bluuebunny/crossref_metadata_2025 huggingface dataset:
CYP11B2
Gene Polymorphisms in Idiopathic Hyperaldosteronism
Authors: Mulatero Paolo , Schiavone Domenica , Fallo Francesco , Rabbia Franco , Pilon Catia , Chiandussi Livio , Pascoe Leigh , Veglio Franco
Published: June 2012

Abstract
—Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the
CYP11B2
gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the
CYP11B2
gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.
Evaluation of the Aldosterone Synthase (CYP11B2) Gene Polymorphism in Patients With Myocardial Infarction
Authors: Hengstenberg Christian , Holmer Stephan R. , Mayer Björn , Löwel Hannelore , Engel Susanne , Hense Hans-Werner , Riegger Günter A. J. , Schunkert Heribert
Published: June 2012

Abstract
—Left ventricular remodeling after myocardial infarction involves activation of the renin-angiotensin-aldosterone system. Recently, the biallelic −344T/C polymorphism of the aldosterone synthase gene was associated with increased aldosterone levels, arterial hypertension, diastolic dysfunction, and left ventricular dilatation. We hypothesized that this polymorphism may also affect left ventricular geometry and function after myocardial infarction. By using a standardized questionnaire, as well as anthropometric and echocardiographic measurements, we thus studied 606 patients (533 men and 73 women) who had a myocardial infarction before the age of 60 years. The aldosterone synthase gene polymorphism was analyzed after polymerase chain reaction amplification and restriction enzyme digestion. The results demonstrated that there was no association of the aldosterone synthase gene polymorphism with echocardiographically determined left ventricular dimensions, wall thicknesses, or indexes of systolic or diastolic function. Furthermore, anthropometric data, including blood pressure levels, were balanced between the different genotypes. Finally, the allele frequency was similar for patients with myocardial infarction and a sample group from the normal population (n=1675). The data indicate that the allele status of the aldosterone synthase gene polymorphism is not useful for the identification of patients with myocardial infarction who have impaired left ventricular function or unfavorable remodeling.
Functional Importance of Angiotensin-Converting Enzyme–Dependent In Situ Angiotensin II Generation in the Human Forearm
Authors: Saris Jasper J. , van Dijk Marjan A. , Kroon Ingrid , Schalekamp Maarten A. D. H. , Danser A. H. Jan
Published: June 2012

Abstract
—To assess the importance for vasoconstriction of in situ angiotensin (Ang) II generation, as opposed to Ang II delivery via the circulation, we determined forearm vasoconstriction in response to Ang I (0.1 to 10 ng · kg
−1
· min
−1
) and Ang II (0.1 to 5 ng · kg
−1
· min
−1
) in 14 normotensive male volunteers (age 18 to 67 years). Changes in forearm blood flow (FBF) were registered with venous occlusion plethysmography. Arterial and venous blood samples were collected under steady-state conditions to quantify forearm fractional Ang I-to-II conversion. Ang I and II exerted the same maximal effect (mean±SEM 71±4% and 75±4% decrease in FBF, respectively), with similar potencies (mean EC
50
[range] 5.6 [0.30 to 12.0] nmol/L for Ang I and 3.6 [0.37 to 7.1] nmol/L for Ang II). Forearm fractional Ang I-to-II conversion was 36% (range 18% to 57%). The angiotensin-converting enzyme (ACE) inhibitor enalaprilat (80 ng · kg
−1
· min
−1
) inhibited the contractile effects of Ang I and reduced fractional conversion to 1% (0.1% to 8%), thereby excluding a role for Ang I-to-II converting enzymes other than ACE (eg, chymase). The Ang II type 1 receptor antagonist losartan (3 mg · kg
−1
· min
−1
) inhibited the vasoconstrictor effects of Ang II. In conclusion, the similar potencies of Ang I and II in the forearm, combined with the fact that only one third of arterially delivered Ang I is converted to Ang II, suggest that in situ–generated Ang II is more important for vasoconstriction than circulating Ang II. Local Ang II generation in the forearm depends on ACE exclusively and results in vasoconstriction via Ang II type 1 receptors.
Effects of Menstrual Cycle and Race on Peripheral Vascular α-Adrenergic Responsiveness
Authors: Freedman Robert R. , Girgis Reda
Published: June 2012

Abstract
—Gender differences in the incidence of many cardiovascular diseases may be due to the effects of sex hormones. Both α
1
- and α
2
-adrenergic receptors produce vasoconstriction in peripheral blood vessels and have demonstrated gender effects in previous studies. In addition, race has been shown to influence the effects of some α-adrenergic stimuli. We therefore sought to determine the effects of the menstrual cycle and race on peripheral blood flow responses to the intra-arterial infusion of phenylephrine (α
1
-agonist) and clonidine (α
2
-agonist). Ten white and 8 black women were studied during the early luteal phase and the follicular phase; these phases were verified in each woman through measurements of plasma estradiol and progesterone. Plasma norepinephrine was measured with HPLC. During phenylephrine infusion, there was significantly greater vasoconstriction in the luteal phase versus the follicular phase (
P
<0.05). There were no differences (
P
>0.8) between white and black women. During clonidine infusion, white women showed significantly more vasoconstriction in the follicular phase than during the luteal phase (
P
<0.006). For black women, the responses for both phases did not differ (
P
>0.9). Blood pressures were significantly higher in the black women (diastolic
P
<0.005, systolic
P
<0.05). The luteal-phase elevation of α
1
-adrenergic responses may be due to elevated levels of estradiol, progesterone, or both. The lack of luteal-phase reduction in α
2
-adrenergic vasoconstriction in black women may contribute to their increased pressor responses to adrenergic stimuli.
Overweight and Hypertension
Authors: Julius Stevo , Valentini Mariaconsuelo , Palatini Paolo
Published: June 2012

Abstract
—Cross-sectionally, higher weight is associated with higher blood pressure levels; prospectively, baseline weight and weight gain predict higher blood pressure. The loss of weight is frequently associated with a decrease in blood pressure. These findings suggest that weight gain may pathophysiologically contribute to blood pressure elevation. In this review, we present data to indicate that the reverse is also true; persons of equal weight who had higher initial blood pressures gain more weight in the future. We also propose a plausible hypothesis to explain this reverse relationship. Both the blood pressure elevation and the gain of weight may reflect a primary increase in sympathetic tone. It is well known that in a milieu of increased sympathetic tone, the β-adrenergic responsiveness decreases. Sympathetic overactivity and decreased cardiovascular β-adrenergic responsiveness have been described in hypertension. β-Adrenergic receptors mediate increases in energy expenditure. If these metabolic receptors were downregulated in hypertension, the ability of hypertensive patients to dissipate calories would decrease and they would gain more weight. The possible relationship of decreased β-adrenergic responsiveness to weight in hypertension can be experimentally tested. Such research may contribute to an explanation of why patients with hypertension can rarely lose weight. An understanding of this pathophysiological relationship may open new avenues for therapeutic interventions.
Prevalence, Treatment, and Control of Hypertension by Sociodemographic Factors Among the Dutch Elderly
Authors: van Rossum Caroline T. M. , van de Mheen Hendrike , Witteman Jacqueline C. M. , Hofman Albert , Mackenbach Johan P. , Grobbee Diederick E.
Published: June 2012

Abstract
—The study objective was to assess the prevalence, level of treatment, and control of hypertension in a general elderly population according to age and sociodemographic factors. We conducted a cross-sectional analysis of 7983 participants of the Rotterdam Study who were ≥55 years old and living in a district of Rotterdam. The prevalence of hypertension was based on blood pressure levels (≥160/95 mm Hg) and the use of blood pressure–lowering medication for the indication of hypertension, type of treatment, and control of hypertension. Systolic blood pressure rises with age, whereas diastolic blood pressure declines. The prevalence of hypertension increases with age and was higher among women (39%) than among men (31%). About 80% of the hypertensives were aware of having hypertension, and 82% of the 80% were treated. For 70% of them, treatment was adequate with reference to conservative criteria. Hypertension was more prevalent among persons not living in a home for the elderly, for more-educated men, and for less-educated women. Persons without a partner and men living in a home for the elderly had a higher risk of being unaware of or of not being treated for existing hypertension. Treatment was more often successful among those living in a home for the elderly. The prevalence of hypertension was higher among older women and increased with age in both genders. A large proportion of hypertensive elderly persons were aware and were successfully treated for hypertension. The degree of awareness and control appeared to be affected by sociodemographic factors. More importantly, the majority of hypertensives did not have their hypertension well controlled. This group requires more attention by medical practitioners to reduce the burden of cardiovascular diseases in elderly persons.
Mental Stress–Induced Increase in Blood Pressure Is Not Related to Baroreflex Sensitivity in Middle-Aged Healthy Men
Authors: Fauvel Jean Pierre , Cerutti Catherine , Quelin Pierre , Laville Maurice , Gustin Marie Paule , Paultre Christian Zacharie , Ducher Michel
Published: June 2012

Abstract
—The baroreflex that acts to blunt blood pressure (BP) variations through opposite variations in heart rate should limit the BP increase produced by an emotional challenge. However, relations between baroreflex sensitivity and BP reactivity induced by a psychological stress in a large group of adults have never been firmly established. In 280 healthy men, rest (10 minutes) and stress (5 minutes) BP and heart rate were recorded beat to beat by a blood pressure monitor. The mental stress was elicited by a well-standardized computerized version of a word color conflict stress test (Stroop Color Test). Rest and stress baroreflex sensitivity was assessed by the cross-spectral analysis of BP and heart rate and by the sequence method. The stress-induced increase in systolic BP (22.4±0.1 mm Hg) was not correlated with resting baroreflex sensitivity but was slightly correlated (
r
=0.2,
P
<0.001) with BP variability assessed either by standard deviation or by mid-frequency band spectral power. Our results suggested that a centrally mediated sympathetic stimulation overcame cardiac autonomic regulation and emphasized the role of the sympathetic vasoconstriction in the pressure response at the onset of the stressing stimulation. During the sustained sympathoexcitatory phase, the cardiac baroreflex blunts BP variations but at a lower sensitivity.
Diurnal Blood Pressure Variation in Progressive Autonomic Failure
Authors: Carvalho Mario J. , van den Meiracker Anton H. , Boomsma Frans , Lima Maria , Freitas Joao , Veld Arie J. Man in ’t , Falcao de Freitas Antonio
Published: June 2012

Abstract
—To investigate the role of the autonomic nervous system (ANS) in the generation of the circadian blood pressure (BP) variation, the degree of impairment of the ANS was related to the results of ambulatory BP recordings in 212 patients with progressive autonomic failure due to familial amyloid polyneuropathy. On the basis of BP and/or heart rate (HR) responses to the Valsalva maneuver, 60° head-up tilting, deep-breathing tests, and plasma norepinephrine levels, 4 groups of patients were distinguished. In all patients and in 38 age-matched control subjects, ambulatory BP was monitored. Patients of group I (n=40, aged 32±3 y), with no evidence yet of impairment of their ANS, had circadian BP and HR variations indistinguishable from controls. Patients of group II (n=41, aged 34±5 y) had a variable degree of impairment of their parasympathetic ANS, but their sympathetic ANS was still intact. Twenty-four–hour HR was higher in these patients than in controls (88±11 versus 78±7 bpm,
P
<0.01). Their circadian HR variation was maintained, but their circadian BP variation was diminished (10±6/11±4 versus 17±6/16±4 mm Hg in controls,
P
<0.01) because of an attenuation of the nocturnal BP decline. Patients of group III (n=69, aged 36±6 y), with parasympathetic failure and intermediate sympathetic dysfunction, had a blunted diurnal BP variation, whereas patients of group IV (n=62, aged 38±6 y), with parasympathetic failure and severe sympathetic dysfunction, had an absent diurnal BP variation. In patients of groups III and IV, a decrease in daytime BP accounted for the blunted circadian BP variation. This extensive study in progressive autonomic failure confirms the important role of the ANS in the generation of circadian BP variation. For the maintenance of a normal circadian BP pattern, not only an intact sympathetic but also an intact afferent parasympathetic ANS is a prerequisite.
Arterial Hypertension, Microalbuminuria, and Risk of Ischemic Heart Disease
Authors: Jensen Jan Skov , Feldt-Rasmussen Bo , Strandgaard Svend , Schroll Marianne , Borch-Johnsen Knut
Published: June 2012

Abstract
—Albumin excretion in urine is positively correlated with the presence of ischemic heart disease and atherosclerotic risk factors. We studied prospectively whether a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the increased risk of ischemic heart disease among hypertensive subjects. In 1983 and 1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma total and HDL cholesterol levels, body mass index, and smoking status were obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who were free from ischemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated arterial hypertension or borderline hypertension was present in 204 subjects, who were followed until 1993 by the National Hospital and Death Certificate Registers with respect to development of ischemic heart disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to 11.9,
P
=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1,
P
=0.05) when adjusted for all other atherosclerotic risk factors, including age and gender. In conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart disease among hypertensive or borderline hypertensive subjects. Urinary albumin excretion should be measured regularly in a hypertension clinic, and a rigorous control of blood pressure and of other atherosclerotic risk factors is recommended in hypertensive patients with microalbuminuria.
Glomerular Hyperfiltration, High Renin, and Low- Extracellular Volume in High Blood Pressure
Authors: Harrap Stephen B. , Cumming Allan D. , Davies David L. , Foy Christopher J. W. , Fraser Robert , Kamitani Atsushi , Connor J. Michael , Lever Anthony F. , Watt Graham C. M.
Published: June 2012

Abstract
—Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (
P
<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (
P
<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (
P
<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.
Synergistic Effects of AT
1
and ET
A
Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model
Authors: Bohlender Jürgen , Gerbaulet Stephan , Krämer Jochen , Gross Michael , Kirchengast Michael , Dietz Rainer
Published: June 2012

Abstract
—Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelin
A
receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (n=12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II–induced hypertension and end-organ damage. Our findings may have clinical implications and provide a rationale for combining angiotensin II type 1 receptor and endothelin
A
receptor blockade to obtain a synergistic effect.
Aldose Reductase Inhibitor Improves Insulin-Mediated Glucose Uptake and Prevents Migration of Human Coronary Artery Smooth Muscle Cells Induced by High Glucose
Authors: Yasunari Kenichi , Kohno Masakazu , Kano Hiroaki , Minami Mieko , Yoshikawa Junichi
Published: June 2012

Abstract
—We examined involvement of the polyol pathway in high glucose–induced human coronary artery smooth muscle cell (SMC) migration using Boyden’s chamber method. Chronic glucose treatment for 72 hours potentiated, in a concentration-dependent manner (5.6 to 22.2 mol/L), platelet-derived growth factor (PDGF) BB–mediated SMC migration. This potentiation was accompanied by an increase in PDGF BB binding, because of an increased number of PDGF-β receptors, and this potentiation was blocked by the aldose reductase inhibitor epalrestat. Epalrestat at concentrations of 10 and 100 nmol/L inhibited high glucose–potentiated (22.2 mmol/L), PDGF BB–mediated migration. Epalrestat at 100 nmol/L inhibited a high glucose–induced increase in the reduced/oxidized nicotinamide adenine dinucleotide ratio and membrane-bound protein kinase C (PKC) activity in SMCs. PKC inhibitors calphostin C (100 nmol/L) and chelerythrine (1 μmol/L) each inhibited high glucose–induced, PDGF BB–mediated SMC migration. High glucose–induced suppression of insulin-mediated [
3
H]-deoxyglucose uptake, which was blocked by both calphostin C (100 nmol/L) and chelerythrine (1 μmol/L), was decreased by epalrestat (100 nmol/L). Chronic high glucose treatment for 72 hours increased intracellular oxidative stress, which was directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by epalrestat (100 nmol/L). Antisense oligonucleotide to PKC-β isoform inhibited high glucose–mediated changes in SMC migration, insulin-mediated [
3
H]-deoxyglucose uptake, and oxidative stress. These findings suggest that high glucose concentrations potentiate SMC migration in coronary artery and that the aldose reductase inhibitor epalrestat inhibits high glucose–potentiated, PDGF BB–induced SMC migration, possibly through suppression of PKC (PKC-β), impaired insulin-mediated glucose uptake, and oxidative stress.
Activation of MAPKs in Proximal Tubule Cells From Spontaneously Hypertensive and Control Wistar-Kyoto Rats
Authors: Parenti Astrid , Cui Xiao-Lan , Hopfer Ulrich , Ziche Marina , Douglas Janice G.
Published: June 2012

Abstract
—The aim of this study was to test the hypothesis that differences exist in the activity and/or expression of mitogen-activated protein kinases (MAPKs) between spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) and that these differences may account for the enhanced activity of the Na
+
/H
+
exchanger (NHE) previously observed in the renal proximal tubule of SHR. Therefore, the activities of c-jun N-terminal kinase
1
(JNK
1
), extracellular signal-regulated kinase
1/2
(ERK
1/2
), and p38 were investigated. A reduced amount of ERK
1
and JNK
1
protein was found in renal cortex specimens of SHR as compared with WKY; however, their activities were the same. To study the cellular basis of this difference, immortalized proximal tubule cell lines were grown on Millicell-CM filter inserts where the cell lines organize as polarized monolayers with separate access to apical and basolateral compartments. Although basal JNK
1
and ERK
1/2
activities were not significantly different between WKY and SHR cells, anisomycin stimulated JNK
1
activity in WKY cells more than in SHR cells (eg, at 15 minutes 300% versus 30%, respectively). Similarly, angiotensin II increased JNK
1
and ERK
1/2
activity in a time- and concentration-dependent manner in WKY cells but not in SHR cells. Western blot analyses showed a deficit in JNK
1
and ERK
1
protein in SHR (0.25 and 0.5, respectively, of the levels in WKY cells), although ERK
2
and p38 protein levels were the same. These observations suggest that, although angiotensin II activates MAPKs and MAPKs have been shown to regulate NHE, this regulatory pathway is unlikely to account for the increased activity of NHE in the proximal tubular epithelium of SHR.
Angiotensin II and the Heart
Authors: De Mello Walmor C. , Danser A. H. Jan
Published: June 2012

Abstract
—The active end product of the renin-angiotensin system, angiotensin II (Ang II), through the activation of specific Ang II receptors, regulates cardiac contractility, cell coupling, and impulse propagation and is involved in cardiac remodeling, growth, and apoptosis. We review these subjects, as well as the second messengers that are involved, and the synthesis of Ang II in the heart under normal and pathological conditions. Finally, we discuss the possibility that there is an intracrine renin-angiotensin system in the heart that plays a role in the control of cell communication and inward Ca
2+
current.
Cardiotrophin-1 Increases Angiotensinogen mRNA in Rat Cardiac Myocytes Through STAT3
Authors: Fukuzawa Jun , Booz George W. , Hunt Rachel A. , Shimizu Noriko , Karoor Vijaya , Baker Kenneth M. , Dostal David E.
Published: June 2012

Abstract
—Cardiotrophin-1, an interleukin-6–related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1–induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1–stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1–induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein–coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1–induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein–coupled and cytokine receptors.
Chronic I
1
-Imidazoline Agonism
Authors: Greenwood John P. , Scott Eleanor M. , Stoker John B. , Mary David A.
Published: June 2012

Abstract
—Evidence exists for a state of sympathetic hyperactivity in essential hypertension, and moxonidine, a new central sympathetic inhibitor, has been introduced for its treatment. Acute administration of moxonidine lowers peripheral sympathetic neural output. This study examined the effect of chronic moxonidine therapy, at increasing therapeutic doses, on resting peripheral sympathetic activity and vascular resistance and their responses to physiological reflex maneuvers. Twelve newly diagnosed patients with essential hypertension were studied sequentially at least 1 month apart, initially on no therapy, then on 200 μg, and finally on 400 μg of oral moxonidine daily. Changes in heart rate, arterial blood pressure, calf vascular resistance, and peripheral sympathetic drive were assessed at rest and during reflex maneuvers. Peroneal microneurography was used to quantify peripheral sympathetic vasoconstrictor activity by single-unit and multiunit techniques. Moxonidine therapy progressively reduced resting mean arterial pressure (
P
<0.0001) without affecting heart rate. At 200 μg daily, there was a significant reduction in sympathetic nerve activity (
P
<0.001) and calf vascular resistance (
P
<0.01). At 400 μg daily, further reductions were smaller and insignificant. Responses to cold stimulus and isometric handgrip exercise showed a similar pattern, with the greatest magnitude of change at 200 μg daily. In patients with essential hypertension, chronic moxonidine therapy inhibited resting sympathetic vasoconstrictor drive and also its reflex responses. The magnitude of inhibition became less as the therapeutic dose was increased, suggesting that moxonidine may be more effective under conditions of high sympathetic activity.
Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B
2
Receptor
Authors: Houle Steeve , Larrivée Jean-François , Bachvarova Magdalena , Bouthillier Johanne , Bachvarov Dimcho R. , Marceau François
Published: June 2012

Abstract
—In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B
2
receptors (B
2
Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16.0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B
2
R–green fluorescent protein (B
2
R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for [
3
H]BK (
K
D
=1.61 nmol/L) similar to that of the wild-type rabbit B
2
R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A
2
assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [
3
H]BK binding to B
2
R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0°C; at 37°C, icatibant or NPC 17731 effects were not reversible. B
2
R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B
2
R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B
2
R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101- to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B
2
R expressed in an heterologous system.
Bradykinin B
2
Receptor Gene Polymorphism Is Associated With Angiotensin-Converting Enzyme Inhibitor–Related Cough
Authors: Mukae Shuji , Aoki Shuichi , Itoh Seiji , Iwata Toshiki , Ueda Hiroaki , Katagiri Takashi
Published: June 2012

Abstract
—The appearance of cough in association with angiotensin-converting enzyme (ACE) inhibitors is thought to be related to bradykinin, and it has been speculated that the elicitation of adverse effects is genetically predetermined. Several polymorphisms of the human bradykinin B
2
receptor gene may be involved in ACE inhibitor–related cough. To investigate this possibility, we identified the −58 thymine (T)/cytosine (C) polymorphism in subjects with ACE inhibitor–related cough. We classified the study population into 4 groups: subjects with and without cough that were treated with ACE inhibitors (n=30/30), nontreated essential hypertensive subjects (n=100), and normotensive subjects (n=100). The −58T/C was genotyped by the polymerase chain reaction single-strand conformation polymorphism method. The frequencies of the CC genotype and C allele of −58T/C were significantly higher in the nontreated hypertensive subjects than in the normotensive subjects. Conversely, the frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in the subjects without cough. These tendencies were more pronounced in females. Among the promoter assays of the human bradykinin B
2
receptor, −58T was found to have a higher transcription rate than that of −58C. This finding seems to suggest that the transcriptional activity of promoter might be involved in the appearance of ACE inhibitor–related cough. A genetic variant of the bradykinin receptor is involved in the elicitation of ACE inhibitor–related cough. It may be possible to predict the side effects of ACE inhibitors in advance.
G Protein β3 Gene
Authors: Rosskopf Dieter , Busch Stefan , Manthey Iris , Siffert Winfried
Published: June 2012

Abstract
—Recent studies have shown that a polymorphism (C825T) in the gene encoding the G protein β3 subunit (
GNB3)
is associated with hypertension and obesity. We characterized the entire
GNB3
gene, which spans 7.5 kb and is composed of 11 exons and 10 introns. Its promoter lacks a TATA box but harbors GC-rich regions. The functional activity of the
GNB3
promoter was verified with reporter gene assays that also demonstrated its inducibility by phorbol esters. A novel polymorphism in the promoter region A(−350)G occurred with frequencies (G allele) of 76%, 97%, and 61% in Africans, Chinese, and Germans, respectively. Reporter gene constructs with either the A or the G allele did not differ with regard to inducement of the reporter protein. A silent nucleotide exchange in the coding region (A657T) occurred with T allele frequencies ranging from 0.5% to 2.4%. Another polymorphism (G814A) results in the replacement of glycine by serine at position 272. In Germans, the A allele occurred at a frequency of 10%. Finally, a C1429T polymorphism in the 3′ untranslated region of
GNB3
was identified that occurred at T allele frequencies of 38%, 17%, and 30% in Africans, Chinese, and Germans, respectively. Haplotype prediction indicated in Germans an almost complete association of
GNB3
825T with 1429T, and vice versa. An analysis of these polymorphic loci in nonhuman primates revealed that the ancestral
GNB3
gene harbored the (−350)G, 825C, and 1429C alleles. This is the first complete characterization of the human
GNB3
gene and its promoter region, which will enable refined epidemiological and biochemical investigations of
GNB3
in hypertension and obesity.
Cardiac Ankyrin Repeat Protein Is a Novel Marker of Cardiac Hypertrophy
Authors: Aihara Yasushi , Kurabayashi Masahiko , Saito Yuichiro , Ohyama Yoshio , Tanaka Toru , Takeda Shin-ichi , Tomaru Kouichi , Sekiguchi Ken-ichi , Arai Masashi , Nakamura Tetsuya , Nagai Ryozo
Published: June 2012

Abstract
—CARP, a cardiac doxorubicin (adriamycin)-responsive protein, has been identified as a nuclear protein whose expression is downregulated in response to doxorubicin. In the present study, we tested the hypothesis that CARP serves as a reliable genetic marker of cardiac hypertrophy in vivo and in vitro. CARP expression was markedly increased in 3 distinct models of cardiac hypertrophy in rats: constriction of abdominal aorta, spontaneously hypertensive rats, and Dahl salt-sensitive rats. In addition, we found that CARP mRNA levels correlate very strongly with the brain natriuretic peptide mRNA levels in Dahl rats. Transient transfection assays into primary cultures of neonatal rat cardiac myocytes indicate that transcription from the CARP and brain natriuretic peptide promoters is stimulated by overexpression of p38 and Rac1, components of the stress-activated mitogen-activated protein kinase pathways. Mutation analysis and electrophoretic mobility shift assays indicated that the M-CAT element can serve as a binding site for nuclear factors, and this element is important for the induction of CARP promoter activity by p38 and Rac1. Thus, our data suggest that M-CAT element is responsible for the regulation of the CARP gene in response to the activation of stress-responsive mitogen-activated protein kinase pathways. Moreover, given that activation of these pathways is associated with cardiac hypertrophy, we propose that CARP represents a novel genetic marker of cardiac hypertrophy.
Augmented Sympathetic Response to Bradykinin in the Diabetic Heart Before Autonomic Denervation
Authors: Pietrzyk Zbigniew , Vogel Stephen , Dietze Guenther J. , Rabito Sara F.
Published: June 2012

Abstract
—We studied whether diabetes mellitus affects the bradykinin (BK)-induced release of norepinephrine (NE) from rat cardiac sympathetic endings in situ. Three groups were studied. Group A (n=12) was rendered diabetic with streptozotocin (STZ), group B (n=13) received STZ and insulin, and group C (n=14) received citrate buffer only. NPH insulin was given to group B from day 7 after STZ. Atria were paced (3Hz) with rectangular voltage pulses at mechanical threshold intensity (0.15 V/cm). The release of NE was assessed through its effects on contractile force in the presence of atropine (1 μmol/L). Intensifying the field stimulation above the neural threshold (≈0.4 V/cm) produced a graded positive inotropic effect that was due to the release of NE from sympathetic nerve endings. The additional effect of 0.1 μmol/L BK on the force of contraction was determined at half-maximal neural stimulation (ie, at ≈0.65 V/cm). Then, after washing out BK and lowering the stimulation intensity to mechanical threshold, a cumulative dose-response curve for added NE was generated, allowing the positive inotropic effects of neural stimulation (with or without BK) to be expressed in terms of an equivalent inotropic concentration of added NE ([NE
eq
]). Neural stimulation, in the absence of BK, gave an [NE
eq
] of 32±3 nmol/L in group A, 44±6 nmol/L in group B, and 37±6 nmol/L in group C. BK increased [NE
eq
] by a factor of 6.2±0.9 in group A, 4.5±0.5 in group B, and 3.7±0.3 in group C. This factor was greater in group A than in group C but indistinguishable in groups B and C. Atria from normal and diabetic rats were incubated in
3
[H]NE for 60 minutes. Excess tracer was removed, and atria were stimulated during a series of 1-minute episodes at half-maximal neural stimulation to cause exocytotic
3
[H]NE release. BK augmented
3
[H]NE release in normal (n=4) and in diabetic (n=4) atria. This BK-induced increase of
3
[H]NE overflow (expressed as a fraction of tissue
3
[H]NE radioactivity) was 4 times greater in diabetic than in normal preparations. The response to BK in releasing sympathetic neurotransmitter is augmented in diabetic rats, recovering in a manner dependent on insulin.
High Triglycerides and Low HDL Cholesterol and Blood Pressure and Risk of Ischemic Heart Disease
Authors: Jeppesen Jørgen , Hein Hans Ole , Suadicani Poul , Gyntelberg Finn
Published: June 2012

Abstract
—Treatment of high blood pressure (BP) has not produced the expected reduction in risk of ischemic heart disease (IHD). Subjects with high BP often have the metabolic syndrome X, an aggregation of abnormalities in glucose and lipid metabolism. We tested the hypothesis that the BP level would be less predictive of risk of IHD in those with high triglycerides (TG) and low HDL cholesterol (HDL-C), the characteristic dyslipidemia in the metabolic syndrome than in those without. Baseline measurements of fasting lipids, systolic BP (SBP), diastolic BP (DBP), and other risk factors were obtained in 2906 men, age 53 to 74 years, free of overt cardiovascular disease. High TG/low HDL-C was defined as TG >1.59 mmol/L and HDL-C <1.18 mmol/L. Within an 8-year period, 229 men developed IHD. In men with high TG/low HDL-C, the incidence of IHD according to SBP (<120, 120 to 140, >140 mm Hg) was 12.5%, 12.9%, and 10.0% (
P
=NS), respectively, and according to DBP, the incidence of IHD was (<75, 75 to 90, >90 mm Hg) 13.7%, 10.6%, and 13.7% (
P
=NS), respectively. The corresponding figures for other men were 5.2%, 8.0%, and 9.7% for SBP (
P
<0.001), and 6.1%, 7.5%, and 9.9% for DBP (
P
<0.03). In conclusion, the BP level did not predict the risk of IHD in those with high TG/low HDL-C. This finding may explain the reason lowering BP has not produced the expected reduction in IHD.
Angiotensin in the Nucleus Tractus Solitarii Contributes to Neurogenic Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition
Authors: Eshima Kenichi , Hirooka Yoshitaka , Shigematsu Hideaki , Matsuo Isamu , Koike George , Sakai Koji , Takeshita Akira
Published: June 2012

Abstract
—Activation of the sympathetic nervous system and renin-angiotensin system has been suggested to contribute to the hypertension caused by chronic nitric oxide synthase inhibition. The aim of the present study was to determine whether angiotensin within the nucleus tractus solitarii (NTS) plays a role in activation of the sympathetic nervous system in this model. Rats were treated with
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 100 mg · kg
−1
· d
−1
in drinking water) for 2 weeks. Experiments were performed on anesthetized rats with denervated arterial and cardiopulmonary baroreceptors. Arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were measured. Microinjection of an angiotensin II type 1 (AT
1
) receptor antagonist (CV11974) or an angiotensin II type 2 (AT
2
) receptor antagonist (PD123319) into the depressor region within the NTS (identified by prior injection of
l
-glutamate) was performed. Microinjection of CV11974, but not of PD123319, produced greater decreases in arterial pressure, heart rate, and RSNA in L-NAME–treated rats than in control rats. The administration of hexamethonium resulted in a larger fall in arterial pressure in L-NAME–treated rats than in control rats. The ACE mRNA level in the brain stem was greater in L-NAME–treated rats than in control rats. These results suggest that increased sympathetic nerve activity plays a role in hypertension caused by chronic nitric oxide synthase inhibition and that activation of the renin-angiotensin system in the NTS is involved at least in part in this increased sympathetic nerve activity via AT
1
receptors.
Renal Changes Induced by a Cyclooxygenase-2 Inhibitor During Normal and Low Sodium Intake
Authors: Rodríguez Francisca , Llinás María T. , González Juan D. , Rivera Jose , Salazar F. Javier
Published: June 2012

Abstract
—Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2–derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non–isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E
2
excretion in both groups but did not modify plasma renin activity in dogs with low (8.1±1.1 ng angiotensin I · mL
−1
· h
−1
) or normal (1.8±0.4 ng angiotensin I · mL
−1
· h
−1
) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2–derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake.
Relationship Between Skin Color and Blood Pressure in Egyptian Adults
Authors: Mosley Jonathan D. , Appel Lawrence J. , Ashour Zeinab , Coresh Josef , Whelton Paul K. , Ibrahim M. Mohsen
Published: June 2012

Abstract
—In many, but not all societies, dark skin color is associated with high blood pressure. Whether the association between skin color and blood pressure is independent of known determinants of blood pressure remains controversial. We examined the association between skin color and blood pressure in 835 Egyptian adults (370 men and 465 women) participating in the National Hypertension Project, a national survey of hypertension prevalence and blood pressure–related complications conducted in Egypt during 1991–1993. Skin color was assessed by measuring the concentration of cutaneous melanin in an unexposed area with the use of reflectance spectrophotometry. Higher concentrations of melanin were associated with lower body mass index, less education, manual labor (among men), and a lower urinary sodium-to-potassium ratio (among women). In multivariate regression analyses adjusted for age, body mass index, and education, there was a significant nonlinear association between blood pressure and skin color among women; in the lower to intermediate range of skin pigmentation, both systolic and diastolic blood pressures were higher in women with greater concentrations of cutaneous melanin. In men, blood pressure was not associated with skin color. When we used a subjective assessment of skin color, there was no significant difference in blood pressure between black-skinned Egyptians (predominantly of Nubian descent) and fair-skinned Egyptians for either gender. While the significant relationship in women appeared to be independent of known risk factors for hypertension, residual confounding may explain the association.
Mechanical Strain–Induced Extracellular Matrix Production by Human Vascular Smooth Muscle Cells
Authors: O’Callaghan Christopher J. , Williams Bryan
Published: June 2012

Abstract
—Elevated blood pressure imposes increased mechanical stress on the vascular wall, and mechanical strain is a mitogenic stimulus for vascular smooth muscle (VSM) cells. The role of mechanical forces in regulating the production of noncellular material by VSM cells for VSM cells of human origin remains undefined. We thus investigated the effects of chronic cyclical mechanical strain on extracellular matrix (ECM) protein production by cultured human VSM cells. To simulate a blood pressure of 120/80 mm Hg, human VSM cells were repetitively stretched and relaxed by 10% to 16% of their original length with the Flexercell apparatus. Fibronectin and collagen protein concentrations, matrix metalloproteinase (MMP) activity, and transforming growth factor-β
1
(TGF-β
1
) mRNA expression by human VSM cells were measured in response to mechanical strain. Exposing human VSM cells to 5 days of chronic cyclical mechanical strain increased fibronectin (+48%,
P
<0.01) and collagen (+50%,
P
<0.001) concentrations when compared with cells grown in static conditions. Mechanical strain also increased MMP-2 activity, the predominant matrix-degrading isoform (+11%,
P
<0.05) in human VSM cells, thus strain-induced ECM accumulation was not due to inhibition of ECM protein degradation. Strain also increased TGF-β
1
mRNA expression and the production of a soluble factor that increased ECM protein production. Moreover, a TGF-β–blocking antibody inhibited the effect of strain-conditioned media on matrix production by human VSM cells. These results suggest that chronic cyclical mechanical strain can directly modulate the fibrogenic activity of human VSM cells by inducing ECM protein synthesis and MMP activity. This occurs, at least in part, through mechanical strain–induced TGF-β
1
production, a mechanism that could explain the increased vascular ECM deposition in hypertension.