAME treated SHR (0.23±0.02 versus 0.16±0.02;
P
<0.05) and was associated with markedly increased apoptosis (15.3±6 versus 1.9±1;
P
<0.05) without smooth muscle cell proliferation (PCNA positive cells). Apoptosis occurred predominantly in hypertrophic coronary arterial smooth muscular cells; myocardial infarction and ventricular fibrosis were exacerbated by impaired hemodynamics induced by L-NAME. These data suggest that coronary endothelial dysfunction and myocardial ischemic disease induced by L-NAME were responsible for apoptosis of coronary arterial smooth muscle cells, myocardial fibrosis, and infarction, all pathological findings that are consistent with what may be found in clinical hypertensive heart disease.
Rarefaction of Skin Capillaries in Borderline Essential Hypertension Suggests an Early Structural Abnormality
Authors: Antonios Tarek F. T. , Singer Donald R. J. , Markandu Nirmala D. , Mortimer Peter S. , MacGregor Graham A.
Published: June 2012

Abstract
—We recently showed that rarefaction of skin capillaries in the dorsum of the fingers of patients with essential hypertension is due to the structural (anatomic) absence of capillaries rather than functional nonperfusion. It is not known whether this rarefaction is primary (ie, antedates the onset of hypertension) or secondary (ie, as a consequence of sustained and prolonged elevation of blood pressure [BP]). The aim of the present investigation was to study skin capillary density in a group of patients with mild borderline hypertension to assess whether rarefaction antedates the onset of sustained elevation of BP. The study group included 18 patients with mild borderline hypertension (mean supine BP, 136/83 mm Hg), 32 normotensive controls (mean BP, 126/77 mm Hg), and 45 patients with established essential hypertension (mean BP, 156/98 mm Hg). The skin of the dorsum of the fingers was examined by intravital capillary videomicroscopy before and after venous congestion at 60 mm Hg for 2 minutes. Patients with borderline essential hypertension had the lowest resting capillary density when compared with normotensive controls and patients with established hypertension. Maximal capillary density with venous congestion in the borderline group remained the lowest. The study confirmed that patients with borderline essential hypertension have skin capillary densities that are equally low as or even lower than patients with established hypertension. Both groups had significantly lower capillary densities than normal controls. One explanation for the results is that capillary rarefaction may be due to an early structural abnormality in essential hypertension.
Contrasting Effects of Selective T- and L-Type Calcium Channel Blockade on Glomerular Damage in DOCA Hypertensive Rats
Authors: Karam Habib , Clozel Jean-Paul , Bruneval Patrick , Gonzalez Marie-Françoise , Ménard Joël
Published: June 2012

Abstract
—Mibefradil and amlodipine are calcium antagonists with different channel selectivities. Mibefradil blocks both L- and T-type calcium channels; although in the usual pharmacological doses, it predominantly blocks the T-type channels. In contrast, amlodipine selectively blocks L-type channels. The goal of the present study was to assess whether this differential selectivity would result in different effects on end-organ damage in experimental hypertension. For this purpose, deoxycorticosterone acetate (DOCA)–salt hypertensive rats were treated either with equipotent doses of mibefradil or amlodipine (30 mg · kg
−1
· d
−1
as food admix). Despite the fact that both drugs decreased systolic arterial pressure to the same extent (140±5 mm Hg in the mibefradil group and 144±3 mm Hg in the amlodipine group versus 225±5 mm Hg in the untreated-DOCA group), only mibefradil decreased proteinuria (35.5±6.5 versus 103.3±14.1 mg/24 h in untreated DOCA-salt animals) and prevented glomerular lesions. Both drugs, however, prevented the occurrence of vascular renal lesions. To elucidate the mechanism responsible for this difference, we evaluated in an additional series of experiments the effects of mibefradil and amlodipine on plasma and renal renin concentrations, as well as the effects of the addition of enalapril, an ACE inhibitor, given on top of both drugs on proteinuria. Amlodipine, in contrast to mibefradil, markedly stimulated the plasma (17.8±2.6 ng Ang I · mL
−1
· h
−1
in the amlodipine group versus 3.9±0.4 ng Ang I · mL
−1
· h
−1
in the mibefradil group and 3.2±0.3 ng Ang I · mL
−1
· h
−1
in the untreated-DOCA group) and renal (2.42±0.37 ng Ang I · mL
−1
· h
−1
in the amlodipine group versus 0.36±0.04 ng Ang I · mL
−1
· h
−1
in the mibefradil group and 0.26±0.08 ng Ang I · mL
−1
· h
−1
in the untreated-DOCA group) renin concentrations. Stimulation of the renin-angiotensin system could explain the absence of a renal protective effect of amlodipine. This was also suggested by the fact that enalapril given in addition to amlodipine could decrease proteinuria. In conclusion, T-type channel blockade by mibefradil decreases blood pressure without stimulation of the renin-angiotensin system and therefore prevents most of the glomerular damage in DOCA hypertensive rats.
Digoxin Prevents Ouabain and High Salt Intake–Induced Hypertension in Rats With Sinoaortic Denervation
Authors: Huang Bing S. , Kudlac Marian , Kumarathasan Raj , Leenen Frans H. H.
Published: June 2012

Abstract
—Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabainlike activity (“ouabain”) in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 μg/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 μg · kg
−1
· d
−1
). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 μg · kg
−1
· d
−1
) or intracerebroventricular (ICV) antibody Fab fragments (200 μg/d), which bind “ouabain” with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na
+
,K
+
-ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and “ouabain” in the brain, thereby delaying ouabain- and preventing high salt–induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain “ouabain” or ouabain.
Contribution of Stroke Volume to the Change in Pulse Pressure Pattern With Age
Authors: Alfie José , Waisman Gabriel D. , Galarza Carlos R. , Cámera Mario I.
Published: June 2012

Abstract
—This study investigated the effect of age on pulse pressure and its underlying mechanisms in unmedicated hypertensive men with the same level of mean arterial pressure. We included 77 men 17 to 76 years old with daytime mean arterial pressure between 95 and 114 mm Hg. In the supine position, pulse pressure showed a significant widening in young (<30 years) and older (≥60 years) patients. Pulse pressure decreased in parallel with stroke index from age >30 to 40 to 49 years. Upright posture, however, eliminated this difference through a larger orthostatic fall in stroke index and pulse pressure in the youngest patients. After age 50 years, pulse pressure exhibited a progressive widening despite the further age-related decrease in stroke index. Supine, upright, and 24-hour pulse pressure fitted a curvilinear correlation with age (
r
=0.55, 0.56, and 0.68, respectively,
P
<0.001), with a transition at age 50 years. Before age 50 years, 24-hour pulse pressure correlated positively with stroke volume (
r
=0.5,
P
<0.001) and negatively with arterial compliance (SV/PP ratio,
r
=−0.37,
P
<0.01). In contrast, in men ≥50 years old, 24-hour pulse pressure correlated negatively with the SV/PP ratio (
r
=−0.5;
P
<0.01), without significant influence of stroke volume. Thus, in hypertensive men, the age-related change in stroke volume significantly accounted for the change in clinic and ambulatory pulse pressure during young adulthood, but its contribution decreased after the fifth decade.
Gender Differences in Ca
2+
Entry Mechanisms of Vasoconstriction in Wistar-Kyoto and Spontaneously Hypertensive Rats
Authors: Crews Janice K. , Murphy Jason G. , Khalil Raouf A.
Published: June 2012

Abstract
—We investigated whether putative vascular protection against hypertension in females reflects differences in the Ca
2+
mobilization mechanisms of vasoconstriction depending on the gender and the status of the gonads. Active stress and
45
Ca
2+
influx were measured in aortic strips isolated from intact and gonadectomized male and female Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In aortic strips of intact male WKY incubated in normal Krebs’ solution (2.5 mmol/L Ca
2+
), both phenylephrine (10
−5
mol/L) and membrane depolarization by 96 mmol/L KCl caused significant increases in active stress and
45
Ca
2+
influx. In intact female WKY, the phenylephrine- and KCl-induced stress and
45
Ca
2+
influx were significantly reduced. In Ca
2+
-free (2 mmol/L EGTA) Krebs’ solution, stimulation of aortic strips with phenylephrine or caffeine (25 mmol/L) to induce Ca
2+
release from intracellular stores caused a transient increase in stress that was not significantly different between males and females. In SHR, the phenylephrine- and KCl-induced stress and
45
Ca
2+
influx were significantly greater than those in WKY in all groups of rats. The reduction in stress and Ca
2+
entry in intact females compared with intact males was greater in SHR than in WKY. The contractile responses and Ca
2+
entry in castrated male and ovariectomized female WKY or SHR were not significantly different from the respective responses in intact males. The contractile responses and Ca
2+
entry in ovariectomized female WKY or SHR with 17β-estradiol implant were not significantly different from the respective responses in intact females. Thus, the phenylephrine- and depolarization-induced vascular reactivity and Ca
2+
entry in vascular smooth muscle are dependent on gender and on the presence or absence of functional female gonads. Ca
2+
release from intracellular stores is not affected by gender or gonadectomy. The gender-specific changes in vascular reactivity and Ca
2+
entry are augmented in hypertension.
Association Between the C825T Polymorphism of the G Protein β3-Subunit Gene and Hypertension in Blacks
Authors: Dong Yanbin , Zhu Haidong , Sagnella Giuseppe A. , Carter Nicholas D. , Cook Derek G. , Cappuccio Francesco P.
Published: June 2012

Abstract
—A polymorphism (C825T) of the G protein β3-subunit gene has been associated with low renin hypertension in whites. The aim of this study was to examine the C825T polymorphism in relation to hypertension in a population-based study of black people of African origin who have high prevalence of low renin, salt-sensitive hypertension. A total of 428 men and women, aged 40 to 59 years (270 Caribbeans and 158 West Africans), who took part in a population-based survey were studied. All were blacks and first-generation immigrants. The C825T polymorphism was detected by polymerase chain reaction followed by restriction-enzyme digestion. The prevalence of hypertension (supine blood pressures ≥160 systolic and/or 95 mm Hg diastolic or on drug therapy) was 43%. The distribution of the genotypes (CC, CT, and TT) was in Hardy-Weinberg equilibrium with observed frequencies of 4.0% (n=17), 33.6% (n=144), and 62.4% (n=267), respectively. Allele frequencies were 20.8% for C and 79.2% for T. No difference was detected between Caribbeans and West Africans. A 3-fold higher risk of hypertension was found among the carriers of the T variant both as heterozygotes (odds ratio [OR], 3.43 [95% CI, 0.94 to 12.4]) and homozygotes (OR, 3.87 [95% CI, 1.09 to 13.8]). The estimate of effect and the blood pressure values in the groups carrying the T variant suggested a dominant model for the T allele. This was confirmed by a significant association between the T allele and hypertension (OR, 3.71 [95% CI, 1.05 to 13.1]), even when adjusted for age, sex, and body mass index (OR, 4.14 [95% CI, 1.11 to 15.4]). The study shows, for the first time, a high frequency of the 825T allele in black people, and it provides evidence that the T allele may be a susceptibility factor for the development of hypertension in blacks. Given the high frequency of the T allele, even a 2-fold increased risk of hypertension among the carriers of the T allele might account for 44% of the cases of hypertension in blacks.
Different Mechanisms for Testosterone-Induced Relaxation of Aorta Between Normotensive and Spontaneously Hypertensive Rats
Authors: Honda Hideo , Unemoto Tamao , Kogo Hiroshi
Published: June 2012

Abstract
—The tension in isolated ring preparations of the thoracic aortae from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) was measured isometrically to study the differences in testosterone-induced relaxation between WKY and SHR aortic rings. Testosterone (9 to 300 μmol/L) induced a concentration-dependent relaxation in both WKY and SHR aortic rings, and the relaxation induced by testosterone was greater in SHR than WKY. The relaxation induced by testosterone was significantly reduced by denudation of endothelium in SHR but not WKY. Indomethacin, an inhibitor of cyclooxygenase, and
N
G
-nitro-
l
-arginine, an inhibitor of nitric oxide (NO) synthase, showed little influence on the relaxation induced by testosterone in both WKY and SHR aortic rings. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, significantly reduced the relaxation induced by testosterone in both WKY and SHR aortic rings, although the extent of reduction was greater in WKY than SHR. On the other hand, 4-aminopyridine, a selective inhibitor of voltage-dependent potassium channels, and tetraethylammonium, an inhibitor of calcium-activated potassium channels, significantly reduced the relaxation induced by testosterone in SHR but not WKY. These results suggest that the mechanisms of testosterone-induced vasorelaxation in both WKY and SHR involve, in part, ATP-sensitive potassium channels in the thoracic aortae and that in SHR aortic rings, testosterone may release endothelium-derived substances that may cause hyperpolarization of the cells by a mechanism that involves potassium channels. Moreover, the data show differences between WKY and SHR in the function of ATP-sensitive, voltage-dependent, and calcium-activated potassium channels.
Salicylate Inhibition of Extracellular Signal-Regulated Kinases and Inducible Nitric Oxide Synthase
Authors: Wang Zhongyan , Brecher Peter
Published: June 2012

Abstract
—The expression of inducible nitric oxide synthase (iNOS) is a characteristic response to inflammation and can be inhibited with sodium salicylate. We used the cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs) may explain the mechanism by which salicylate exerts its anti-inflammatory effects. Tumor necrosis factor-α (TNF-α) alone can induce extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in a rapid and transient manner, whereas interferon-γ (IFN-γ) can induce only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with selective inhibitors blocked cytokine-induced iNOS protein and nitrite production. Salicylate treatment inhibited iNOS expression induced by TNF-α and IFN-γ and attenuated the phosphorylation of ERK by TNF-α and IFN-γ either alone or in combination. Salicylate had no obvious effect on the activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that salicylate inhibited the phosphorylation of ERK and iNOS expression induced by cytokines in a dose-dependent manner and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK pathway and iNOS induction.
Ion Channels and Vascular Tone
Authors: Jackson William F.
Published: June 2012

Abstract
—Ion channels in the plasma membrane of vascular muscle cells that form the walls of resistance arteries and arterioles play a central role in the regulation of vascular tone. Current evidence indicates that vascular smooth muscle cells express at least 4 different types of K
+
channels, 1 to 2 types of voltage-gated Ca
2+
channels, ≥2 types of Cl
−
channels, store-operated Ca
+
(SOC) channels, and stretch-activated cation (SAC) channels in their plasma membranes, all of which may be involved in the regulation of vascular tone. Calcium influx through voltage-gated Ca
2+
, SOC, and SAC channels provides a major source of activator Ca
2+
used by resistance arteries and arterioles. In addition, K
+
and Cl
−
channels and the Ca
2+
channels mentioned previously all are involved in the determination of the membrane potential of these cells. Membrane potential is a key variable that not only regulates Ca
+2
influx through voltage-gated Ca
2+
channels, but also influences release of Ca
2+
from internal stores and Ca
2+
- sensitivity of the contractile apparatus. By controlling Ca
2+
delivery and membrane potential, ion channels are involved in all aspects of the generation and regulation of vascular tone.
Angiotensin I–Converting Enzyme Antisense Gene Therapy Causes Permanent Antihypertensive Effects in the SHR
Authors: Wang Hongwei , Reaves Phyllis Y. , Gardon Monica L. , Keene Kimberley , Goldberg Drew S. , Gelband Craig H. , Katovich Michael J. , Raizada Mohan K.
Published: June 2012

Abstract
—The renin-angiotensin system plays a critical role in the control of blood pressure (BP), and its hyperactivity is associated with the development and maintenance of hypertension. Although traditional pharmacological therapies targeted toward the inhibition of the renin-angiotensin system are effective in the control of this disease, they pose significant limitations. We used an antisense gene delivery strategy to circumvent these limitations and established that a single intracardiac administration of angiotensin type 1 receptor antisense (AT
1
R-AS) causes permanent prevention of hypertension in the spontaneously hypertensive rat (SHR), an animal model of primary human hypertension. Our objectives in this study were 2-fold: to determine (1) whether the targeting of angiotensin I–converting enzyme (ACE) mRNA by a similar antisense strategy would prevent the SHR from developing hypertension and (2) whether the antihypertensive phenotype is transmitted to the offspring from the antisense-treated parents. Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP (≈15±2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovascular pathophysiological alterations that are characteristic of hypertension. Like their parents, the F
1
generation offspring of the LNSV-ACE-AS–treated SHR expressed lower BP, decreased cardiac hypertrophy, and normalization of renal arterial excitation-coupling compared with offspring derived from the LNSV-ACE-tS (truncated sense)–treated SHR. In addition, the endothelial dysfunction commonly observed in the SHR renal arterioles was significantly prevented in both parents and offspring of the LNSV-ACE-AS–treated SHR. Polymerase chain reaction followed by Southern analysis revealed that the ACE-AS was integrated into the SHR genome and transmitted to the offspring. These observations suggest that transmission of ACE-AS by retroviral vector may be responsible for the transference of normotensive phenotypes in the SHR offspring.
Angiotensin I–Converting Enzyme Antisense Prevents Altered Renal Vascular Reactivity, but Not High Blood Pressure, in Spontaneously Hypertensive Rats
Authors: Gelband Craig H. , Wang Hongwei , Gardon Monica L. , Keene Kimberley , Goldberg Drew S. , Reaves Phyllis Y. , Katovich Michael J. , Raizada Mohan K.
Published: June 2012

Abstract
—The renin-angiotensin system plays a critical role in the control of blood pressure, and its hyperactivity is associated with the development of human primary hypertension. Because low-dose angiotensin I–converting enzyme (ACE) inhibitors cause small reductions in blood pressure that are associated with the complete reversal of altered vascular pathophysiology, our objective in this study was to determine whether ACE antisense (ACE-AS) gene delivery prevents alterations in renal vascular physiology in the parents and F
1
offspring of AS-treated spontaneously hypertensive rats (SHR). A single bolus intracardiac injection of ACE-AS (2×10
8
colony-forming units) in SHR neonates caused a modest (18±3 mm Hg, n=7 to 9) lowering of blood pressure, which was maintained in the F
1
generation offspring (n=7 to 9). Alterations in renal vascular reactivity, electrophysiology, and [Ca
2+
]
i
homeostasis are underlying mechanisms associated with the development and establishment of hypertension. Renal resistance arterioles from truncated ACE sense–treated SHR showed a significantly enhanced contractile response to KCl and phenylephrine (n=24 rings from 6 animals,
P
<0.01) and significantly attenuated acetylcholine-induced relaxations (n=24 rings from 6 animals,
P
<0.01) compared with arterioles from ACE-AS–treated SHR. In addition, compared with cells dissociated from arterioles of ACE-AS–treated SHR, cells from truncated ACE sense–treated animal vessels had a resting membrane potential that was 22±4 mV more depolarized (n=38,
P
<0.01), an enhanced L-type Ca
2+
current density (2.2±0.3 versus 1.2±0.2 pA/pF, n=23,
P
<0.01), a decreased Kv current density (16.2±1.3 versus 5.4±2.2 pA/pF, n=34,
P
<0.01), and increased Ang II–dependent changes in [Ca
2+
]
i
(n=142,
P
<0.01). Similar effects of ACE-AS treatment were observed in the F
1
offspring. These results demonstrate that ACE-AS permanently prevents alterations in renal vascular pathophysiology in spite of the modest effect that ACE-AS had on high blood pressure in SHR.
Estradiol Inhibits Smooth Muscle Cell Growth in Part by Activating the cAMP-Adenosine Pathway
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Mi Zaichuan , Rosselli Marinella , Keller Paul J. , Jackson Edwin K.
Published: June 2012

Abstract
—Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001 to 1 μmol/L) on serum-induced DNA, collagen, and total protein synthesis and cell number in the absence and presence of 1,3-dipropyl-8-
p
-sulfophenylxanthine (10 nmol/L; A
1
/A
2
adenosine receptor antagonist), KF17837 (10 nmol/L; selective A
2
adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A
1
adenosine receptor antagonist), and 2′,5′-dideoxyadenosine (10 μmol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measures of cell growth, and the concentration-dependent inhibitory curves for estradiol were shifted to the right (
P
<0.05) by 1,3-dipropyl-8-
p
-sulfophenylxanthine, KF17837, and 2′,5′-dideoxyadenosine but not by 8-cyclopentyl-1,3-dipropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine, and these effects were blocked by 2′,5′-dideoxyadenosine (
P
<0.05). Our results support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived adenosine regulates smooth muscle cell growth via A
2
adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.
A
2B
Receptors Mediate Antimitogenesis in Vascular Smooth Muscle Cells
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Shue Holly , Jackson Edwin K.
Published: June 2012

Abstract
—Adenosine inhibits growth of vascular smooth muscle cells. The goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat aortic vascular smooth muscle cells, platelet-derived growth factor–BB (PDGF-BB) (25 ng/mL) stimulated DNA synthesis ([
3
H]thymidine incorporation), cellular proliferation (cell number), collagen synthesis ([
3
H]proline incorporation), total protein synthesis ([
3
H]leucine incorporation), and mitogen-activated protein (MAP) kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5′-
N
-methylcarboxamidoadenosine, but not
N
6
-cyclopentyladenosine or
CGS21680
, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A
2B
receptor–mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-
p
-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5′-
N
-methylcarboxamidoadenosine, an antagonist profile consistent with an A
2
receptor–mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A
2B
receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and MAP kinase activity. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5′-
N
-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A
2B
receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of vascular smooth muscle cell growth by activating A
2B
receptors coupled to inhibition of MAP kinase activity. Pharmacological or molecular biological activation of A
2B
receptors may prevent vascular remodeling associated with hypertension, atherosclerosis, and restenosis following balloon angioplasty.
Inhibition of Adrenal Cell Aldosterone Synthesis by Endogenous Nitric Oxide Release
Authors: Hanke Craig J. , O’Brien Timothy , Pritchard Kirkwood A. , Campbell William B.
Published: June 2012

Abstract
—Adrenal zona glomerulosa (ZG) cells do not contain nitric oxide (NO) synthase (NOS). We conferred endothelial NOS activity onto adrenal ZG cells through transduction with a recombinant adenovirus encoding the endothelial NOS gene (AdeNOS) to determine the effect of endogenous NO on aldosterone synthesis. A 135-kDa protein band immunoreactive to anti–endothelial NOS antibody was observed in Western blots of AdeNOS-transduced ZG cells but not in control cells or cells transduced with adenovirus encoding the β-galactosidase gene (AdβGal). Nitrate/nitrite production in AdeNOS-transduced ZG cells increased from 0.15±0.01 to 0.27±0.01 μmol/L after stimulation with 1 nmol/L angiotensin II. The treatment of AdeNOS-transduced cells with 30 μmol/L
l
-nitro-arginine decreased angiotensin II–stimulated nitrite production from 0.27±0.01 to 0.17±0.01 μmol/L. Basal and angiotensin II–stimulated nitrite production was not increased in AdβGal-transduced or control cells. AdeNOS-transduced cells demonstrated diaminofluorescein-2 diacetate fluorescence, which was blocked by pretreatment with
l
-nitro-arginine. Angiotensin II–stimulated aldosterone synthesis decreased from 5123±177 pg/mL in AdβGal-transduced ZG cells to 72±27 pg/mL in AdeNOS-transduced cells. Treatment with the NOS inhibitor thiocitrulline (30 μmol/L) increased angiotensin II–stimulated aldosterone synthesis to 2158±45 pg/mL after AdeNOS transduction. These data demonstrate that adenovirus-mediated gene transfer of eNOS in ZG cells results in the expression of active endothelial NOS enzyme and that this endogenous NO production by ZG cells decreases aldosterone synthesis.
Integration of Aortic Nerve Inputs in Hypertensive Rats
Authors: Zhang Jing , Mifflin Steve W.
Published: June 2012

Abstract
—The integration of arterial baroreceptor afferent inputs was studied in renal wrap hypertensive (HT) and normotensive (NT) rats. In anesthetized and paralyzed rats, aortic nerve (AN)-evoked depressor responses were reduced in HT compared with NT rats (
P
<0.05). We tested the hypothesis that the attenuated baroreflex was associated with altered integration of baroreceptor inputs within the nucleus of the solitary tract. Based on onset latency and the ability of monosynaptic neurons (MSNs) to respond to each of 2 AN stimuli separated by 5 ms, cells in HT and NT rats were divided into 3 groups: short-latency MSNs (SLMSNs), long-latency MSNs (LLMSNs), and polysynaptic neurons (PSNs). A higher percentage of PSNs (73% versus 61%) and a lower percentage of SLMSNs (20% versus 27%) or LLMSNs (7% versus 12%) were found in HT rats (
P
<0.05). In addition, in HT compared with NT rats, the AN onset latency was greater in PSNs (29.9±1.1 versus 26.7±0.8 ms) but not in SLMSNs (5.0±0.5 versus 5.0±0.3 ms) or LLMSNs (22.9±1.2 versus 24.1±0.7 ms) (
P
<0.05). Finally, in HT compared with NT rats, the number of PSNs responding to a single AN stimulus with multiple action potentials was increased (40% versus 19%) (
P
<0.05). This was not observed in SLMSNs (26% versus 13%) or LLMSNs (12% versus 18%). The results indicate that renal wrap hypertension is associated with reduced AN-evoked depressor responses. There also were alterations in the integration of AN afferent inputs within the nucleus of the solitary tract, and these alterations were most marked in the PSN population.
Mechanisms of Increased Venous Smooth Muscle Tone in Desoxycorticosterone Acetate-Salt Hypertension
Authors: Fink Gregory D. , Johnson Ron J. , Galligan James J.
Published: June 2012

Abstract
—The purpose of the present study was to identify mechanisms that contribute to increased venous smooth muscle tone in desoxycorticosterone acetate (DOCA)-salt hypertension in rats. Male Sprague-Dawley rats were uninephrectomized, received subcutaneous implants of DOCA, and drank 1% sodium chloride/0.2% potassium chloride solutions. Sham-operated rats received only uninephrectomy and drank tap water. Three to 4 weeks later, arterial and venous catheters were implanted for measurements of arterial and central venous pressures, respectively, and a silicone balloon catheter was permanently fixed in the right atrium to produce brief circulatory arrest. Venous smooth muscle activity was estimated on the basis of repeated measurements of mean circulatory filling pressure in conscious rats resting in their home cages. DOCA-salt–treated rats were hypertensive and had elevated mean circulatory filling pressure compared with normotensive sham-operated rats. Blockade of the endothelin subtype A receptor with 1 mg/kg ABT-627 IV decreased arterial blood pressure and mean circulatory filling pressure significantly more in hypertensive rats than in normotensive rats. Ganglionic blockade with 30 mg/kg hexamethonium IV also decreased arterial blood pressure and mean circulatory filling pressure more in hypertensive than in normotensive rats. Pretreatment with ABT-627 did not affect subsequent hemodynamic responses to ganglionic blockade. We conclude that venous smooth muscle tone is increased in DOCA-salt hypertension through the independent actions of both endogenous endothelin-1 acting on subtype A receptors and sympathetically mediated venoconstrictor activity.
Increased Chymase Activity in Internal Thoracic Artery of Patients With Hypercholesterolemia
Authors: Uehara Yoshinari , Urata Hidenori , Sasaguri Manabu , Ideishi Munehito , Sakata Noriyuki , Tashiro Tadashi , Kimura Michio , Arakawa Kikuo
Published: June 2012

Abstract
—Apart from ACE, various angiotensin II (Ang II)–forming serine proteinases (eg, chymase, kallikrein, and cathepsin G) are known to exist in human tissues, but their clinical significance or the regulatory mechanisms that control their activities are not well established. A recent clinical study has shown that chymase activity was significantly increased in human atherosclerotic or aneurysmal aorta. The association between vascular Ang II–forming activities (AIIFAs) in the human internal thoracic artery (ITA) and various clinical parameters was studied with the use of ITAs obtained from 32 patients who underwent coronary artery bypass graft surgery. Total and ACE- and chymase-dependent AIIFAs in homogenates of ITAs were determined. Total AIIFA was 8.67±0.86 (nmol Ang II formed · min
−1
· mg protein
−1
[U]), and ≈95% of the activities were due to chymase. Serum total cholesterol level, but no other risk factors, significantly correlated with chymase- (
r
=0.60,
P
<0.001) and ACE- (
r
=0.35,
P
<0.05) dependent AIIFAs, respectively. LDL cholesterol level was also correlated with chymase-dependent AIIFAs (
r
=0.47,
P
<0.05). Mast cells identified through the use of toluidine blue or immunohistochemical staining appeared in the adventitia but not in the intima or media of ITAs. Our results suggest that an increased plasma LDL cholesterol level may induce increased arterial chymase and ACE activity.
Dissociation Between Neural and Vascular Responses to Sympathetic Stimulation
Authors: Jacob Giris , Costa Fernando , Shannon John , Robertson David , Biaggioni Italo
Published: June 2012

Abstract
—Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27±5 versus 17±2 U,
P
=0.05) despite lower norepinephrine spillover (0.28±0.04 versus 0.4±0.05 mg · min
−1
· dL
−1
,
P
=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20±9% versus −7±4%,
P
=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate β-mediated vasodilation and α-induced vasoconstriction, respectively. β-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.
Regulation of Sodium Balance and Blood Pressure by the AT
1A
Receptor for Angiotensin II
Authors: Oliverio Michael I. , Best Christopher F. , Smithies Oliver , Coffman Thomas M.
Published: June 2012

Abstract
—To examine the role of the angiotensin II (AT)
1A
receptor in the regulation of blood pressure and sodium balance, we measured systolic blood pressure responses in AT
1A
receptor–deficient (
Agtr1a
−/−) and wild-type (
Agtr1a
+/+) mice while dietary sodium content was systematically altered. On a 0.4% sodium diet, systolic blood pressures were significantly lower in
Agtr1a
−/− than in +/+ mice. In
Agtr1a
+/+ mice, changing dietary sodium content did not affect blood pressure. In contrast, when
Agtr1a
−/− mice were fed a high-salt diet (6% NaCl), their systolic blood pressures increased significantly from 79±4 to 94±4 mm Hg (
P
<0.006). The low blood pressures of
Agtr1a
−/− mice decreased further while on a low-salt diet from 82±3 to 69±3 mm Hg (
P
<0.03). On the high-salt diet, urinary sodium excretion increased to similar levels in
Agtr1a
+/+ and −/− mice. Although urinary sodium excretion was substantially reduced in both groups during the low-salt diet, cumulative sodium balances became negative in
Agtr1a
−/− mice despite a 6-fold increase in urinary aldosterone. We infer, therefore, that the reduced blood pressures in
Agtr1a
−/− mice on a normal diet are caused by depletion of sodium and extracellular volume. Their “sodium sensitivity” suggests a critical role for renal AT
1A
receptors to modulate sodium handling.
Role of α
2
-Adrenergic Receptor Subtypes in the Acute Hypertensive Response to Hypertonic Saline Infusion in Anephric Mice
Authors: Makaritsis Konstantinos P. , Johns Conrado , Gavras Irene , Gavras Haralambos
Published: June 2012

Abstract
—Experimental evidence suggests that the acute hypertensive response induced in anephric animals by infusion of a hypertonic saline solution is mediated by disinhibition of the presynaptic sympathoinhibitory α
2
-adrenergic receptors (α
2
-AR) of the central nervous system. The purpose of the present experiments was to dissect the role of the 3 distinct α
2
-AR subtypes (α
2A
-, α
2B
, - and α
2C
-AR) in this response. Groups of genetically engineered mice deficient in each one of these α
2
-AR subtype genes were submitted to bilateral nephrectomy followed by a 0.4-mL infusion of 4% saline over a 2-hour period, with constant direct blood pressure (BP) monitoring. The α
2A
-AR–deficient and α
2C
-AR–deficient mice responded with significant BP elevations (by 11.8±2.5 and 16.7±1.7 mm Hg, respectively), and so did their wild-type counterparts (17.8±2.5 and 11.8±2.0 mm Hg, respectively) and the wild-type α
2B
+/+ (13.1±2.4 mm Hg). However, the α
2B
-AR–deficient mice were unable to raise their BP and had a slightly lowered BP (by −3.0±4.0 mm Hg) at the end of the infusion period. All 6 groups exhibited elevated plasma norepinephrine levels ranging between 0.8 and 1.8 ng/mL at the end of the infusion. In all cases, the α
2
-AR–deficient groups tended to have higher norepinephrine levels than their wild-type counterparts. Surprisingly, this difference was significant only in the α
2B
-AR–deficient mice, which, despite the elevated norepinephrine, were unable to raise their BP. The data suggest that a full complement of the α
2B
-AR is needed to mediate the hypertensive response to acute saline load, even though its absence does not prevent the release of norepinephrine under these conditions.
Effect of Age on Brachial Artery Wall Properties Differs From the Aorta and Is Gender Dependent
Authors: van der Heijden-Spek Janneke J. , Staessen Jan A. , Fagard Robert H. , Hoeks Arnold P. , Boudier Harry A. Struijker , Van Bortel Luc M.
Published: June 2012

Abstract
—Compliance and distensibility are wall properties of large arteries, which may play a role in cardiovascular disease. The purpose of this study was to investigate whether the influence of age on these vessel wall properties differs between vascular territories and is gender-dependent. In a population sample of 498 men and women 20 to 79 years of age, diameter, distensibility, and compliance coefficient of the muscular brachial artery were measured with an echo-tracking device. Distensibility of the aorta was measured with the use of pulse-wave velocity. The effects of age and gender were assessed and adjusted for confounding factors such as mean blood pressure, pulse rate, body mass index, smoking, alcohol intake, and antihypertensive treatment. Covariance analysis showed no relation between gender and distensibility of the elastic aorta. Distensibility of the muscular brachial artery was lower in men, whereas men had a larger diameter and larger compliance of the brachial artery. With age, distensibility of the aorta decreased in both sexes to the same extent, whereas distensibility of the brachial artery did not change significantly. With age, brachial artery diameter increased; this increase was more pronounced in women. In men brachial artery compliance did not change with age, whereas in women compliance of the brachial artery increased with age. This study (1) confirms that distensibility of the aorta, an elastic artery, decreases with age. (2) In contrast to the aorta, after adjustment for confounding factors, in both men and women, no relation exists between age and distensibility of the muscular brachial artery. (3) Brachial artery diameter increase with age is more pronounced in women than in men. (4) In contrast to the well-known decrease in arterial compliance of elastic arteries with age, brachial artery compliance is not decreased with age and is increased in women. In conclusion, the effect of age on large-artery wall properties is not uniform but depends on gender and vascular territory.