bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Na+/H+ Exchanger Genes
Authors: Yu Hongrun , Freedman Barry I. , Rich Stephen S. , Bowden Donald W.
Published: June 2012

Abstract
—The Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes play a critical role in pH homeostasis and cellular volume regulation and can be considered candidate genes for essential hypertension and renal disease. This study was performed to determine whether the NHE genes contributed to genetic susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of the NHE genes is unknown, we used cDNA sequences to design polymerase chain reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1:
D1S197
,
D1S2677
; NHE2:
D2S373
,
D2S1789
; and NHE3:
D5S678
,
D5S2005
). We used these markers, and other previously identified polymorphic markers for NHE5, in linkage and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD. However, NHE5 showed significant evidence for association (
P
≤1.0×10
−4
). The strongest evidence for association was observed with allele 6 of NHE5 (
P
≤0.001 to 0.01). Allele 6 appeared to have a renoprotective effect, with a frequency of 0.15 in the control population and 0.06 to 0.09 in patients with ESRD. The combined approach of designing primers from cDNA and radiation hybrid mapping has proven successful in identifying polymorphisms for human genes of which only cDNA sequences were previously available. The NHE primers and associated polymorphic loci identified in this study can be used in genomic, linkage, and association analysis of NHE genes in future genetic studies of hypertension and renal failure. Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted.
Inhibitory Regulation of Hypertrophy by Endogenous Atrial Natriuretic Peptide in Cultured Cardiac Myocytes
Authors: Horio Takeshi , Nishikimi Toshio , Yoshihara Fumiki , Matsuo Hisayuki , Takishita Shuichi , Kangawa Kenji
Published: June 2012

Abstract
—Atrial natriuretic peptide (ANP) may function as an endogenous regulator of cardiac hypertrophy, because the natriuretic peptide receptor has been found in the heart and because mice lacking its receptor have been shown to have a markedly elevated ventricular mass. We examined the role of endogenous ANP in cardiac hypertrophy in vitro. The effects of the blockade of endogenous ANP by its receptor antagonist, HS-142–1, on cell hypertrophy were investigated with the use of cultured neonatal rat ventricular myocytes. HS-142–1 increased the basal and phenylephrine (PE, 10
−5
mol/L)–stimulated protein syntheses in a concentration-dependent manner (1 to 300 μg/mL). A significant increase in the cell size of myocytes was also induced by this antagonist. In addition, the expression levels of skeletal α-actin, β-myosin heavy chain, and ANP genes, markers of hypertrophy, were partially elevated by treatment with HS-142–1 (100 μg/mL) under nonstimulated or PE-stimulated conditions. A cGMP-specific phosphodiesterase inhibitor, zaprinast (5×10
−4
mol/L), and a cGMP analogue (10
−4
mol/L) suppressed the basal and PE-stimulated protein syntheses. Our observations suggest that endogenous ANP inhibits cardiac myocyte hypertrophy under basal and PE-stimulated conditions, probably through a cGMP-dependent process. ANP may play a role as an autocrine factor in the regulation of cardiac myocyte growth.
Cytochrome P450 and Cyclooxygenase Metabolites Contribute to the Endothelin-1 Afferent Arteriolar Vasoconstrictor and Calcium Responses
Authors: Imig John D. , Pham Bao Thang , LeBlanc Elizabeth A. , Reddy K. Malla , Falck John R. , Inscho Edward W.
Published: June 2012

Abstract
—Arachidonic acid metabolites contribute to the endothelin-1 (ET-1)–induced decrease in renal blood flow, but the vascular sites of action are unknown. Experiments performed in vitro used the rat juxtamedullary nephron preparation combined with videomicroscopy. The response of afferent arterioles to ET-1 was determined before and after cytochrome P450 (CYP450) or cyclooxygenase (COX) inhibition. Afferent arteriolar diameter averaged 20±1 μm (n=17) at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.001 to 10 nmol/L ET-1 caused a graded decrease in diameter of the afferent arteriole. Vessel diameter decreased by 30±2% and 41±2% in response to 1 and 10 nmol/L ET-1, respectively. The afferent arteriolar response to ET-1 was significantly attenuated during administration of the CYP450 hydroxylase inhibitor
N
-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), such that afferent arteriolar diameter decreased by 19±3% and 22±3% in response to 1 and 10 nmol/L ET-1, respectively. COX inhibition also greatly attenuated the vasoconstriction elicited by ET-1, whereas the CYP450 epoxygenase inhibitor
N
-methylsulfonyl-6-(2-proparglyoxyphenyl) hexanamide enhanced the ET-1–mediated vascular response. Additional studies were performed using freshly isolated smooth muscle cells prepared from preglomerular microvessels. Renal microvascular smooth muscle cells were loaded with the calcium-sensitive dye fura 2 and studied by use of single-cell fluorescence microscopy. Basal renal microvascular smooth muscle cell [Ca
2+
]
i
averaged 95±3 nmol/L (n=42). ET-1 (10 nmol/L) increased microvascular smooth muscle cell [Ca
2+
]
i
to a peak value of 731±75 nmol/L before stabilizing at 136±8 nmol/L. Administration of DDMS or the COX inhibitor indomethacin significantly attenuated the renal microvascular smooth muscle cell calcium response to ET-1. These data demonstrate that CYP450 hydroxylase and COX arachidonic acid metabolites contribute importantly to the afferent arteriolar diameter and renal microvascular smooth muscle cell calcium responses elicited by ET-1.
Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo
Authors: Barton Matthias , Carmona Renata , Morawietz Henning , d’Uscio Livius V. , Goettsch Winfried , Hillen Heinz , Haudenschild Christian C. , Krieger Jose E. , Münter Klaus , Lattmann Thomas , Lüscher Thomas F. , Shaw Sidney
Published: June 2012

Abstract
—In the C57BL/6J mice model, we investigated whether obesity affects the function or expression of components of the tissue renin-angiotensin system and whether endothelin (ET)-1 contributes to these changes. ACE activity (nmol · L His-Leu · mg protein
−1
) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with
LU135252
, an orally active ET
A
receptor antagonist. ACE mRNA expression was measured in the kidney, and the effects of
LU135252
on purified human ACE were determined. Aortic and renal tissue ET-1 protein content was measured, and the vascular contractility to angiotensin II was assessed. Obesity was associated with a tissue-specific increase in ACE activity in the kidney (55±4 versus 33±3 nmol/L) but not in the lung (34±2 versus 32±2 nmol/L). Long-term
LU135252
treatment completely prevented this activation (13.3±0.3 versus 55±4 nmol/L,
P
<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity. Obesity potentiated contractions in response to angiotensin II in the aorta (from 6±2% to 33±5% KCl) but not in the carotid artery (4±1% to 3.6±1% KCl), an effect that was completely prevented with
LU135252
treatment (6±0.4% versus 33±5% KCl). No effect of
LU135252
on purified ACE was observed. Thus, obesity is associated with the activation of renal ACE in vivo independent of its mRNA expression and enhanced vascular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonists may exert organ protection.
Angiotensin-Converting Enzyme Expression in Human Carotid Artery Atherosclerosis
Authors: Fukuhara Masayo , Geary Randolph L. , Diz Debra I. , Gallagher Patricia E. , Wilson John A. , Glazier Steven S. , Dean Richard H , Ferrario Carlos M.
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of atherosclerosis in animal models and reinfarction rates after myocardial infarction in humans. Although expression of components of the renin-angiotensin system has been reported in human coronary arteries, no data regarding their presence in carotid arteries, a frequent site for the occurrence of atherosclerosis plaques, are available. The following study sought to determine whether ACE mRNA and protein can be detected in human carotid atheromatous lesions. Twenty-four intact endarterectomy specimens were obtained from patients with severe carotid occlusive disease (17 males and 7 females, aged 68±1 years) and fixed within 30 minutes. Carotid artery specimens contained advanced Stary type V and VI lesions, and human ACE mRNA expression and protein were localized in cross sections by the combination of in situ hybridization and immunohistochemistry. Cell type–specific antibodies were used to colocalize ACE to smooth muscle cells, endothelial cells, macrophages, or lymphocytes. ACE protein was localized in the intima, whereas the overlying media was largely free of ACE staining. In less complicated lesions, ACE staining was modest and could be visualized in scattered clusters of macrophages and on the luminal side of carotid artery vascular endothelium. Smooth muscle cells were largely negative. ACE staining increased as lesions became more complex and was most prominent in macrophage-rich regions. The shoulder regions of plaques contained numerous ACE-positive macrophage foam cells and lymphocytes. In these areas, microvessels were positive for endothelial cell and smooth muscle cell ACE expression. However, microvessels in plaques free of inflammatory cells were stained only faintly for ACE expression. Labeling for ACE mRNA mirrored the pattern of protein expression, localizing ACE mRNA to macrophages and microvessels within the intima. In conclusion, atherosclerosis alters carotid artery ACE production, increasing transcription and translation within regions of plaque inflammation. These data provide another important mechanism by which inflammation associated with increased ACE expression may contribute to the progression of atherosclerosis.
Inhibition of cADP-Ribose Formation Produces Vasodilation in Bovine Coronary Arteries
Authors: Geiger Jason , Zou Ai-Ping , Campbell William B. , Li Pin-Lan
Published: June 2012

Abstract
—cADP-ribose (cADPR) induces the release of Ca
2+
from the intracellular stores of coronary artery smooth muscle cells. However, little is known about the role of cADPR-mediated intracellular Ca
2+
release in the control of vascular tone. The present study examined the effects of nicotinamide, a specific inhibitor of ADP-ribosylcyclase, on the vascular tone of bovine coronary arteries. A bovine coronary artery homogenate stimulated the conversion of nicotinamide guanine dinucleotide into cGDP-ribose, which is a measure of ADP-ribosylcyclase activity. Nicotinamide significantly inhibited the formation of cGDP-ribose in a concentration-dependent manner: at a concentration of 10 mmol/L, it reduced the conversion rate from 3.34±0.11 nmol · min
−1
· mg
−1
of protein in control cells to 1.42±0.11 nmol · min
−1
· mg
−1
of protein in treated cells, a 58% reduction. In U46619-precontracted coronary artery rings, nicotinamide produced concentration-dependent relaxation. Complete relaxation with nicotinamide occurred at a dose of 8 mmol/L; the median inhibitory concentration (IC
50
) was 1.7 mmol/L. In the presence of a cell membrane–permeant cADPR antagonist, 8-bromo-cADPR, nicotinamide-induced vasorelaxation was markedly attenuated. Pretreatment of the arterial rings with ryanodine (50 μmol/L) significantly blunted the vasorelaxation response to nicotinamide. However, iloprost- and adenosine-induced vasorelaxation was not altered by 8-bromo-cADPR. Moreover, nicotinamide significantly attenuated KCl- or Bay K8644–induced vasoconstriction by 60% and 70%, respectively. These results suggest that the inhibition of cADPR formation by nicotinamide produces vasorelaxation and blunts KCl- and Bay K8644–induced vasoconstriction in coronary arteries and that the cADPR-mediated Ca
2+
signaling pathway plays a role in the control of vascular tone in coronary circulation.
Increase in Renal Medullary Nitric Oxide Synthase Activity Protects From Norepinephrine-Induced Hypertension
Authors: Szentiványi Mátyás , Zou Ai-Ping , Maeda Celso Y. , Mattson David L. , Cowley Allen W.
Published: June 2012

Abstract
—Studies were performed in conscious Sprague-Dawley rats to determine the role of the α
2
-adrenergic receptor–mediated increase in the renal medullary nitric oxide synthase (NOS) activity as a counterregulatory mechanism of blood pressure control in response to increased renal adrenergic stimulation. A subpressor dose of norepinephrine (NE, 8 μg · kg
−1
· h
−1
) was infused intravenously, and NOS activity was determined with arginine-citrulline conversion by high-performance liquid chromatography in renal cortical and outer and inner medullary tissues. It was found that after 7 days of intravenous NE infusion, NOS activity was significantly higher in both the outer and inner medullary tissues (158±45 versus 30±24 pmol · mg
−1
· h
−1
[outer medulla] and 5.1±0.7 versus 2.0±0.5 nmol · mg
−1
· h
−1
[inner medulla] for NE-treated versus control rats, respectively). To determine whether the increase of NOS activity was mediated through renal medullary α
2
-receptors, the receptor antagonist rauwolscine (RAU, 1 μg · kg
−1
· min
−1
) was infused via an implanted renal medullary interstitial catheter, and the consequences of intravenous NE administration were evaluated. NOS activity was significantly lower in the RAU-infused animals and did not increase with infusion of NE. To determine the systemic effects of the renal medullary α
2
-receptors, studies were performed to determine the consequences of chronic intravenous infusion of subpressor amounts of NE in the presence and absence of renal medullary α
2
-receptor inhibition. Under conditions in which RAU was continuously infused into the renal medulla, the same subpressor dose of NE caused sustained and reversible hypertension (mean arterial pressure increased from 120±3 to 131±3 mm Hg). Chronic blunting of the renal medullary NOS activity with
N
G
-nitro-
l
-arginine methyl ester (75 μg · kg
−1
· h
−1
) also enabled NE to produce a significant rise in mean arterial pressure (from 117±2 to 134±4 mm Hg). We conclude that the hypertensive effects of moderate elevations of renal adrenergic activity were chronically buffered by the α
2
-receptor–mediated increase in NOS activity within the renal medulla.
Role of FMRFamide-Activated Brain Sodium Channel in Salt-Sensitive Hypertension
Authors: Nishimura Masato , Ohtsuka Ken , Takahashi Hakuo , Yoshimura Manabu
Published: June 2012

Abstract
—FMRFamide, a cardioexcitatory neuropeptide, directly activates a newly cloned amiloride-sensitive sodium channel that is expressed specifically in the brain and blocked by benzamil hydrochloride. In the present study, we investigated the effects of short- and long-term intracerebroventricular infusion of FMRFamide on arterial pressure, sympathetic activity, vasopressin release, and brain renin-angiotensin system genes in rats and studied the role of FMRFamide-activated brain sodium channels in salt-sensitive hypertension. The intracerebroventricular preinjection of FMRFamide and subsequent intracerebroventricular infusion of 0.15 mol/L NaCl increased mean arterial pressure (FMRFamide: 30 nmol/kg +13±2.6 mm Hg,
P
<0.01; 100 nmol/kg +21±1.8 mm Hg,
P
<0.01), heart rate, abdominal sympathetic activity, and plasma vasopressin concentration compared with vehicle. The intracerebroventricular copreinjection with either benzamil or CV-11974 abolished these increases. In rats administered a high-salt diet (8% NaCl), the continuous intracerebroventricular infusion of FMRFamide (50 and 200 nmol · kg
−1
· d
−1
) for 5 days increased mean arterial pressure, heart rate, urinary excretion of vasopressin and norepinephrine, and mRNAs of renin, angiotensin I–converting enzyme, and angiotensin II type 1 receptor in hypothalamus and brain stem compared with vehicle. These increases were abolished by intracerebroventricular coinfusion of benzamil. In rats administered a low-salt diet (0.3% NaCl), however, increases in these variables were smaller than those in rats receiving a high-salt diet. Together, these findings suggest that brain FMRFamide-activated sodium channels may be involved in the mechanism of salt-sensitive hypertension through regulation of the brain renin-angiotensin system.
Contribution of Ras GTPase/MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt–Induced Hypertension
Authors: Muthalif Mubarack M. , Benter Ibrahim F. , Khandekar Zinat , Gaber Lillian , Estes Anne , Malik Suzanna , Parmentier Jean-Hugues , Manne Veeraswamy , Malik Kafait U.
Published: June 2012

Abstract
—We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt–induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166±5 mm Hg, n=19) compared with that of normotensive controls (95±5 mm Hg, n=7) (
P
<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (
P
<0.05) attenuated MABP to 139±4 mm Hg (n=14) and 126±1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt–induced hypertension and associated vascular pathology consequent to activation of CYP450.
Hypertension Incidence Is Predicted by High Levels of Hopelessness in Finnish Men
Authors: Everson Susan A. , Kaplan George A. , Goldberg Debbie E. , Salonen Jukka T.
Published: June 2012

Abstract
—Recent studies have reported that hopelessness is an important factor in cardiovascular morbidity and mortality, including ischemic heart disease, acute myocardial infarction, and atherosclerotic progression. This study examined the relationship between hopelessness and incident hypertension in a population-based sample of 616 initially normotensive, middle-aged men from eastern Finland, an area with high rates of cardiovascular disease. Participants completed a medical examination and a series of psychological questionnaires at baseline and at the 4-year follow-up. Hopelessness was measured by 2 items assessing negative expectancy about the future and one’s goals. A logistic regression model with adjustments for age, body mass index, baseline resting blood pressure, physical activity, smoking, alcohol consumption, education, parental history of hypertension, and self-reported depressive symptoms revealed that men reporting high levels of hopelessness at baseline were 3 times more likely to become hypertensive (systolic blood pressure ≥165 mm Hg and/or a diastolic blood pressure ≥95 mm Hg or confirmed use of antihypertensive medication) in the intervening 4 years than men who were not hopeless (odds ratio, 3.22; 95% confidence interval, 1.56, 6.67). Men reporting moderate levels of hopelessness were not at a significantly increased risk of hypertension (odds ratio, 1.27; 95% confidence interval, 0.79, 2.07). This is the first study to identify a significant relationship between hopelessness and incident hypertension. Research is needed to explore the neuroendocrine and central nervous system mechanisms underlying this association.
Contribution of Autosomal Loci and the Y Chromosome to the Stress Response in Rats
Authors: Dumas Pierre , Pausová Zdenka , Kren Vladimír , Krenová Drahomíra , Pravenec Michal , Dumont Marc , Ely Daniel , Turner Monte , Sun Yulin , Tremblay Johanne , Hamet Pavel
Published: June 2012

Abstract
—Stress is a critical contributor to cardiovascular diseases through its impact on blood pressure variability and cardiac function. Familial clustering of reactivity to stress has been demonstrated in human subjects, and some rodent models of hypertension are hyperresponsive to stress. Therefore, the present study was designed to uncover the genetic determinants of the stress response. We performed a total genome linkage search to identify the loci of the body temperature response to immobilization stress in a set of recombinant inbred strains (RIS) originating from reciprocal crosses of spontaneously hypertensive rats (SHR) with a normotensive Brown Norway Lx strain. Two quantitative trait loci (QTLs) were revealed on chromosomes (Chrs) 10 and 12 (logarithm of odds scores, 2.2 and 1.3, respectively). The effects of these QTLs were enhanced by a high sodium diet (logarithm of odds scores, 4.0 and 3.3 for Chrs 10 and 12, respectively), which is suggestive of a salt-sensitive component for the phenotype. Congenics for Chr 10 confirmed both the QTL and the salt effect in RIS. Negatively associated loci were also identified on Chrs 8 and 11. Interaction between the loci of Chrs 10 and 12 was demonstrated, with the rat strains bearing SHR alleles at both loci having the highest thermal response to stress. Furthermore, the Y Chr of SHR origin enhanced the response to immobilization stress, as demonstrated in 2 independent models, RIS and Y Chr consomics. However, its full effect requires autosomes of the SHR strain. These findings provide the first evidence for the genetic determination of reactivity to stress with interactions between autosomal loci and between the Y and autosomal Chrs that contribute to the explanation of the 46% of variance in the stress response.
Attenuation of the “White-Coat Effect” by Antihypertensive Treatment and Regression of Target Organ Damage
Authors: Parati Gianfranco , Ulian Luisa , Sampieri Lorena , Palatini Paolo , Villani Alessandra , Vanasia Alessandro , Mancia Giuseppe
Published: June 2012

Abstract
—This study assessed whether 2 common surrogate measures of the “white-coat effect,” namely the clinic-daytime and the clinic-home differences in blood pressure (BP), were attenuated by long-term antihypertensive treatment and whether this attenuation is relevant to the treatment-induced regression of left ventricular hypertrophy, thus having clinical significance. We considered data from 206 patients with essential hypertension (aged 20 to 65 years) who had a diastolic BP between 95 and 115 mm Hg and echocardiographic evidence of left ventricular hypertrophy. In each patient, clinic BP, 24-hour ambulatory BP, and left ventricular mass index were assessed at baseline, after 3 and 12 months of treatment with an angiotensin-converting enzyme inhibitor, and after a final 4-week placebo run-off period. At baseline, the clinic-daytime differences in systolic and diastolic BP were 12.1±15.4 and 6.8±10.1 mm Hg, respectively; the corresponding values for the clinic-home differences were 5.7±10.6 and 2.9±6.1 mm Hg, respectively. These differences were reduced by 57.6% and 77.1% (
P
<0.01) and by 65.7% and 64.3% (
P
<0.01), respectively, after 12 months of treatment, with a partial return toward the pretreatment differences after the final placebo period. The observed treatment-induced reductions in left ventricular mass index and those in the clinic-daytime or clinic-home differences for systolic and diastolic BP showed no significant relationship when tested by multiple regression analysis. This provides the first longitudinal evidence that clinic-daytime and clinic-home differences in BP have no substantial value in predicting the regression of target organ damage, such as left ventricular hypertrophy, that has prognostic relevance.
Sympathoinhibition by Central and Peripheral Infusion of Nifedipine in Spontaneously Hypertensive Rats
Authors: Murzenok Piotr P. , Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
—The present study assessed whether central mechanisms may contribute to the hypotensive effect of the calcium channel blocker nifedipine. In conscious, spontaneously hypertensive rats (SHR) on a high-salt diet, hemodynamic (mean arterial pressure [MAP] and heart rate) and sympathetic (renal sympathetic nerve activity) responses to low, central, intracerebroventricular infusion rates (25 μg · kg
−1
· h
−1
for 2 hours) and peripheral intravenous rates (50 μg · kg
−1
· h
−1
for 3 hours and then 100 μg · kg
−1
· h
−1
for 2 hours) of nifedipine were evaluated. The distribution of nifedipine in the blood and tissues was assessed at the end of the infusions. Nifedipine significantly inhibited renal sympathetic nerve activity and lowered MAP in SHR beginning 30 minutes after the start of the intracerebroventricular infusion. The decrease of MAP by intravenous infusion began at 60 minutes and was more profound with 100 μg · kg
−1
· h
−1
. Inhibition of sympathetic activity preceded and then paralleled the decrease in blood pressure; it occurred earlier with central (15 to 30 minutes) than with peripheral (30 to 60 minutes) infusion. Intravenous infusion resulted in concentrations of nifedipine in brain structures (brain stem, midbrain, and cortex) that were 30% to 40% of those in the heart, kidneys, and liver. From the hemodynamic and sympathetic responses and the distribution of nifedipine into the central nervous system, we conclude that the peripheral infusion of nifedipine at relatively low rates may evoke a hypotensive response in SHR, not only via peripheral mechanisms, but also through central mechanisms, which will lead to an inhibition of sympathetic outflow and, therefore, a lowering of blood pressure.
p38 MAP Kinase Is Required for Vasopressin-Stimulated HSP27 Induction in Aortic Smooth Muscle Cells
Authors: Ito Takeshi , Kozawa Osamu , Tanabe Kumiko , Niwa Masayuki , Matsuno Hiroyuki , Sakai Noboru , Ito Hidenori , Kato Kanefusa , Uematsu Toshihiko
Published: June 2012

Abstract
—We previously showed that arginine vasopressin (AVP) stimulates heat shock protein 27 (HSP27) induction through protein kinase C activation in aortic smooth muscle A10 cells. In the present study, we examined whether the mitogen-activated protein (MAP) kinase superfamily is involved in the AVP-stimulated HSP27 induction in A10 cells. AVP stimulated the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase. On the contrary, AVP had little effect on SAPK (stress-activated protein kinase)/JNK (c-
Jun
N
-terminal kinase) phosphorylation. The HSP27 accumulation by AVP was not affected by PD98059, an inhibitor of the upstream kinase that activates p42/p44 MAP kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, suppressed the AVP-induced accumulation of HSP27. 12-
O
-tetradecanoylphorbol 13-acetate, an activator of protein kinase C, induced accumulation of HSP27 and was not inhibited by PD98059 but was inhibited by SB203580. Calphostin C and ET-18-OCH
3
, inhibitors of protein kinase C, reduced the phosphorylation of p38 MAP kinase by AVP. SB203580 and PD169316 suppressed the AVP-increased levels in mRNA for HSP27. Dissociation of the aggregated HSP27 to the dissociated HSP27 was induced by AVP. These results strongly suggest that p38 MAP kinase takes part in the pathway of the AVP-stimulated induction of HSP27 in vascular smooth muscle cells.
Aldosterone Stimulation by Angiotensin II
Authors: Giacché Mara , Vuagnat Albert , Hunt Steven C. , Hopkins Paul N. , Fisher Naomi D. L. , Azizi Michel , Corvol Pierre , Williams Gordon H. , Jeunemaitre Xavier
Published: June 2012

Abstract
—The aldosterone response to infused angiotensin II (Ang II) in patients receiving a low-salt diet has been described as an important phenotype for genetic studies on human hypertension. The objectives of the present study were to determine the parameters that influence this intermediate phenotype as a quantitative trait and to assess the importance of its familial resemblance in hypertensive sibling pairs. Two hundred one white hypertensive subjects (95 families: 84 pairs and 11 trios) were selected in 3 centers. The patients followed the same protocol, which included a 4-week withdrawal period of antihypertensive therapy, a 1-week period on a low-salt diet, and a 30-minute infusion of Ang II. The increase in the aldosterone level was greater in women than in men (29.1±16.2 versus 18.2±9.6 ng/dL,
P
<0.0001). A strong relationship was found with age (
r
=−0.54,
P
<10
−4
) and plasma renin activity (
r
=0.32,
P
<10
−4
) in women but not in men. Weak correlations of the aldosterone response to Ang II were observed for the whole set of sibling pairs (
r
=0.11, NS). Conversely, strong sibling correlations were found among brother-brother pairs (
r
=0.40, n=36) and among sister-sister pairs as soon as age or menopausal status was considered. Similar results were obtained when the Ang I–aldosterone response was analyzed as a qualitative trait (κ=0.35,
P
<0.008 in brother-brother pairs). We conclude that age, gender, and plasma renin are strong determinants of the aldosterone response to Ang II, with strong sibling correlations in men and postmenopausal women. These relationships will have to be considered in future linkage and association studies.
Racial Differences in Endothelin-1 at Rest and in Response to Acute Stress in Adolescent Males
Authors: Treiber Frank A. , Jackson Robert W. , Davis Harry , Pollock Jennifer S. , Kapuku Gaston , Mensah George A. , Pollock David M.
Published: June 2012

Abstract
—Blacks exhibit greater vasoconstriction-mediated blood pressure (BP) increases in response to stress than do whites. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, has been proposed as having a role in racial differences in stress reactivity. We evaluated the hemodynamic and plasma ET-1 levels of 41 (23 whites, 18 blacks, mean age 18.6 years) normotensive adolescent males at rest and in response to a video game challenge and forehead cold stimulation. Measurements were performed at catheter insertion and before and immediately after the 2 stressors, which were separated by 20-minute rest periods. Blacks exhibited higher absolute levels of diastolic blood pressure, total peripheral resistance index, or both in response to catheter insertion and to the video game challenge and during recovery from video game challenge and cold stimulation (
P
<0.05 for all). Blacks exhibited higher absolute levels of ET-1 at every evaluation point (
P
<0.05 for all) and greater increases in ET-1 in response to both stressors (ps<0.05). These findings suggest that altered endothelial function may be involved in racial differences in hemodynamic reactivity to stress and possibly in the development of essential hypertension.
Allopurinol Normalizes Endothelial Dysfunction in Type 2 Diabetics With Mild Hypertension
Authors: Butler Robert , Morris Andrew D. , Belch Jill J. F. , Hill Alexander , Struthers Allan D.
Published: June 2012

Abstract
—Therapeutic strategies against free radicals have mostly focused on the augmentation of antioxidant defenses (eg, vitamins C and E). A novel approach is to prevent free radical generation by the enzyme system xanthine oxidase. We examined whether the inhibition of xanthine oxidase with allopurinol can improve endothelial function in subjects with type 2 diabetes and coexisting mild hypertension compared with control subjects of a similar age. We examined 23 subjects (11 patients with type 2 diabetes and 12 healthy age-matched control subjects) in 2 parallel groups. The subjects were administered 300 mg allopurinol in a randomized, placebo-controlled study in which both therapies were administered for 1 month. Endothelial function was assessed with bilateral venous occlusion plethysmography, in which the forearm blood flow responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators were measured. Allopurinol significantly increased the mean forearm blood flow response to acetylcholine by 30% (3.16±1.21 versus 2.54±0.76 mL · 100 mL
−1
· min
−1
allopurinol versus placebo;
P
=0.012, 95% CI 0.14, 1.30) but did not affect the nitroprusside response in patients with type 2 diabetes. There was no significant impact on either endothelium-dependent or -independent vascular responses in age-matched control subjects. Allopurinol improved endothelial function to near-normal levels. Regarding markers of free radical activity, the level of malondialdehyde was significantly reduced (0.30±0.04 versus 0.34±0.05 μmol/L for allopurinol versus placebo,
P
=0.03) in patients with type 2 diabetes but not in control subjects. The xanthine oxidase inhibitor allopurinol improves endothelial dysfunction in patients with type 2 diabetes with mild hypertension but not in matched control subjects. In the former group, allopurinol restored endothelial function to near-normal levels.
N
-Acetyl-
l
-Cysteine Potentiates Interleukin-1β Induction of Nitric Oxide Synthase
Authors: Jiang Bingbing , Brecher Peter
Published: June 2012

Abstract
—We have reported previously that
N
-acetyl-
l
-cysteine facilitated interleukin-1β–induced nitric oxide synthase (iNOS) expression in rat vascular smooth muscle cells. The present study compares the effect of
N
-acetyl-
l
-cysteine with other antioxidants and tested the possibility that
N
-acetyl-
l
-cysteine potentiates iNOS induction by a mechanism involving activation of p44/42 mitogen-activated protein kinases (MAPKs). The effect of
N
-acetyl-
l
-cysteine on potentiating interleukin-1β–induced nitrite production and iNOS expression was mimicked either by the enantiomers,
l
-cysteine and
d
-cysteine, or by a non–thiol-containing antioxidant,
l
-ascorbic acid. Interleukin-1β activated p44/42 MAPK, and this activation was enhanced in the presence of
N
-acetyl-
l
-cysteine. Inhibition of p44/42 MAPK phosphorylation by the selective inhibitor PD98059 clearly inhibited iNOS expression induced by interleukin-1β either in the absence or in the presence of
N
-acetyl-
l
-cysteine. These observations, combined with previous results, indicate that p44/42 MAPK activation is required for interleukin-1β induction of iNOS and that
N
-acetyl-
l
-cysteine may act as a reducing agent and facilitate interleukin-1β–induced iNOS expression through a reduction/oxidation-related mechanism involving potentiation of cytokine activation of the p44/42 MAPK signaling pathway.
Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension
Authors: Sherman Debra L. , Keaney John F. , Biegelsen Elizabeth S. , Duffy Stephen J. , Coffman Jay D. , Vita Joseph A.
Published: June 2012

Abstract
—Increased production of superoxide anion may contribute to impaired bioactivity of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of scavenging superoxide anion; however, experimental studies have shown that high physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated vascular dysfunction. To seek kinetic evidence that superoxide anion contributes to endothelial vasomotor dysfunction in human hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra-arterial infusions on forearm blood flow responses to methacholine or sodium nitroprusside in 30 patients with hypertension and 22 age-matched controls. Endothelium-dependent vasodilation to methacholine was significantly impaired in the hypertensive patients, with a response to the highest dose of methacholine (10 μg/min) of 12.3±6.7 compared with 16.1±5.8 mL · min
−1
· dL tissue
−1
in the controls (
P
<0.001). The response to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methacholine in hypertensive patients with a peak response of 16.1±7.1 mL · min
−1
· dL tissue
−1
(
P
=0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2±1.4 mmol/L. In contrast, ascorbic acid at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypertensive patients or the methacholine response in the controls. These results agree with the predicted kinetics for superoxide anion–mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension.
Cyclophilin B Expression in Renal Proximal Tubules of Hypertensive Rats
Authors: Kainer Daniel B. , Doris Peter A.
Published: June 2012

Abstract
—Rat cyclophilin-like protein (Cy-LP) is a candidate hypertension gene initially identified by differential hybridization and implicated in renal mechanisms of salt retention and high blood pressure. We report the molecular characterization of rat cyclophilin B (CypB) and demonstrate, through sequence analysis and an allele-specific polymerase chain reaction primer assay, that CypB but not Cy-LP is expressed in rat kidney. CypB is an endoplasmic reticulum–localized prolyl-isomerase that interacts with elongation initiation factor 2-β, an important regulator of protein translation and a central component of the endoplasmic reticulum stress response to hypoxia or ATP depletion. Active renal transport of sodium is increased in the spontaneously hypertensive rat (SHR), and there is evidence that this coincides with hypoxia and ATP depletion in the renal cortex. In the present studies we have examined expression of CypB in rat proximal tubules, which contributes to the increased renal sodium reabsorption in this model of hypertension. We report that CypB transcript abundance is significantly elevated in proximal convoluted tubules from SHR compared with the control Wistar-Kyoto strain. This upregulation occurs in weanling animals and precedes the development of hypertension, indicating that it is not a simple response to hypertension in SHR. Further, CypB expression is also higher in a proximal tubule cell line derived from SHR compared with a similar line derived from Wistar-Kyoto rats, indicating that this difference is genetically determined. No sequence differences were observed in the CypB cDNA from these 2 strains. These observations suggest that a genetically determined alteration in proximal tubules from SHR occurs that leads to increased expression of CypB. In view of evidence linking CypB to the regulation of elongation initiation factor-2, the upregulation of CypB may result from metabolic stress.
Increased Cardiac Angiotensin II Levels Induce Right and Left Ventricular Hypertrophy in Normotensive Mice
Authors: Mazzolai Lucia , Pedrazzini Thierry , Nicoud Françoise , Gabbiani Giulio , Brunner Hans-R. , Nussberger Jürg
Published: June 2012

Abstract
—Angiotensin II is a potent arterial vasoconstrictor and induces hypertension. Angiotensin II also exerts a trophic effect on cardiomyocytes in vitro. The goals of the present study were to document an in vivo increase in cardiac angiotensins in the absence of elevated plasma levels or hypertension and to investigate prevention or regression of ventricular hypertrophy by renin-angiotensin system blockade. We demonstrate that high cardiac angiotensin II is directly responsible for right and left ventricular hypertrophy. We used transgenic mice overexpressing angiotensinogen in cardiomyocytes characterized by cardiac hypertrophy without fibrosis and normal blood pressure. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent or normalize ventricular hypertrophy. Surprisingly, in control mice, receptor blockade decreases tissue angiotensin II despite increased plasma levels. This suggests that angiotensin II may be protected from metabolization by binding to its receptor. Blocking of the angiotensin II type 1 receptor rather than enhanced stimulation of the angiotensin II type 2 receptor may prevent remodeling and account for the beneficial effects of angiotensin antagonists.
Skip Patterns in DINAMAP-Measured Blood Pressure in 3 Epidemiological Studies
Authors: Rose Kathryn M. , Arnett Donna K. , Ellison R. Curtis , Heiss Gerardo
Published: June 2012

Abstract
—Blood pressure measured by the oscillometric, automated device DINAMAP in 3 large population-based studies sponsored by the National Heart, Lung, and Blood Institute (The Atherosclerosis Risk in Communities Study, The Family Heart Study, and the Hypertension Genetic Epidemiology Network Study) were reviewed to determine an apparent skip pattern in the measurement values. Across the 3 studies, 2 different DINAMAP models were evaluated on >350 000 different blood pressure measurements. Measurements were taken in various positions, on both arm and ankles, and under various conditions (eg, resting and during stress). The following systolic blood pressure values were consistently skipped by the device: 89, 119, 120, 124, 125, 130, 140, 141, 150, 160, 170, 180, 190, and 200 mm Hg. No skip pattern was detected for diastolic blood pressure. Pulse data, which were only available in the Hypertension Genetic Epidemiology Network Study, also showed the following skipped values: 95, 99, 103, 106, and 109 bpm. Consultation with the manufacturer, the Critikon Corporation, indicated that the use of an algorithm designed to improve the accuracy of the DINAMAP device prevents these values from being displayed. Assessment of the extent and direction of bias caused by the skipped values is difficult, given that the algorithm is proprietary. While the implications of the skipped values are not clear, it is important for clinicians and researchers to be aware of this feature.
Vascular NADH/NADPH Oxidase Is Involved in Enhanced Superoxide Production in Spontaneously Hypertensive Rats
Authors: Zalba Guillermo , Beaumont Francisco J. , José Gorka San , Fortuño Ana , Fortuño María A. , Etayo Juan C. , Díez Javier
Published: June 2012

Abstract
—This study was designed to test the hypothesis that stimulation of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase is involved in increased vascular superoxide anion (·O
2
−
) production in spontaneously hypertensive rats (SHR). The study was performed in 16-week-old and 30-week-old normotensive Wistar-Kyoto rats (WKY
16
and WKY
30
, respectively) and in 16-week-old and 30-week-old SHR (SHR
16
and SHR
30
, respectively). In addition, 16-week-old SHR were treated with oral irbesartan (average dose 20 mg/kg per day) for 14 weeks (SHR
30
-I). Aortic NADH/NADPH oxidase activity was determined by use of chemiluminescence with lucigenin. The expression of
p22phox
messenger RNA was assessed by competitive reverse transcription–polymerase chain reaction. Vascular responses to acetylcholine were determined by isometric tension studies. Aortic wall structure was studied, determining the media thickness and the cross-sectional area by morphometric analysis. Whereas systolic blood pressure was significantly increased in the 2 groups of hypertensive animals compared with their normotensive controls, no differences were observed in systolic blood pressure between SHR
30
and SHR
16
. No other differences in the parameters measured were found between WKY
16
and SHR
16
. In SHR
30
compared with WKY
30
, we found significantly greater
p22phox
mRNA level, NADH/NADPH-driven ·O
2
−
production, media thickness, and cross-sectional area and an impaired vasodilation in response to acetylcholine. Treated SHR had similar NADH/NADPH oxidase activity and
p22phox
expression as the WKY
30
group. The vascular functional and morphological parameters were improved in SHR
30
-I. These findings suggest that an association exists between
p22phox
gene overexpression and NADH/NADPH overactivity in the aortas of adult SHR. Enhanced NADH/NADPH oxidase–dependent ·O
2
−
production may contribute to endothelial dysfunction and vascular hypertrophy in this genetic model of hypertension.
Inversion of the Intracellular Na
+
/K
+
Ratio Blocks Apoptosis in Vascular Smooth Muscle Cells by Induction of RNA Synthesis
Authors: Orlov Sergei N. , Taurin Sebastien , Thorin-Trescases Nathalie , Dulin Nickolai O. , Tremblay Johanne , Hamet Pavel
Published: June 2012

Abstract
—This study examines the involvement of RNA and protein synthesis in the modulation of apoptosis in vascular smooth muscle cells (VSMC) by intracellular monovalent cations. In VSMC transfected with E1A adenovirus (VSMC-E1A), inversion of the [Na
+
]
i
/[K
+
]
i
ratio by an inhibitor of the Na
+
,K
+
pump, ouabain, prevented the development of apoptosis triggered by serum withdrawal. Inhibition of apoptosis by ouabain was abolished by inhibitors of RNA and protein synthesis, actinomycin D, and cycloheximide, respectively. In VSMC-E1A, incubation with ouabain for 4 and 24 hours augmented RNA synthesis by 20% to 50% and 3-fold to 4-fold, respectively. In quiescent VSMC, the effect of ouabain and serum on RNA synthesis was additive. Ouabain did not affect the level of phosphorylation of ERK, JNK, and p38 MAP kinases and blocked apoptosis independent of the presence of the MAPK kinase inhibitors PD98059 and SB 202190. Equimolar substitution of NaCl with KCl in the incubation medium abolished the effect of ouabain on intracellular Na
+
and K
+
concentration, apoptosis, and RNA synthesis. Thus, our results demonstrate that the antiapoptotic effect of the inverted [Na
+
]
i
/[K
+
]
i
ratio is mediated by MAPK-independent induction of de novo synthesis of RNA species encoding inhibitor(s) of programmed cell death.
Effects of Aspirin-Like Drugs on Nitric Oxide Synthesis in Rat Vascular Smooth Muscle Cells
Authors: Shimpo Masahisa , Ikeda Uichi , Maeda Yoshikazu , Ohya Ken-ichi , Murakami Yoshiaki , Shimada Kazuyuki
Published: June 2012

Abstract
—The purpose of this study was to investigate the effects of aspirin-like drugs on nitric oxide (NO) synthesis in rat vascular smooth muscle cells (VSMCs). We measured the accumulation of nitrite, a stable oxidation product of NO, and the expression of inducible NO synthase (iNOS) mRNA and protein in rat cultured VSMCs. Sodium salicylate, aspirin, and indomethacin dose-dependently enhanced nitrite production by interleukin (IL)-1β–stimulated VSMCs at therapeutic plasma concentration ranges. Increased nitrite production by aspirin-like drugs was accompanied by increased iNOS mRNA and protein accumulation in VSMCs. Addition of IL-1β activated nuclear factor κB (NF-κB) in VSMCs, but sodium salicylate did not affect IL-1β–induced NF-κB activation. The nonselective lipoxygenase (LO) inhibitor nordihydroguaiaretic acid inhibited sodium salicylate–induced nitrite production, whereas the selective 5-LO inhibitor caffeic acid did not influence production of nitrite. The 12-LO product 12-HETE dose-dependently enhanced nitrite production by IL-1β–stimulated VSMCs, whereas the 15-LO product 15-HETE did not. Our study demonstrates that aspirin and the aspirin-like drugs, sodium salicylate and indomethacin, increase NO synthesis in IL-1β–stimulated VSMCs by upregulation of iNOS transcription via a 12-LO pathway. These effects were independent of NF-κB activation. In addition to the direct inhibition of platelet function, aspirin-like drugs may contribute to the reduction of atherothrombotic risk in myocardial ischemia via enhancing NO production by VSMCs.