bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the Trough-to-Peak Ratio in Parallel-Group Trials
Authors: Staessen Jan A. , Thijs Lutgarde , Bijttebier Geert , Clement Denis , O'Brien Eoin T. , Palatini Paolo , Rodicio José L. , Rosenfeld Joseph , Fagard Robert
Published: June 2012

We explored how in parallel-group trials interindividual variability, correction for placebo effects, and smoothing of blood pressure profiles can be handled in measuring the trough-to-peak ratio in 244 individuals with isolated systolic hypertension (≥60 years) enrolled in the placebo-controlled Systolic Hypertension in Europe Trial. Net treatment effects were computed by subtracting the mean changes from baseline during placebo (n=133) from those during active treatment (n=111). At entry, systolic/diastolic pressures averaged 176/86 mm Hg in the clinic and 149/80 mm Hg on 24-hour ambulatory monitoring. With corrections applied for baseline and placebo, nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d), reduced (
P
<.001) these blood pressure values by 16.6/7.3 and 9.8/4.7 mm Hg, respectively. The net trough-to-peak ratios were first determined from blood pressure profiles (12 hours) with 1-hour precision, synchronized by the morning and evening doses of the double-blind medication. According to the usual approach, disregarding interindividual variability, the systolic/diastolic net trough-to-peak ratios were 0.46/0.40 in the morning and 0.77/0.99 in the evening. In individual subjects, the baseline-adjusted trough-to-peak ratios were nonnormally distributed. We therefore used a nonparametric technique to calculate the net trough-to-peak ratios from the results in individual subjects. In the morning, these ratios averaged 0.25 systolic (95% confidence interval, 0.09 to 0.41) and 0.15 diastolic (95% confidence interval, 0.00 to 0.31) and in the evening, 0.19 and 0.36 (95% confidence intervals, 0.00 to 0.38 and 0.14 to 0.56), respectively. When the blood pressure profiles were smoothed by substituting the 1-hour averages by moving or fixed 2-hour averages or by Fourier modeling, the trough-to-peak ratios remained unchanged after the morning dose (0.20/0.13, 0.20/0.14, and 0.16/0.21, respectively) but tended to increase in the evening (0.32/0.38, 0.28/0.40, and 0.48/0.49). In conclusion, the parallel-group analysis proposed makes it possible for one to correct the trough-to-peak ratio for baseline as well as placebo, to account for interindividual variability, and to calculate a confidence interval for the net trough-to-peak ratio. Accounting for interindividual variability reduces the trough-to-peak ratio. Smoothing affects the individualized net trough-to-peak ratios in an unpredictable way and should therefore be avoided.
Effects of Chronic Arterial Hypertension on Constitutive and Induced Intercellular Adhesion Molecule-1 Expression In Vivo
Authors: Komatsu Shunichiro , Panés Julián , Russell Janice M. , Anderson Donald C. , Muzykantov Vladimir R. , Miyasaka Masayuki , Granger D. Neil
Published: June 2012

Recent reports indicate that bacterial endotoxin (lipopolysaccharide) and cytokines elicit a more profound increase in the surface expression of intercellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells derived from spontaneously hypertensive (SHR) versus normotensive Wistar-Kyoto rats (WKY). Our objective in this study was to characterize and compare in vivo ICAM-1 expression in SHR and WKY under basal conditions and after 5 hours of endothelial cell activation with either lipopolysaccharide (5 mg/kg IP) or tumor necrosis factor-α (TNF-α; 1, 5, and 10 μg/kg IP). ICAM-1 expression was quantified in different tissues by the double-radiolabeled monoclonal antibody technique. When constitutive (baseline) ICAM-1 expression was corrected for endothelial cell surface area, significantly higher values were noted in SHR than WKY but only in splanchnic organs. Lipopolysaccharide and TNF-α elicited significant increases in ICAM-1 expression in all tissues of both WKY and SHR. However, the magnitude of the lipopolysaccharide-induced ICAM-1 upregulation in heart, stomach, skeletal muscle, and brain was significantly lower in SHR than WKY. A similar blunted ICAM-1 upregulation was noted in the stomach of SHR after administration of 5 μg/kg TNF-α. The differences in induced ICAM-1 expression between SHR and WKY do not appear to be due to differences in endothelial cell surface area or plasma glucocorticoid levels. These results suggest that chronic arterial hypertension results in altered ICAM-1 expression on the endothelium, which may contribute to the abnormal inflammatory responses associated with this disease.
Characteristics of Diabetes, Blood Pressure, and Cardiac and Renal Complications in Otsuka Long-Evans Tokushima Fatty Rats
Authors: Yagi Keiko , Kim Shokei , Wanibuchi Hideki , Yamashita Tatsuya , Yamamura Yoshitaka , Iwao Hiroshi
Published: June 2012

To characterize the molecular mechanism of cardiac and renal complications in non–insulin-dependent diabetes mellitus (NIDDM), we examined the gene expression of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new animal model for human NIDDM, at the ages of 14 weeks (prediabetic stage), 30 weeks (NIDDM stage), and 54 weeks (IDDM stage). Tissue mRNA levels were measured by Northern blot analysis. In 14-week-old OLETF rats, cardiac mRNAs for transforming growth factor-β
1
(TGF-β
1
) and extracellular matrix, including collagen types I, III, and IV and laminin, were significantly increased compared with control rats (Long-Evans Tokushima Otsuka rats). Cardiac β-myosin heavy chain (MHC) mRNA of OLETF was increased at 30 and 54 weeks of age, whereas α-MHC mRNA of OLETF was inversely decreased at 54 weeks. Marked perivascular fibrosis was seen in the hearts of OLETF rats from 30 weeks of age. In the kidney of OLETF rats, glomerular TGF-β
1
expression was temporally increased at 30 weeks of age, followed by glomerulosclerosis characterized by mesangial proliferation, thickening of the basement membrane, and nodular lesions. Blood pressure of OLETF rats remained higher than that of control rats from the prediabetic stage to the IDDM stage. Thus, in OLETF rats, cardiac fibrosis–related gene expressions were already enhanced at the prediabetic stage, which supports the involvement of these gene expressions in cardiac perivascular fibrosis. The antithetical change in β- and α-MHC expressions seems to participate in the decreased cardiac contractility seen in diabetes. Furthermore, TGF-β
1
may also contribute to glomerulosclerosis of OLETF rats. OLETF rats seem to be a useful model to study the mechanism of hypertension and cardiac and renal complications in NIDDM.
Aortic Changes in Experimental Renal Failure
Authors: Amann Kerstin , Wolf Bettina , Nichols Cornelia , Törnig Johannes , Schwarz Ute , Zeier Martin , Mall Gerhard , Ritz Eberhard
Published: June 2012

Cardiovascular complications are a well-known feature of chronic renal failure. Increased wall thickness of intramyocardial arterioles and elastic (aorta) and peripheral (mesenteric) arteries is seen even after normalization of blood pressure. It is currently unknown whether such increases result from hyperplasia of vascular smooth muscle cells, hypertrophy, or a combination of both or from an increase in aortic extracellular matrix. Using a recently developed unbiased stereological technique (the dissector), we investigated the aortas of subtotally nephrectomized rats and sham-operated controls after perfusion fixation. We determined aortic wall thickness, cross-sectional area of aortic media, total number of vascular smooth muscle cells per unit aortic length (1 mm), mean cell and nuclear volumes, volume density of elastic fibers, extracellular matrix, vascular smooth muscle cells, and total volumes of these structures per unit of aortic length (1 mm). Blood pressure was not significantly increased in subtotally nephrectomized rats. In contrast, wall thickness, cross-sectional media, total number of aortic vascular smooth muscle cells, and volume of extracellular matrix including collagen were significantly increased after subtotal nephrectomy, whereas cellular hypertrophy was only modest and an increase in elastic fibers did not occur. In conclusion, increased aortic wall thickness in experimental renal failure results primarily from an increase in aortic extracellular matrix. In addition, however, proliferation of aortic vascular smooth muscle cells resulting in cell hyperplasia also contributed to aortic wall thickening to a minor degree. It appears that aortic wall thickening is caused by secretory stimulation of the proliferating vascular smooth muscle cells, resulting in increased matrix production. The nature of the underlying stimulus requires further investigation.
Dietary Salt Intake Modulates Angiotensin II Type 1 Receptor Gene Expression
Authors: Schmid Charlotte , Castrop Hayo , Reitbauer Jürgen , Della Bruna Roberto , Kurtz Armin
Published: June 2012

Abstract
This study aimed to characterize the influence of dietary salt intake on the gene expression of angiotensin II type 1 (AT
1
) receptor subtypes in different organs. Male Sprague-Dawley rats were fed low salt (0.2 mg/g), normal salt (6 mg/g), or high salt (40 mg/g) diets for 5, 10, and 20 days. mRNA levels for the two AT
1
receptor subtypes were determined in adrenal gland, kidney, liver, and lung. In all of the organs examined, with the exception of the adrenal glands, low salt diet led to a transient decrease in the abundance of AT
1A
receptor mRNA but not of AT
1B
mRNA, which reached their nadirs between days 5 and 10 of feeding. In the adrenal gland, in which the AT
1B
receptor is predominant, low salt diet led to a transient increase in the expression of this receptor gene, with a maximum around day 10 of feeding. High salt diet exerted no significant influence on AT
1
receptor gene expression in these organs. These findings indicate that the rate of salt intake, in particular, a reduction of salt intake, significantly influences AT
1
receptor gene expression in an organ-, time-, and subtype-dependent fashion. It appears that AT
1
receptor subtypes are differentially influenced by low salt intake, in that AT
1B
receptor gene expression increases and AT
1A
receptor gene expression decreases in this situation. This differential response of AT
1
receptor gene expression may be relevant for the organism to be able to adapt to a reduction in oral salt intake.
ANP Enhances Bradycardic Reflexes in Normotensive but Not Spontaneously Hypertensive Rats
Authors: Thomas Colleen J. , Rankin Andrew J. , Head Geoffrey A. , Woods Robyn L.
Published: June 2012

Abstract
Baroreflex control of heart rate in spontaneously hypertensive rats (SHR) is defective, largely because of a poor vagal contribution to the reflex. We have demonstrated previously that atrial natriuretic peptide (ANP) enhances reflex bradycardia in normotensive rats through an action on nonarterial vagal afferent pathways. In the present study, we investigated whether ANP could reverse the baroreflex abnormality in SHR. Heart rate reflexes were activated by three different methods in conscious, instrumented SHR and Wistar-Kyoto rats (WKY) in the presence of intravenous infusions of vehicle (saline) or rat ANP (150 ng/kg per minute). Heart rate responses were measured by (1) the steady-state changes in blood pressure after alternating slow infusions (over approximately 15 to 30 seconds) of a pressor (methoxamine) and depressor (nitroprusside) drug (stimulating predominantly arterial baroreceptors), (2) the ramp method of rapid infusion of methoxamine (over <10 seconds; stimulating arterial and cardiopulmonary baroreceptors), and (3) the von Bezold–Jarisch method of activating chemically sensitive cardiac receptors through serotonin injections. ANP enhanced the heart rate range of the arterial baroreflex (steady-state method) by 13±3% in WKY but had no significant effect on the sensitivity or any other parameter of the steady-state baroreflex. When a very rapid rise in blood pressure was elicited by the ramp method in WKY, ANP significantly enhanced baroreflex bradycardia (sensitivity increased by 29±9%,
P
<.05). ANP also enhanced the bradycardia of the von Bezold–Jarisch reflex (by 33±16%,
P
<.05) in WKY. By contrast, ANP did not influence baroreceptor or chemoreceptor heart rate reflex responses in SHR. We conclude that in normotensive rats, ANP facilitates cardiopulmonary bradycardic reflexes. The lack of effect of ANP in SHR may be related to an underlying structural or genetic alteration in their cardiac sensors, perhaps associated with cardiac hypertrophy, that prevents the ANP-induced activation of cardiac sensory afferents, resulting in cardioinhibition.
Placebo-Controlled Biofeedback Blood Pressure Effect in Hypertensive Humans
Authors: Hunyor Stephen N. , Henderson Robyn J. , Lal Saroj K. L. , Carter Norman L. , Kobler Henry , Jones Michael , Bartrop Roger W. , Craig Ashley , Mihailidou Anastasia S.
Published: June 2012

Abstract
The role of biofeedback in blood pressure control remains ill-defined because of nonspecific (placebo) effects, small study numbers, and the technical limitations of continuous pressure feedback. Clarification of its potential is awaited by those seeking a nonpharmacological approach to blood pressure control. This study examines the capability for systolic pressure lowering of 5 mm Hg or more using continuous pressure feedback in a statistical sample of untreated, well-characterized, mildly hypertensive individuals. Subjects were randomized in a double-blind study to active or placebo biofeedback. Placebo consisted of a modified contingency approach, using a partial disguise based on a digital high pass filter with 15 elements. Blood pressure–lowering capability was assessed during two laboratory sessions. Continuous visual feedback resulted in 11 of 28 subjects on active treatment and 12 of 28 on placebo treatment lowering their systolic pressure by 5 mm Hg or more (11±5.6 and 12±8.4 mm Hg, respectively;
P
=NS). Prestudy pressure was well-matched (153±9/97±4 and 154±8/98±4 mm Hg, respectively). An initial small difference in diurnal profile did not change. These findings indicate that among mildly hypertensive individuals, almost half can lower systolic pressure at will for short periods. This capability is independent of the real or placebo nature of the feedback signal. We conclude that there is no specific short-term biofeedback pressure-lowering capability in hypertensive individuals. Further exploration is needed to determine whether specific components of the placebo effect can be delineated, whether personality characteristics influence the response, and whether further biofeedback training can alter the outcome.
Pressure Natriuresis in Salt-Sensitive and Salt-Resistant Sabra Rats
Authors: Gross Volkmar , Lippoldt Andrea , Yagil Chana , Yagil Yoram , Luft Friedrich C.
Published: June 2012

Abstract
Salt-resistant (SBN/y) and salt-sensitive (SBH/y) Sabra rats are a useful model of salt-sensitive hypertension with incompletely explored renal mechanisms. We investigated their pressure-natriuresis curves, with and without deoxycorticosterone acetate (DOCA)–salt treatment. To differentiate between extrinsic neural and hormonal mechanisms and intrinsic renal influences, we performed experiments with neural denervation, adrenalectomy, and infusions of vasopressin, norepinephrine, 17-hydroxycorticosterone, and aldosterone as well as without these maneuvers. In untreated SBN/y without controlled neural and circulating hormonal factors, urine flow and sodium excretion increased from 32 to 95 μL/min per gram kidney weight (gkwt) and from 4 to 17 μmol/min per gkwt, respectively, as renal perfusion pressure was increased from 85 to 146 mm Hg. Renal blood flow and glomerular filtration rate were autoregulated and averaged 7.5 and 1.2 mL/min per gkwt. In untreated SBN/y with controlled neural and circulating factors, pressure-diuresis and -natriuresis curves were shifted toward the right, and renal blood flow and glomerular filtration rate ranged between 4.2 and 9.1 or 1 and 1.3 mL/min per gkwt as perfusion pressure was increased from 99 to 164 mm Hg. In both protocols, values in SBH/y did not differ. DOCA-salt increased blood pressure in SBH/y. In SBH/y without controlled neural and hormonal factors, pressure-diuresis and -natriuresis curves were shifted approximately 20 mm Hg toward the right. Fractional sodium and water excretion curves, renal blood flow, and glomerular filtration rate were shifted rightward in parallel. On the other hand, SBH/y with DOCA-salt and controlled neural and hormonal factors had lower sodium and water excretion rates only at the renal perfusion pressure of 150 mm Hg as well as decreased renal blood flow and glomerular filtration rate compared with DOCA-salt SBN/y. These data suggest that both extrinsic and intrinsic factors are responsible for reduced sodium and water excretory capacity in DOCA-salt SBH/y; however, the extrinsic factors may be more important.
Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients.
Authors: Esler M , Jackman G , Bobik A , Leonard P , Kelleher D , Skews H , Jennings G , Korner P
Published: June 2012

To assess sympathetic nervous system function in essential hypertension, we measured the rates of release to and removal from plasma of the sympathetic neurotransmitter, norepinephrine. In normal subjects, disappearance of tritiated l-norepinephrine from plasma, after infusion to steady state, was biexponential, with t1 1/2 = 2.0 +/- 0.4 minutes (mean +/- standard deviation) and t2 1/2 = 33 +/- 15 minutes. The rapid component of removal seemed to represent neuronal uptake of norepinephrine: the t1 1/2 was lengthened by the selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal uptake blocker, cortisol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction (idiopathic autonomic insufficiency). In eight of 37 hypertensive patients, the t1 1/2 was greater than 2.8 minutes (range, 3.3-6.0 min), longer than in any normal subject; this appears to be presumptive evidence of the existence of defective neuronal norepinephrine uptake. In these patients the rate of spillover of norepinephrine to plasma, of transmitter escaping uptake after release, was 0.73 +/- 0.39 micrograms/m2/min (4.3 +/- 2.3 nmoles/m2/min), higher than in normal subjects, 0.36 +/- 0.14 micrograms/m2/min (2.1 +/- 0.8 nmoles/m2/min) (p less than 0.01). A defect in neuronal uptake of norepinephrine, by exposing adrenergic receptors to high local norepinephrine concentration, may be important in the pathogenesis of blood pressure elevation in some patients with essential hypertension.
Clonidine attenuation of a cardiogenic hypertensive chemoreflex.
Authors: Hageman G R , Urthaler F , James T N , Swatzell R H
Published: June 2012

Clonidine is an antihypertensive agent with a primary action mediated by alpha adrenergic stimulation in the central nervous system, thus inhibiting sympathetic efferent activity. Serotonin activates a cardiogenic hypertensive chemoreflex which induces discharges of sympathetic efferent neurons. The purpose of this study was to determine the effects of intravenous clonidine upon the thoracic sympathetic efferent discharges in chloralose-anesthetized dogs, their peripheral autonomic receptors being blocked with atropine, propranolol, and phentolamine. Efferent nerve traffic was quantified using a Schmitt trigger and Digital PDP8/e computer. Control spontaneous activity (tone) following autonomic blockade was normalized at 100%. Serotonin (100 microgram/ml, 2 ml, left atrium) caused an increase in the reflex efferent sympathetic activity to 192% +/- 16% of control (p less than 0.001). Following clonidine, the tone was decreased to 63% +/- 6% of control, and the reflex sympathetic discharge elicited by serotonin was significantly (p less than 0.001) reduced from 192% to 116% +/- 9% of control tone (before clonidine). The attenuation of the reflexly elicited discharge was significantly (p less than 0.05) greater than the attenuation of the tone. In four dogs that did not receive atropine, the vago-vagal reflex sinus bradycardia induced by serotonin was not affected by clonidine.
Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension.
Authors: Gavras H , Waeber B , Kershaw G R , Liang C S , Textor S C , Brunner H R , Tifft C P , Gavras I
Published: June 2012

Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.
Blood concentration and urinary excretion of captopril (SQ 14,225) in patients with chronic renal failure.
Authors: Onoyama K , Hirakata H , Iseki K , Fujimi S , Omae T , Kobayashi M , Kawahara Y
Published: June 2012

Blood concentration and urinary excretion of captopril following 50 mg oral administration were determined by high-performance liquid chromatography in normal subjects and patients with chronic renal failure. In normal subjects, the maximum blood concentration of the free form of captopril was obtained within 1 hour and was not detectable after 6 hours; 41% of administered captopril was excreted into the urine as free form and metabolites within 2 hours, and 58% within 6 hours. In chronic renal failure patients with an average serum creatinine of 5.1 mg/dl, the absorption constant (Ka), maximum concentration (Cmax), and area under the blood concentration curve (AUC) were not significantly different from those in the normal subjects, but the elimination constant (Ke) and biological half-life (T1/2) showed a significant delay in the disappearance of captopril from the blood (p less than 0.01 respectively). The cumulative amount of urinary excretion of either free-form captopril or its' metabolites was significantly decreased at 2, 4, and 6 hours in chronic renal failure patients (p less than 0.01 or less, respectively). Impairment of kidney function is suggested to be an important factor in the promotion of blood retention of captopril.
Specific changes in hypothalamic alpha-adrenoceptors in young spontaneously hypertensive rats.
Authors: Morris M J , Devynck M A , Woodcock E A , Johnston C I , Meyer P
Published: June 2012

Changes in the activity of hypothalamic and brain-stem adrenergic neurons have been reported in young spontaneously hypertensive rats (SHR) prior to the development of hypertension. We have measured central alpha- and beta-adrenoceptor concentrations in 4-week-old SHR and Wistar-Kyoto (WKY) controls by direct radioligand binding studies using [3H]prazosin (alpha 1), [3H]clonidine (alpha 2), and [125I]iodohydroxybenzlpindolol (beta). The concentration of alpha 2-adrenoceptors was significantly elevated in the hypothalamus of the SHR, 156.9 +/- 10.4 compared with WKY, 119.4 +/- 10.0 fmole/mg protein (n = 7, mean +/- SEM, p less than 0.0125). Alpha 2-adrenoceptor concentrations in both the brain stem and cerebral cortex were similar in the two groups of animals. The increase in hypothalamic adrenoceptors was specific for alpha 2-adrenoceptors, since similar concentrations of alpha 2- and beta-adrenoceptors were found in this region.
Effects of [D-Ala2]-methionine-enkephalin on blood pressure, heart rate, and baroreceptor reflex sensitivity in conscious cats.
Authors: Yukimura T , Stock G , Stumpf H , Unger T , Ganten D
Published: June 2012

Effects of intracerebroventricular (i.c.v) injection of [D-Ala2]-methionine-enkephalinamide (DAME) on blood pressure (BP), heart rate, and baroreceptor reflex sensitivity were studied in conscious cats. DAME was administered at doses between 5 and 100 nmoles. Blood pressure and heart rate increased dose dependently. The sensitivity of the baroreceptor reflex was attenuated for 15 to 60 minutes after DAME administration; this was independent of the BP changes. The effects of enkephalin on BP and baroreceptor reflex were abolished by i.c.v. naloxone. DAME caused pathological changes in the electroencephalogram (EEG) characterized by sharp waves in the hippocampus recordings and a loss of theta activity in the electrocorticogram. Behavioral changes were characterized by decreased physical mobility and anxiousness. These behavioral and EEG changes lasted for a longer period of time than the cardiovascular changes; they were also counteracted by naloxone. It is concluded that DAME produces a centrally mediated vasopressor response and a baroreceptor reflex attenuation and that, with respect to the time course, the effects on the baroreceptor reflex are separated from those on BP behavior and EEG, but not on heart rate. The fact that all effects of enkephalin on the parameters tested in the present experiment were completely antagonized by naloxone suggests that they are mediated by naloxone-sensitive enkephalin brain receptors.
Cation fluxes and Na+-K+-activated ATPase activity in erythrocytes of patients with essential hypertension.
Authors: Swarts H G , Bonting S L , De Pont J J , Stekhoven F M , Thien T A , Van't Laar A
Published: June 2012

Recently it has been claimed that the active potassium influx in erythrocytes of patients with essential hypertension would be increased. In view of the diagnostic and possibly therapeutic potential of this claim, we have determined the Na+-K+ activated ATPase activity and the affinity of the enzyme for Na+, K+, and ATP in membranes isolated from erythrocytes of hypertensive (with and without medication) and normotensive subjects. Subsequently, the active (ouabain-sensitive) sodium and potassium fluxes and their ratios have been determined after treatment of intact erythrocytes either with cold or with p-chloromercuribenzene-sulfonate (PCMBS). Finally, in view of a subsequent claim that the furosemide-sensitive, ouabain-insensitive cation fluxes would be greatly reduced in erythrocytes of patients with essential hypertension, we have determined these fluxes in choline chloride medium containing ouabain with and without furosemide. For none of these parameters has any significant difference between hypertensive and normotensive subjects been found except for a decrease in the ouabain-sensitive K+ influx after cold treatment in hypertensives. This is also true for the hypertensive subjects who had a known hypertensive parent. It is concluded that the results do not support a role of Na+-K+ activated ATPase or the furosemide-sensitive cation carrier in the pathogenesis of essential hypertension, and that ouabain-sensitive and furosemide-sensitive cation flux determinations in erythrocytes do not seem to be useful for the diagnosis of this condition.
Sodium intake alters the effects of norepinephrine on blood pressure.
Authors: Rankin L I , Luft F C , Henry D P , Gibbs P S , Weinberger M H
Published: June 2012

To examine the interactions between sodium balance and the sympathetic nervous system, we studied eight normotensive men after high (800 mEq/day) and low (10 mEq/day) sodium intake. We measured blood pressure (BP), arterial, venous, and urinary norepinephrine (NE) before and during incremental infusion of NE. We found significant direct, linear relationships (p less than 0.001) between the dose of NE infused and arterial and venous NE levels, and with mean arterial BP at both levels of sodium balance. In addition. the sensitivity was greater and the threshold of pressor response to NE as well as the basal concentrations of NE in arterial and venous plasma significantly lower (p less than 0.05) after the high sodium period. These observations expose heretofore unrecognized qualitative and quantitative interactions between sodium balance and NE that are capable of influencing BP in man.
Blunted Blood Pressure Response to Central Sympathoinhibition in Normotensive Blacks
Authors: Lang Chim C. , Stein C. Michael , He Huai B. , Belas Frank J. , Blair Ian A. , Wood Margaret , Wood Alastair J. J.
Published: June 2012

Abstract
Enhanced sympathetic reactivity may predispose blacks to the development of hypertension and may occur because of increased sympathetic stimulation and/or attenuated sympathoinhibition. A potential site for such attenuated sympathetic inhibition may be at the level of central α
2
-adrenergic receptors, which play an important role in the feedback inhibition of norepinephrine release. We used cumulative doses (1, 2, and 3 μg/kg IV) of the centrally acting α
2
-adrenergic agonist clonidine to measure the sensitivity of α
2
-adrenoceptor–mediated sympathoinhibition and the resultant hypotensive response in 8 normotensive blacks and 10 normotensive whites. Sympathetic activity was determined by radioisotope dilution methodology. Basal norepinephrine spillover was similar in blacks (0.80±0.14 μg/min) and whites (0.73±0.19 μg/min,
P
=NS) and after clonidine decreased significantly in both blacks (0.21±0.07 μg/min,
P
<.0001) and whites (0.24±0.06 μg/min,
P
<.0001), with no difference between the groups (
P
=NS). Despite this similar degree of sympathoinhibition, the hypotensive response to clonidine was markedly blunted in blacks, such that mean arterial pressure decreased by only 10% in blacks but by 21% in whites (
P
<.0001). The smaller blood pressure decrement after clonidine in normotensive blacks, in the face of an equal degree of sympathoinhibition, suggests that even when sympathetic tone is decreased to the same level in blacks and whites, normotensive blacks have less reduction in blood pressure than whites, implying that nonadrenergic mechanisms contribute more to blood pressure maintenance in blacks than whites. Whether a similar interethnic difference in response to sympathoinhibition occurs in hypertensive patients is as yet unknown.
Nocturnal Decline in Blood Pressure Is Attenuated by NaCl Loading in Salt-Sensitive Patients With Essential Hypertension
Authors: Higashi Yukihito , Oshima Tetsuya , Ozono Ryoji , Nakano Yukiko , Matsuura Hideo , Kambe Masayuki , Kajiyama Goro
Published: June 2012

Abstract
We investigated the effect of NaCl on the circadian blood pressure rhythm in patients with essential hypertension classified according to the presence or absence of salt sensitivity. We obtained 24-hour noninvasive ambulatory blood pressure measurements in 64 Japanese patients with mild to moderate essential hypertension who ate a low NaCl diet (50 mmol/d) for 1 week, followed by a high NaCl diet (340 mmol/d) for 1 week. Twenty-six patients whose mean blood pressure was increased more than 10% by NaCl loading were classified as salt sensitive. The remaining 38 patients were classified as salt resistant. The nocturnal decline in mean blood pressure was significantly smaller in salt-sensitive patients (8.3±1.0%) than in salt-resistant patients (11.5±0.9%) (
P
<.05) during a high NaCl diet but was similar in both groups during a low NaCl diet. There was no significant difference in the prevalence of the non-dipper pattern between groups on a low NaCl diet, but the prevalence of the non-dipper pattern was significantly higher in salt-sensitive patients than in salt-resistant patients on a high NaCl diet (0.57 versus 0.26, χ
2
=6.4;
P
=.02; odds ratio, 3.82). These findings suggest that the NaCl loading blunted the nocturnal decline in blood pressure in salt-sensitive patients but not in salt-resistant patients.
Intrarenal Determinants of Sodium Retention in Mild Heart Failure
Authors: Volpe Massimo , Magri Paola , Rao Maria A. E. , Cangianiello Sara , DeNicola Luca , Mele Alessandro F. , Memoli Bruno , Enea Iolanda , Rubattu Speranza , Gigante Bruna , Trimarco Bruno , Epstein Murray , Condorelli Mario
Published: June 2012

Abstract
The onset and the mechanisms leading to Na
+
retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na
+
handling in the early or mild stages of CHF, Na
+
balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7±2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d PO). At the end of the high salt diet, in patients with mild HF the cumulative Na
+
balance exceeded by 110 mmol that of normal subjects (F=3.86,
P
<.001). During high salt intake, renal plasma flow and glomerular filtration rate were similarly increased in both normal subjects and mild HF patients. In spite of comparable increases of filtered Na
+
in the two groups, fractional excretion of Na
+
, fractional clearance of free water, and fractional excretion of K
+
(indexes of distal delivery of Na
+
) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na
+
balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na
+
. Our results indicate that a defective adaptation of Na
+
reabsorption in the proximal nephron is associated with Na
+
retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na
+
handling are largely reversed by enalapril.
Characterization of a Sodium-Response Transcriptional Mechanism
Authors: Ruiz-Opazo Nelson , Cloix Jean-François , Melis Maria-Grazia , Xiang Xie Hou , Herrera Victoria L. M.
Published: June 2012

Abstract
On the basis of paradigms in development wherein discrete transcriptional events are pivotal regulatory steps, we tested the hypothesis that transcriptional sodium (Na
+
)–response mechanisms are involved in in vivo Na
+
-induced responses relevant to normal (homeostatic) and pathophysiological (salt-sensitive hypertension) conditions. We used Na,K-ATPase α-subunit genes as molecular probes and the Na
+
ionophore monensin to induce a dose-specific incremental increase in [Na
+
]
i
in rat A10 embryonic aortic smooth muscle cells. RNA blot analysis of rat A10 cells revealed a dose-specific (0.022 to 30 μmol/L monensin) upregulation of α
1
-, α
2
-, and β
1
-subunit Na,K-ATPase RNA levels. Control β-actin and α-tropomyosin RNA levels did not change. With the use of chloramphenicol acetyltransferase (CAT) as reporter gene, CAT assays of rat α
1
[−1288]CAT and human α
2
[−798]CAT promoter constructs exhibited induction of CAT activity in monensin (10 μmol/L)–treated A10 cells compared with untreated A10 cells. Promoter deletion constructs for rat α
1
[−1288]CAT defined a positive Na
+
-response regulatory region within −358 to −169 that is distinct from the basal transcriptional activation region of −155 to −49 previously defined. Similarly, a positive Na
+
-response regulatory region is delimited to within −301 in the human α
2
Na,K-ATPase 5′ flanking region. Analysis of transgenic TgHα
2
[−798]CAT rats demonstrated sodium activation of human α
2
[−798]CAT transgene expression in aorta parallel to observations made in rat A10 aortic tissue culture cells. Southwestern blot analysis of nuclear extracts from monensin (10 μmol/L)–treated and control untreated A10 cells revealed a nuclear DNA binding protein (approximately 95 kD) that is upregulated by increased [Na
+
]
i
. These data provide initial characterization of a transcriptional Na
+
-response mechanism delimiting a positive Na
+
-response regulatory region in two target genes (α
1
and α
2
Na,K-ATPase) as well as detection of a Na
+
-response nuclear DNA binding protein. The in vitro data are corroborated by in vivo experimental and transgenic promoter expression studies, thus validating the biological relevance of the observations.
Congenic Strains for the Blood Pressure Quantitative Trait Locus on Rat Chromosome 2
Authors: Deng Alan Y. , Dene Howard , Rapp John P.
Published: June 2012

Abstract
A quantitative trait locus (QTL) for blood pressure was previously detected by linkage analysis in a region of rat chromosome 2 using segregating populations derived from crosses of the Dahl salt-sensitive (Dahl S) rat with rats of the Wistar-Kyoto (WKY) strain or Milan normotensive strain (MNS). Two congenic strains, S.WKY-D2N35/
Nep
and S.MNS-
Adh
/D2Mit5, have been constructed by replacing a region of chromosome 2 of the Dahl S rat with the homologous region (ie, low blood pressure QTL allele) of either the WKY or MNS rat, respectively. Systolic pressures of congenic strains S.WKY-D2N35/
Nep
and S.MNS-
Adh
/D2Mit5 fed a 2% NaCl diet for 24 days were 44±4.6 and 29±4.5 mm Hg lower, respectively, than that of the comparably treated Dahl S rats. The differences between congenic and Dahl S rats in blood pressure were highly significant (
P
<.001) and were corroborated by significantly (
P
<.001) lower ratio of heart weight to body weight in the congenic strains compared with Dahl S rats. The data from two congenic strains combined unequivocally establish the existence of a blood pressure QTL on rat chromosome 2.
Aging and Severity of Hypertension Attenuate Endothelium-Dependent Renal Vascular Relaxation in Humans
Authors: Higashi Yukihito , Oshima Tetsuya , Ozono Ryoji , Matsuura Hideo , Kajiyama Goro
Published: June 2012

Abstract
Endothelial dysfunction may be related to cardiovascular risk factors, such as aging, hypertension, and atherosclerosis. We investigated whether aging and hypertension independently alter endothelial function in the renal circulation in humans in the absence of abnormalities in lipid and glucose metabolism.
l
-Arginine (500 mg/kg over 30 minutes) was intravenously administered to 33 patients with essential hypertension and 35 normotensive subjects. The
l
-arginine–induced increases in renal plasma flow (10.1±0.8% versus 15.8±0.9%,
P
<.05) and plasma cGMP (53±4% versus 82±5%,
P
<.05) were significantly smaller in patients with essential hypertension than in the normotensive subjects. Multivariate stepwise regression analysis showed that age (
P
<.0002) and the mean blood pressure (
P
<.0001) were independently and negatively correlated with the renal plasma flow response to
l
-arginine. Age (
P
<.002), mean blood pressure (
P
<.0001), and male sex (
P
<.05) were independently correlated with the
l
-arginine–induced increase in plasma cGMP. The peak change in plasma cGMP was significantly correlated with the
l
-arginine–induced increase in renal plasma flow (
r
=.63,
P
<.001). These findings suggest that aging and hypertension may independently impair endothelium-dependent renovascular dilation and that this effect may be caused at least in part by a decrease in nitric oxide production.
Effects of Renin-Angiotensin Blockade on Sympathetic Reactivity and β-Adrenergic Pathway in the Spontaneously Hypertensive Rat
Authors: Laflamme Annik K. , Oster Laurence , Cardinal René , de Champlain Jacques
Published: June 2012

Abstract
As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac β-adrenergic–coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac β-adrenoceptors was significantly lower, and β
2
-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which β
1
-adrenoceptor subtype was dominant. Enalaprilat treatment increased total β-adrenoceptor density, whereas both treatments restored the binding affinity and β
1
- and β
2
-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]–, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC
50
) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of β-adrenergic signaling pathway sensitivity.
Renal Neurogenic Mediation of Intracerebroventricular Angiotensin II Hypertension in Rats Raised on High Sodium Chloride Diet
Authors: Osborn Jeffrey L. , Camara Amadou K.S.
Published: June 2012

Abstract
Chronic elevation of sodium intake may affect the sensitivity of the central nervous system to intracerebroventricular (ICV) angiotensin II (Ang II) infusion. Experiments were conducted to determine the influence of raising Sprague-Dawley rats from 2 to 3 weeks of age on low (5.0 mmol/L per kg food), normal (50 mmol/L per kg food), or high (250 mmol/L per kg food) NaCl diets on renal and cardiovascular responses to low-dose ICV Ang II infusion. At 12 weeks of age, Sprague-Dawley rats were instrumented for chronic study, including brain lateral ventricular cannulation. Artificial cerebrospinal fluid was infused (0.25 μL/min ICV) during control and recovery, whereas Ang II (20 ng/min) was infused for 5 days. During the experiment, respective sodium intakes were infused intravenously over 24 hours. In rats fed high sodium, control mean arterial pressure was 115±2 mm Hg and increased to 132±4 mm Hg by day 5 of ICV Ang II infusion. This increase in arterial pressure was associated with significant (
P
<.05) decreases in sodium excretion, leading to the retention of 5.4±0.6 mmol/L total sodium over the 5 days of Ang II infusion. In rats raised on low and normal sodium intakes from weaning and in 10-week-old rats exposed to a high sodium diet for only 2 weeks, arterial pressure was not increased and sodium was not retained during ICV Ang II infusion at 20 ng/min. In rats raised on the high sodium diet, bilateral renal denervation abolished the arterial hypertension and reduced the sodium retention over 5 days of ICV Ang II infusion. Thus, chronic elevation of sodium intake increases the hypertensive response to low-dose ICV Ang II infusion, which is dependent on intact renal nerves. We conclude that elevated postnatal NaCl intake enhances the pressor sensitivity of the brain to Ang II.
Regulation of Type 1 Angiotensin II Receptor in Adrenal Gland
Authors: Wang Donna H. , Qiu Jingxin , Hu Zhaoyong , Du Yong
Published: June 2012

Abstract
We have previously shown that sodium restriction upregulates the genes encoding angiotensin II receptor (AT
1
) subtypes, AT
1A
and AT
1B
, in the adrenal gland and that this upregulation is mediated by activation of the AT
1
receptor. There are multiple interactions between the renin-angiotensin and the adrenergic nervous systems; thus, we conducted the present experiment to investigate whether low sodium-induced upregulation of adrenal AT
1A
and AT
1B
is modulated by the α
1
-adrenoreceptor. Seven-week-old male Wistar rats were divided into four groups and given normal sodium diet (0.5%, NS), NS+prazosin (3.5 μg · kg
−1
· min
− 1
by osmotic pump), low sodium diet (0.07%, LS), or LS+prazosin. Body weight and mean arterial pressure were not modified over the 2 weeks of treatment (
P
>.05). Pressor responses to bolus injection of the α
1
-agonist phenylephrine were inhibited in both prazosin groups, compared with NS and LS rats (
P
<.05). Adrenal AT
1A
mRNA, determined by Northern blot analysis, was increased in LS (
P
<.05) but not in NS+prazosin (
P
>.05), compared with NS. Prazosin enhanced the LS-induced increase of AT
1A
mRNA (
P
<.05). Adrenal AT
1B
mRNA was increased in both LS and NS+prasozin rats, compared with NS rats (
P
<.05). Prazosin also enhanced the LS-induced increase in AT
1B
mRNA (
P
<.05). Therefore, blockade of α
1
-adrenoreceptor results in an enhancement of LS-induced upregulation of adrenal mRNA for AT
1A
and AT
1B
. These data suggest that the sympathetic nervous system exerts an inhibitory action, via activation of the α
1
-adrenoreceptor, on AT
1A
and AT
1B
gene expression in the adrenal gland during sodium depletion.
Growth-Dependent Induction of Angiotensin II Type 2 Receptor in Rat Mesangial Cells
Authors: Goto Masahisa , Mukoyama Masashi , Suga Shin-ichi , Matsumoto Tsunekazu , Nakagawa Masayo , Ishibashi Rieko , Kasahara Masato , Sugawara Akira , Tanaka Issei , Nakao Kazuwa
Published: June 2012

Abstract
Angiotensin II acts on at least two receptor subtypes, AT
1
and AT
2
. Although the physiological role of the AT
2
receptor is still poorly defined, it may be implicated in inhibition of cell growth, vasorelaxation, and apoptosis. In the present study, to investigate the role of the AT
2
receptor in the kidney and its implication in hypertensive states, we examined its expression using cultured mesangial cells (MC) from normotensive Wistar-Kyoto rats (WKY) and from stroke-prone spontaneously hypertensive rats (SHRSP). Receptor binding assays were performed using a nonselective ligand, [Sar
1
,Ile
8
]angiotensin II, or AT
2
-selective CGP42112A. Binding assays revealed that MC from WKY exhibited both AT
1
and AT
2
receptors, the ratio of which was confluence-dependent. In contrast, MC from SHRSP, whose proliferation activity was much higher than those from WKY, showed only the AT
1
subtype. In receptor binding and Northern blot analyses, expression of the AT
2
receptor of WKY-MC was low in the growing state but significantly induced upon confluence to become abundant in the postconfluent state, whereas that of SHRSP-MC was undetectable in either state. Gene expressions of AT
1A
and AT
1B
receptors were not significantly altered in either strain during the time in culture. These results indicate that the mesangial AT
2
-receptor expression is growth-dependent and suggest a role in the inhibition of MC growth in WKY. Much lower expression of the AT
2
receptor in MC from SHRSP may suggest involvement in their higher proliferation activity and possibly in consequent renal disorders.