bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflections on Telomeres, Growth, Aging, and Essential Hypertension
Authors: Aviv Abraham , Aviv Hana
Published: June 2012

Abstract
Here we review the “telomere hypothesis of cellular aging.” We propose that this hypothesis is relevant to our understanding of the roles of genetics as well as growth and development in the etiology of essential hypertension and its cardiovascular complications. Elements of this hypothesis and the speculations that we make can be directly tested using tissues (cells) obtained from human beings.
Left Ventricular Mass in the Elderly
Authors: Gardin Julius M. , Arnold Alice , Gottdiener John S. , Wong Nathan D. , Fried Linda P. , Klopfenstein H. Sidney , O’Leary Daniel H. , Tracy Russell , Kronmal Richard
Published: June 2012

Abstract
Left ventricular (LV) mass, as estimated from M-mode echocardiography (echo), has previously been shown to be an independent predictor of incident cardiovascular disease morbidity and mortality. We evaluated the relationship at baseline of echo LV mass to relevant cardiovascular disease risk factors and other potential covariates in the Cardiovascular Health Study, multicenter study sponsored by the National Heart, Lung, and Blood Institute of 5201 men and women aged 65 years or older (mean, 73). Two-dimensionally directed M-mode echo LV mass measurements could be obtained in 1357 men and 2053 women (66% of this elderly cohort). Stepwise linear regression analyses of the relationship of echo LV mass to demographic and risk factor, physical activity, electrocardiographic, and prevalent disease variables resulted in a model that explained 37% of the variance for the entire cohort. In order of decreasing importance, factors positively associated with echo LV mass were body weight, male sex, systolic pressure, presence of congestive heart failure, present smoking, major and minor electrocardiographic abnormalities, treatment for hypertension, valvular heart disease, aortic regurgitation by color Doppler, and mitral regurgitation by color Doppler (in men) whereas diastolic pressure, bioresistance (a measure of adiposity), and high-density lipoprotein cholesterol were inversely related to echo LV mass. Although height and weight were both related to LV mass, height added nothing once weight was entered in multiple linear regression analyses. Furthermore, in the multiple regression models, diastolic pressure was inversely and systolic BP positively related to LV mass, with similar magnitudes for their coefficients. In consonance with these findings, pulse pressure was positively related to LV mass in bivariate analyses. Multiple linear regression analyses explained less of the variance for ventricular septal thickness (
R

2

=.13) and LV posterior wall thickness (
R

2

=.14) than for LV mass (
R

2

=.37) and LV diastolic dimension (
R

2

=.27). Intriguing findings in the elderly Cardiovascular Health Study cohort included the presence of pulse pressure as a positive correlate, and high-density lipoprotein cholesterol as an inverse correlate, of LV mass. Longitudinal studies in the Cardiovascular Health Study cohort will help to clarify the importance of demographic, risk factor, and other variables, and changes in these variables, in predicting changes in echo LV mass and its components as well as the prognostic significance of LV mass in the elderly.
Distinct Mechanisms of Modulation of Angiotensin II Type I Receptor Gene Expression in Heart and Aorta
Authors: Wang Donna H. , Yao Aqing , Zhao Huawei , DiPette Donald J.
Published: June 2012

Abstract
The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT
1
) in the thoracic aorta and heart through an Ang II–dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT
1
to GAPDH mRNA in the aorta was significantly higher in RRM (1.85±0.52) compared with sham-operated (0.21±0.04) and RRM+Cap (0.55±0.20) rats. In contrast, the ratio of AT
1
to GAPDH mRNA in the heart was significantly increased in both RRM (1.09±0.23) and RRM+Cap (1.00±0.09) compared with sham-operated (0.34±0.06) rats. Thus, RRM hypertension upregulates AT
1
mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT
1
mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT
1
gene regulation exist; ie, in aorta, an Ang II– or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT
1
mRNA may be pressure dependent.
Time Course Changes of the Mechanical Properties of the Carotid Artery in Renal Hypertensive Rats
Authors: Zanchi Anne , Wiesel Philippe , Aubert Jean-François , Brunner Hans R. , Hayoz Daniel
Published: June 2012

Abstract
Distensibility of the carotid artery is not altered 2 weeks after renal artery clipping despite adaptive vascular hypertrophy related to hypertension. The purpose of this study was to assess arterial wall behavior with hypertension persisting for a longer period. Male Wistar rats were examined 1, 5, 9, and 24 weeks after renal artery clipping (two-kidney, one clip renal hypertension; n=40) or after sham operation (n=39). Mean blood pressure increased significantly to 132±4, 143±4, 153±4, and 144±4 versus 98±2, 107±2, 115±3, and 108±3 mm Hg, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls. Cardiac and vascular hypertrophy increased in parallel and were correlated to mean blood pressure. Wall stress at mean blood pressure did not differ between the hypertensive and normotensive groups (3.79±0.24, 4.60±0.34, 4.49±0.27, and 4.14±0.28 versus 3.15±0.12, 4.14±0.25, 4.80±0.28, and 4.69±0.32 10
3
dyne/cm
2
, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls). Distensibility-pressure data from the two groups fell on a common curve for all study periods. The intrinsic properties of the wall constituents were similar in controls and hypertensive rats at 1 and 5 weeks. However, the arteries became stiffer in the 9- and 24-week hypertensive rats, as illustrated by a shift to higher levels of the incremental elastic modulus–stress curve. Wall stress remains constant at mean blood pressure as a result of the increase in wall tissue mass. With time, even though the distensibility-pressure curve is not shifted downward, the thickened wall becomes stiffer in the hypertensive rats, which may predispose them to accelerated alterations of the wall material.
Sympathoexcitatory Effect of Hypothalamic/ Hypophysary Inhibitory Factor in Rats
Authors: Huang Bing S. , Sancho Jose M. , Garcia-Robles Rafael , Leenen Frans H. H.
Published: June 2012

Abstract
We recorded changes in arterial blood pressure, heart rate, and renal sympathetic nerve activity in response to intracerebroventricular injection of bovine hypothalamic/hypophysary inhibitory factor and ouabain in conscious Wistar rats. Ouabain at 0.3 to 0.6 μg caused dose-related increases in blood pressure, heart rate, and nerve activity (peak increases: 19±2 mm Hg, 42±4 beats per minute, and 48±4%, respectively;
P
<.05 versus basal). These responses were all blocked by central antibody Fab fragments, which bind ouabain and related steroids with high affinity. The inhibitory factor significantly increased blood pressure but decreased heart rate and nerve activity. Dose-dependent increases in blood pressure as well as heart rate and nerve activity were observed when the inhibitory factor was injected after intravenous injection of the vasopressin antagonist
d
-(CH
2
)
5
Tyr-(Me)AVP. Central Fab fragments, however, did not affect these responses. Both ouabain and the inhibitory factor inhibited Na
+
,K
+
-ATPase activity in vitro. Fab fragments blocked this inhibition by ouabain but not by the inhibitory factor. These data indicate that the ouabainlike sympathoexcitatory effect of this factor is masked probably by a potent central effect on vasopressin release. In contrast to rat brain “ouabain,” this factor does not exhibit a high affinity for the Fab fragments, supporting the previous finding that this compound is structurally a nonouabain Na
+
,K
+
-ATPase inhibitor.
Shear Stress Augments Expression of C-Type Natriuretic Peptide and Adrenomedullin
Authors: Chun Tae-Hwa , Itoh Hiroshi , Ogawa Yoshihiro , Tamura Naohisa , Takaya Kazuhiko , Igaki Toshio , Yamashita Jun , Doi Kentaro , Inoue Mayumi , Masatsugu Ken , Korenaga Risa , Ando Joji , Nakao Kazuwa
Published: June 2012

Abstract
Shear stress is known to dilate blood vessels and exert antiproliferative effects on vascular walls; these effects have been ascribed to shear stress–induced upregulation of endothelium-derived vasoactive substances, mainly nitric oxide and prostacyclin. We have demonstrated the significance of C-type natriuretic peptide (CNP) as a novel endothelium-derived relaxing peptide (EDRP) that shares a cGMP pathway with nitric oxide. Adrenomedullin is a recently isolated EDRP that elevates intracellular cAMP as prostacyclin does. To elucidate the possible role of these EDRPs under shear stress, we examined the effect of physiological shear stress on CNP mRNA expression in endothelial cells derived from the human umbilical vein (HUVECs), bovine aorta (BAECs), and murine lymph nodes (MLECs) as well as adrenomedullin mRNA expression in HUVECs. CNP mRNA was stimulated prominently in HUVECs under shear stress of 15 dyne/cm
2
in a time-dependent manner (4 hours, sixfold increase compared with that in the static condition; 24 hours, 30-fold increase). Similar results were obtained in BAECs (4 hours, twofold increase; 24 hours, threefold increase) and MLECs (4 hours, threefold increase; 24 hours, 10-fold increase). Augmentation of CNP mRNA expression that was dependent on shear stress intensity was also observed (5 dyne/cm
2
, 2.5-fold increase of static; 15 dyne/cm
2
, 4.5-fold increase). Increased CNP secretion was also confirmed by the specific radioimmunoassay for CNP. Adrenomedullin mRNA expression in HUVECs increased under shear stress of 15 dyne/cm
2
in a time-dependent manner (4 hours, 1.2-fold increase of static; 24 hours, threefold increase) and shear stress intensity–dependent manner (15 dyne/cm
2
, threefold increase compared with that at 5 dyne/cm
2
). These results suggest that the coordinated augmentation of mRNA expression of these novel EDRPs may constitute shear stress–dependent vasodilator and antiproliferative effects.
Hypothalamic Hypophyseal Inhibitory Factor (HHIF) Increases Intrasynaptosomal Free Calcium Concentration
Authors: Ricote Mercedes , Garcia-Martin Elena , Sancho Jose , Gutierrez-Merino Carlos
Published: June 2012

Abstract
We have isolated from bovine hypothalamic and pituitary tissues a sodium pump inhibitor that is structurally different from ouabain. By mass spectrometric analysis, this purified factor revealed a single unique molecular ion with an accurate mass of 412.277 and a mass spectra different from that of ouabain. It has been previously shown that this factor inhibits the Ca
2+
,Mg
2+
-ATPase of the plasma membrane of synaptosomes. Because Ca
2+
plays a major role in cellular excitability, we carried out a systematic study of the effects of this inhibitor on the Ca
2+
transport processes across the plasma membrane of synaptosomes: We measured ATP-dependent calcium uptake, Na
+
-Ca
2+
exchange, and passive permeability using
45
Ca
2+
and Millipore filtration, chlortetracycline fluorescence, and light-scattering, respectively. This factor inhibits the Na
+
,K
+
-ATPase activity of the synaptosomal plasma membrane vesicles in the same range of concentrations that produced an increase of intrasynaptosomal free calcium, with nearly the same
K
0.5
value. In addition, in this concentration range, this factor stimulated 10- to 11-fold the passive flux of Ca
2+
and 2.5- to 3-fold the Ca
2+
influx via the Na
+
-Ca
2+
exchange in these membranes with respect to control values. Measurements of fluorescence anisotropy showed that in this concentration range, the inhibitor did not significantly change the order parameter (fluidity) of these membranes. These results suggest that besides its known inhibition of the sodium pump, this factor could play a role in the control of Ca
2+
homeostasis by direct modulation of transport systems implicated in the control of intracellular calcium.
Essential hypertension: abnormal renal vascular and endocrine responses to a mild psychological stimulus.
Authors: Hollenberg N K , Williams G H , Adams D F
Published: June 2012

We have assessed the influence of a mild emotional stimulus on arterial blood pressure, heart rate, renal blood flow, plasma renin activity (PRA), and plasma aldosterone concentration in 24 normal subjects, eight of who had a parent with hypertension, and in 15 patients with essential hypertension. A nonverbal IQ test, Raven's Progressive Matrices, was employed as the stimulus. In 11 of the 15 hypertensives, arterial blood pressure rose transiently by 7 mm Hg or more, but in only three of 16 normal subjects (x2 = 7.23, p less than 0.01). Transient moderate increases in heart rate were also more common in the hypertensives (p less than 0.01). Renal blood flow rose in 11 of 16 normal subjects and fell in each of the 15 patients with essential hypertension (x2 = 15.1; p less than 0.005). As opposed to the transient changes in arterial pressure and heart rate, the fall in renal perfusion was sustained. The PRA fell in 10 of the 16 normal subjects with a negative family history and rose in 14 of 15 patients with essential hypertension (p less than 0.005). Changes in plasma angiotensin II concentration and in plasma aldosterone were in accord with the changes in PRA, but plasma cortisol did not change. Both the renal vascular response and the change in PRA were intermediate in normal subjects in whom family history was positive for hypertension. For the entire group of 39 subjects there was statistically significant agreement between the direction of the renal vascular response and the directional change in PRA: renal blood flow rose when PRA fell and fell when PRA rose (p less than 0.005). We conclude that there is an abnormality in the control of both the renal circulation and of renin release in patients with essential hypertension in response to psychological provocation, and that a similar process is present in some normotensive subjects whose parents have hypertension.
Renal sympathetic nerve activity and the exaggerated natriuresis of the spontaneous hypertensive rat.
Authors: Francisco L L , Sawin L L , DiBona G F
Published: June 2012

To evaluate the role of altered efferent renal sympathetic nerve activity in the exaggerated natriuresis of the spontaneous hypertensive rat (SHR), we measured efferent renal sympathetic nerve activity in anesthetized age- and sex-matched SHR and normotensive Wistar Kyoto (WKY) control rats during control and intravenous saline volume expansion. Mean arterial pressure was 40-60 mm Hg higher in SHR than in WKY. During volume expansion, the increment in urinary flow rate (17.5 +/- 3.1 vs 42.8 +/- 8.0 microliters/100 g/min) and sodium excretion (8.1 +/- 1.5 vs 15.2 +/- 2.3 muEq/min) were greater in SHR than in WKY. During control, efferent renal sympathetic nerve activity was 12.2 +/- 0.4 Hz in WKY and 12.0 +/- 0.5 Hz in SHR and fell equally during volume expansion to 5.0 +/- 0.6 Hz in WKY and to 4.0 +/- 0.8 Hz in SHR. Thus, these studies demonstrate that the exaggerated natriuresis of SHR as compared to WKY cannot be attributed to differences in reflex withdrawal of renal sympathetic nerve activity.
Isolation of aldosterone-stimulating factor (ASF) and its effect on rat adrenal glomerulosa cells in vitro.
Authors: Sen S , Shainoff J R , Bravo E L , Bumpus F M
Published: June 2012

A protein fraction has been isolated from normal human urine which upon chronic administration produced hypertension in rats. The hypertension is associated with retention of sodium and increased circulating aldosterone. The protein fraction has been purified to homogeneity, and its molecular weight has been determined to be 26,134 daltons by equilibrium ultracentrifugation. The compound has been identified to be clearly different from ACTH, angiotensin II, and beta-lipotropin. It stimulated aldosterone production from rat glomerulosa cells in vitro in a dose-dependent fashion from 10(-9) to 10(-4)M with a maximum stimulation at 10(-7) where a fourfold increase was obtained during 2 hours of incubation. Removal of some carbohydrate moieties by insoluble neuraminidase caused a twofold increase in aldosterone production in vitro. The protein fraction has been named "aldosterone-stimulating factor" or "ASF." Further studies are in progress to define its physiological role.
Low plasma renin activity in normotensive patients with diabetes mellitus: relationship to neuropathy.
Authors: Fernandez-Cruz A , Noth R H , Lassman M N , Hollis J B , Mulrow P J
Published: June 2012

To determine the effect of diabetes mellitus on the renin-aldosterone system, independent of age, nephropathy, or hypertension, 16 normotensive diabetics with long-term disease (mean duration, 15 years) and no (14) or minimal (2) proteinuria, were compared to nine age-matched, normotensive controls. Plasma renin activity (PRA) measured supine and after 4 hours of quiet ambulation, both on an ad libitum diet and on Day 4 of a 10 mEq low sodium diet, was always lower in the diabetics (31%-56% of control values). After the combined stimulus of sodium depletion and ambulation, PRA was 2.2 +/- 0.4 in the diabetics compared to 3.4 +/- 0.2 ng/ml/hr in controls (p less than 0.025). On the low sodium diet, PRA and the postural response of PRA correlated directly with the degree of autonomic dysfunction as quantitated by the velocity of esophageal peristalsis (r = 0.60, p less than 0.05; r = 0.75, p less than 0.005 respectively), suggesting that autonomic neuropathy was an important factor contributing to low PRA in these patients. No other parameters correlated with PRA. Plasma renin substrate (PRS) tended to be lower in diabetics (1053 +/- 95 vs 1358 +/- 132 ng AI/ml; p less than 0.07) but not sufficiently so to account for the substantial difference in PRA. Furthermore, PRS did not correlate with PRA. Fasting blood sugar, while higher in diabetics (209 vs 96 mg/dl), and creatinine clearance, which was lower (112 +/- 13 vs 78 +/- 4 ml/min; p less than 0.01), also did not correlate with PRA. Other factors, including serum creatinine, serum potassium, urinary aldosterone, blood pressure, and body weight, and the responses of these parameters to sodium depletion, were similar in diabetics and controls. These data implicate visceral neuropathy as a major factor in the hyporeninemia of these diabetics.
Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension.
Authors: Moore T J , Crantz F R , Hollenberg N K , Koletsky R J , Leboff M S , Swartz S L , Levine L , Podolsky S , Dluhy R G , Williams G H
Published: June 2012

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.
Management of the hypertensive patient: a continuing dilemma.
Authors: Alderman M H , Madhavan S
Published: June 2012

The proper management of mild and moderate hypertension remains a matter of considerable professional disagreement. Major clinical and population research has largely been designed to define a level of blood pressure (BP) at which treatment should be initiated. This paper reviews studies of the natural history of hypertension and the findings of intervention trials to determine whether the BP level alone is adequate to identify, diagnose, and predict the future course of hypertensive patients. Observational data suggest that patients defined by mild elevation of BP are a heterogeneous group who do not share a common prognosis. Moreover, intervention trials reveal that not all those at risk of cardiovascular disease will benefit from hypotensive therapy. Thus, BP level alone defines neither the group at risk nor those likely to benefit from BP reduction. It is therefore concluded that the management of each patient with hypertension should be determined on the basis of available clinical, biochemical, and behavioral as well as epidemiological data.
Effect of chronic sodium depletion on cerebrospinal fluid and plasma catecholamines.
Authors: Brosnihan K B , Szilagyi J E , Ferrario C M
Published: June 2012

To test the role of central neurogenic factors in sodium-depleted states, cerebrospinal fluid (CSF) norepinephrine, epinephrine, and dopamine were measured in mongrel dogs first on a normal sodium intake (65 mEq sodium/day) and then on a 21-day regime of low sodium diet (4 mEq/day combined with diuretics). Plasma catecholamines were measured in the same group of dogs. Three weeks of sodium depletion supplemented with diuretics caused a 24-fold increase in plasma renin activity, hemoconcentration, and elevated serum protein concentration. Both plasma and CSF sodium decreased significantly. After sodium depletion, plasma norepinephrine rose 76% but epinephrine and dopamine did not change. The same pattern was observed whether samples were obtained in conscious or anesthetized animals. In CSF, norepinephrine rose 44% during sodium depletion, while epinephrine and dopamine remained unchanged. The CSF norepinephrine was related inversely to the CSF sodium concentration and directly to plasma renin activity. These observations support the view that the combined procedure of restricted dietary sodium intake and diuretic therapy causes alterations in CSF norepinephrine in a direction compatible with possible overactivity of central noradrenergic neurons.
Renal prostaglandin excretion and metabolism in male and female New Zealand normotensive and genetically hypertensive rats.
Authors: Baer P G , Cagen L M
Published: June 2012

Reduced renal 15-hydroxyprostaglandin dehydrogenase (PGDH) activity has been proposed as a cause, subsequent to elevation of intrarenal prostaglandin (PG) E2 levels, of the development or maintenance of high blood pressure (BP) in the New Zealand genetically hypertensive (NZGH) rat. To test this hypothesis, PGDH activity in homogenates of kidneys and lungs and in urine concentration and excretion of PGE2 were determined in male and female NZGH and normotensive control (NZNR) rats. Lung PGDH activities of the four groups were similar. Renal PGDH activity was 50% lower for the male NZGH than for the male NZNR, but for the female rats no difference in renal PGDH activity was found between NZGH and NZNR. In addition, there was a large sex-related difference in renal PGDH activities, values for the female rats being only 5% to 10% of the values for males. Urine PGE2 concentration and excretion were two to five times greater for the female rats than for the males, but did not differ between male NZGH and male NZNR. From these observations, it appears that neither renal PGDH activity nor urine PGE2 levels is associated with hypertension in the New Zealand genetically hypertensive strain of rats.
Hydralazine: effect on contraction mechanics of WKY and SHR rat heart muscle.
Authors: Michael L H , Seidel C L
Published: June 2012

Chronic hydralazine treatment (2 weeks) in 22-week-old normotensive (WKY) and spontaneously hypertensive rats (SHR) significantly lowered the systolic blood pressure in both groups. Left ventricular papillary muscles from nontreated and treated WKY and SHR were placed in an isometric myography, and contractile indices monitored. Nontreated WKY and SHR were not statistically different comparing: tension, maximum contraction and relaxation rates, time to maximum tension, total contraction time, or passive and active length-tension curves. Hydralazine-treated WKY and SHR had significantly reduced tension and maximum rates of tension development and relaxation; passive length-tension characteristics were not altered. Stressing the papillary muscles with increased frequency of electrical stimulation (0.1-2 Hz) did not differentiate the various groups. Significant (p less than 0.05) alteration with isoproterenol (10(-9)-10(-5) M) occurred with the hydralazine-treated WKY, which responded with a greater increase in relaxation rate than the hydralazine-treated SHR. It is suggested that the clinically very useful drug, hydralazine, causes a distinct contractile state alteration in rat myocardium after treatment sufficient to lower SHR blood pressure to a normal range.
Hemodynamic responses to bilateral lesions of the nucleus tractus solitarii in spontaneously hypertensive and normotensive rats.
Authors: Kitamura Y , Ishise S , Pegram B L , Kawamura H , Frohlich E D
Published: June 2012

Systemic and regional hemodynamic responses to bilateral lesions of the nucleus tractus solitarii (NTS) were studied in alpha-chloralose-urethane anesthetized American Wistar rats (NR), Wistar-Kyoto rats (WKY), and spontaneously hypertensive rats (SHR) by microsphere methods. After NTS lesions, arterial pressure rose by virtue of increased total peripheral resistance in each strain. Cardiac output was lower in NR and WKY, but not in SHR. In all strains, vasoconstriction was nonuniformly distributed among the systemic vasculatures: hepatosplanchnic, renal, and carcass (i.e. skin, skeletal muscle, bone, fat) vascular resistances were higher, but cerebral and coronary vascular resistance remained unchanged. There were some differences, however, in regional vascular responses to NTS lesions among these strains: carcass vasoconstriction was predominant in NR; it was less evident in SHR; and the WKY responses were intermediate. These results indicate that, although systemic hemodynamic responses were similar in these strains, and the reflex inhibition of central sympathetic outflow is not evidently deteriorated in SHR, the regional hemodynamics (i.e., hepatosplanchnic and renal vasculatures) in the SHR demonstrated greater arteriolar constriction.
Collagen metabolism and reversal of aortic medial hypertrophy in spontaneously hypertensive rats treated with methyldopa.
Authors: Ehrhart L A , Ferrario C M
Published: June 2012

Collagen synthesis, content, and concentration were determined in the hypertrophied intima media of thoracic aortas from 10-, 15-, and 20-week-old spontaneously hypertensive rats (SHR). Although the rates of aortic collagen synthesis declined with age, the dry weight of the intima media and the total collagen content increased proportionally. Collagen concentration thus remained unchanged. Methyldopa was administered orally to SHR when they were 12 to 15 weeks of age, when their body weight were identical to the untreated group. Blood pressure and the degree of aortic medial hypertrophy, judged by medial dry weight per kilogram body weight, were significantly lower compared with untreated SHR. Collagen synthesis was likewise decreased to a mean rate not significantly higher than age-matched normotensive Wistar-Kyoto controls. This reduction in collagen synthesis, however, was not sufficient to decrease measurably the total collagen content of the aortas compared with untreated SHR. Since medial dry weights were lower in the treated rats, collagen concentration in aortas from SHR given methyldopa for 3 weeks was actually increased. The increase in collagen concentration also suggests that medial hypertrophy was reversed.
Effect of potassium chloride on the blood pressure in two-kidney, one clip Goldblatt hypertensive rats.
Authors: Suzuki H , Kondo K , Saruta T
Published: June 2012

The effects of potassium loading on blood pressure (BP) and the renin-angiotensin-aldosterone system were investigated in two-kidney, one clip Goldblatt hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, and the other, after hypertension had developed. Potassium loading significantly attenuated the development of hypertension, and was also able to abate existing renovascular hypertension. In both studies, potassium loading increased fluid intake and urine volume, which were accompanied by increased excretion of sodium and potassium. In spite of the massive diuretic effect, potassium loading significantly attenuated the increased plasma renin activity (PRA) induced by renal artery constriction, while it further enhanced the increased plasma aldosterone concentration (PAC) in two-kidney, one clip Goldblatt hypertensive rats. There was no significant difference in the values of serum sodium and potassium between the two groups with or without potassium loading. These results suggest that potassium may attenuate the development of hypertension and reduce the elevated BP by diuresis and natriuresis and by suppression of the PRA in two-kidney, one clip Goldblatt rats.
Defect in the excretion of a vasoactive polypeptide fraction A possible genetic marker of primary hypertension.
Authors: Wollheim E , Peterknecht S , Dees C , Wiener A , Wollheim C B
Published: June 2012

A polypeptide fraction isolated from the urine of normotensive subjects lowers the blood pressure (BP) in a rabbit bioassay (mean BP decrease 33.8% +/- 0.6%, SEM). Patients with primary hypertension exhibit reduced or no activity (mean BP decrease 8.8% +/- 1.2%). In contrast, patients with secondary forms of hypertension show activity like normotensives (mean BP decrease 33.4% +/- 1.0%). The results of the bioassay in the two patient groups correlate well with the family incidence of hypertension (68% and 37% for primary and secondary hypertension respectively). Cases with borderline hypertension fall into two groups; a larger one with vasoactivity inthe bioassay and lower family incidence of hypertension; and a smaller group reacting like patients with primary hypertension. Only the latter group may represent an initial stage of primary hypertension. In normotensive children and young men, an inactive fraction was found in 31% and 28% respectively. These inactive groups had twice the family incidence of hypertension compared to the groups with vasoactivity. These results suggest the existence of a possible genetic marker of primary hypertension and may offer the possibility to detect the disease before its manifestation.
Changing sodium intake in children. The Minneapolis Children's Blood Pressure Study.
Authors: Gillum R F , Elmer P J , Prineas R J
Published: June 2012

To assess the effects of modifying dietary sodium intake, 80 school children with blood pressures above the 95th percentile for age and sex but below 130/90 mm Hg at school screening were randomized to a family intervention program or a control group. Twenty children aged 6 to 9 years and their families began a program to modify the family diet toward a goal of 70 mEq sodium per person per day. Adherence was assessed by 3-day food records and urine collections in children and adults. The sodium intakes and blood pressures of the intervention and control group were compared 1 year after randomization. Sodium intake was significantly lower in the intervention group only in the active participants as compared to dropouts and controls (87 vs 130 and 133 mmoles/24 hr). There were no significant differences between the groups in height, weight, or blood pressure.
Effect of age and spontaneous hypertension on the tachyphylaxis to 5-hydroxytryptamine and angiotensin II in the isolated rat kidney.
Authors: De Mey C , Vanhoutte P M
Published: June 2012

The isolated and perfused kidney of the mature spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to 5-hydroxytryptamine, when compared to weight-matched normotensive animals. To evaluate the influence of the duration of the hypertensive state on these differences, the vascular reactivity to 5-hydroxytryptamine was determined in isolated kidneys from age-matched normotensive and spontaneously hypertensive rats of 3.5, 6 and 12 months of age. Responses to increasing doses of 5-hydroxytryptamine were compared. At all ages the responses to the agonist were greater in the SHR than in the control rats. In the normotensive rats, the sensitivity to the monoamine decreased, while the maximal response increased with aging. The vascular reactivity to increasing doses of 5-hydroxytryptamine was not altered by aging in the SHR. There was a significant correlation between the maximal vasoconstrictor response to 5-hydroxytryptamine in the isolated kidneys and the systolic arterial blood pressure (SBP) of the donor rats. Maximal constrictor responses to 5-hydroxytryptamine were repeated at given intervals. The degree of tachyphylaxis was decreased in hypertensive rats compared with normotensive rats at 3.5, and 6 months age. Tachyphylaxis to 5-hydroxytryptamine was depressed by aging in both normotensive and hypertensive rats. By contrast, tachyphylaxis to angiotensin II (AII) was not effected by either age or hypertension. There was no cross-tachyphylaxis between 5-hydroxytryptamine and AII. Lowering the Ca2+-concentration of the perfusate did not affect tachyphylaxis to either 5-hydroxytryptamine or AII. The present experiments indicate that the delayed tachyphylaxis to 5-hydroxytryptamine in the kidneys of SHR is due to a specific alteration of th vascular smooth muscle cells, which may be the consequence of premature aging.
Angiotensin I, II, and III in sheep. A model of angiotensin production and metabolism.
Authors: Fei D T , Scoggins B A , Tregear G W , Coghlan J P
Published: June 2012

The arterial and central venous concentrations of angiotensin I (AI), Val5-angiotensin II ([Val5]AII), and Val5-angiotensin III ([Val5]AIII(2-8)) were quantitatively determined in conscious sheep before and after sodium depletion. All three angiotensins were elevated in blood with progressive sodium loss. During sodium deficiency the arteriovenous concentration ratios (A:V) of AI, [Val5]AII, and [Val5]AIII(2-8) were found to be 0.48 +/- 0.03 (n = 9), 1.30 +/- 0.05 (n = 16), and 1.52 +/- 0.05 (n = 11) respectively. Intravenous infusion of [Val5]AII or [Val5]AIII(2-8) significantly elevated the A:V of respective angiotensins, being 2.09 +/- 0.28 (n = 5) for [Val5]AII and 2.2 +/- 0.37 (n = 6) for [Val5]AIII(2-8). The blood clearance rates of exogenous [Val5]AII and [Val5]AIII(2-8) in sodium-depleted sheep were calculated to be 135 +/- 15 liter/hr (n = 10) and 140 +/- 13 liter/hr (n = 10) respectively. Based on these experimental data, a steady-state model of angiotensin metabolism was constructed. If it is assumed that endogenous arterial blood [Val5]AII and [Val5]AIII(2-8) cleared metabolically at a similar rate as exogenous arterial blood angiotensins, it can be calculated that at steady-state 55% of the arterial [Val5]AII concentration was derived from the peripheral vascular bed. For [Val5]AIII(2-8), 63% of the arterial concentration was derived from the pulmonary circulation. The concentration of [Val5]AIII(2-8) in arterial blood was 42% of [Val5]AII.
Mechanosensitive Cation Channels in Aortic Endothelium of Normotensive and Hypertensive Rats
Authors: Hoyer Joachim , Köhler Ralf , Distler Armin
Published: June 2012

Abstract
In response to humoral and hemodynamic stimuli, vascular endothelium regulates vascular tone by releasing endothelium-derived vasoactive factors. Stretch-activated cation channels have been postulated to act as endothelial mechanosensors that respond to changes in hemodynamic forces. We report the presence of a nonselective (n=98) and K
+
-selective (n=53) stretch-activated channel in rat intact aortic endothelium and isolated aortic endothelial cells. The nonselective channel showed a permeability ratio for Na
+
, K
+
, and Ca
2+
of 1:0.95:0.23 and was completely blocked by 50 μmol/L gadolinium, a blocker of stretch-activated channels. The K
+
-selective channel was selectively permeable for K
+
, with a K
+
-Na
+
permeability ratio of 10.9:1. In whole-cell current recordings, hyposmotic cell swelling induced an increase in cell conductance. The swelling-induced current was completely blocked by 50 μmol/L gadolinium, showing that stretch-activated channels were activated by cell swelling and carry macroscopic cell currents. In a comparative study with normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), the K
+
-selective stretch-activated channel was observed in a 4.4-fold higher density in adult SHR compared with WKY. Also, in adult SHR, the stretch sensitivity of the nonselective channel was nearly twice as high as in WKY. In contrast, channel properties were unchanged in young SHR (5 to 6 weeks old) compared with age-matched WKY. These data suggest that stretch-activated channels are regulated in their sensitivity and density when subjected to increased hemodynamic forces such as in hypertension. Since the channels are capable of acting as endothelial mechanosensors, the altered channel properties might contribute to an altered mechanoreception in hypertension.
Blood Pressures and Cardiovascular Homeostasis in Mice Having Reduced or Absent Angiotensin-Converting Enzyme Gene Function
Authors: Tian Baohong , Meng Qing Cheng , Chen Yiu-Fai , Krege John H. , Smithies Oliver , Oparil Suzanne
Published: June 2012

Abstract
We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/−), and homozygous mutant (−/−) mice for an insertional inactivation of the angiotensin-converting enzyme (ACE) gene (
Ace
in mice,
ACE
in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/− mice but was reduced by 51±4 mm Hg in −/− mice. Although the pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by
Ace
genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/− group and virtually abolished (+1%) in the −/− group. The depressor response to injected bradykinin was significantly enhanced in the +/− and −/− groups compared with the +/+ group.
Ace
expression and ACE activity were directly related to functional
Ace
copy number, and renin and angiotensinogen mRNA levels were inversely related to
Ace
copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the +/+, +/−, and −/− groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one
Ace
copy, which include increased expression of renin, normalize blood pressure in heterozygotes.
Basal Release of Nitric Oxide Is Decreased in the Coronary Circulation in Patients With Heart Failure
Authors: Mohri Masahiro , Egashira Kensuke , Tagawa Tatsuya , Kuga Takeshi , Tagawa Hirofumi , Harasawa Yasuhiko , Shimokawa Hiroaki , Takeshita Akira
Published: June 2012

Abstract
It is unknown whether basal release of endothelium-derived nitric oxide in the coronary artery is altered in heart failure in humans. The aim of the present study was to evaluate the effect of inhibition of nitric oxide synthesis on basal tone of the conduit and resistance coronary arteries in awake patients. Coronary blood flow velocity (Doppler guide wire) and coronary arterial diameter (quantitative coronary angiography) were measured in 14 patients with heart failure caused by nonischemic left ventricular dysfunction (7 idiopathic dilated cardiomyopathy and 7 valvular insufficiency) and 7 patients with normal ventricular function (controls). Intracoronary
N
G
-monomethyl-
l
-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, at graded doses decreased coronary blood flow in both groups. However, the magnitude of flow reduction was smaller in patients with heart failure than in control patients (
P
<.0001). The magnitude of coronary blood flow reduction in response to L-NMMA inversely correlated to indexes of left ventricular contractile function (
P
<.01) but was not affected by the cause of heart failure. Constriction of the large epicardial coronary artery with L-NMMA also tended to be attenuated in patients with heart failure. In summary, vasoconstricting response to L-NMMA was blunted in the coronary resistance artery in heart failure in vivo. These findings suggest that basal release of nitric oxide in the coronary circulation is decreased in patients with heart failure.
The Sympathetic Nervous System Is Involved in the Maintenance but Not Initiation of the Hypertension Induced by
N
ω
-Nitro-
l
-Arginine Methyl Ester
Authors: Sander Mikael , Hansen Jim , Victor Ronald G.
Published: June 2012

Abstract
Studies in anesthetized animals have advanced the theory that there is an important neurogenic component to the hypertension caused by pharmacological inhibition of nitric oxide, but studies in conscious animals have produced conflicting evidence for and against this theory. To try to reconcile the seemingly contradictory data, we hypothesized that the neurogenic component of this hypertension is time dependent such that the sympathetic nervous system is involved primarily in the maintenance, rather than the initiation, of the hypertension. We measured intra-arterial pressure in conscious, unrestrained rats with and without guanethidine-induced sympathectomy during varying durations of intravenous
N
ω
-nitro-
l
-arginine methyl ester (L-NAME). The major new finding is that sympathectomy had no effect on the hypertensive response to bolus injections of L-NAME but in the same rats it produced a greater than 50% attenuation in the hypertension seen after 6 days of continuous L-NAME (change in mean arterial pressure, 23±4 versus 55±4 mm Hg,
P
<.01, sympathectomy versus control). Using 8-hour infusions of L-NAME, we found that 60 minutes was the minimum time required for detecting a sympathectomy-sensitive component of L-NAME–induced hypertension. Furthermore, we demonstrate that the magnitude of this component increases further between 8 hours to 6 days of continuous L-NAME: it accounted for only 18% of the total hypertensive response at 8 hours but 61% after 6 days. From these experiments, we conclude that the importance of the sympathetic system in the pathogenesis of L-NAME–induced hypertension accrues slowly over hours and days, and thus its importance can be overlooked by focusing on the initial phase of the hypertension.
Clonidine and ST-91 May Activate Imidazoline Binding Sites in the Heart to Release Atrial Natriuretic Peptide
Authors: Mukaddam-Daher Suhayla , Lambert Chantal , Gutkowska Jolanta
Published: June 2012

Abstract
It is well established that the antihypertensive drug clonidine acts through specific imidazoline receptors in the brain and kidney to increase diuresis, natriuresis, and kaliuresis. We have previously shown that the effects of clonidine are associated with elevated plasma atrial natriuretic peptide (ANP). Similar to clonidine, ST-91, a clonidine analogue that does not cross the blood-brain barrier, evokes renal responses that are also associated with elevated plasma ANP. The mechanisms of ANP increase elicited by these imidazoline drugs are unclear. Since ANP is primarily released from the cardiac atria, we investigated the direct effect of the imidazoline drugs on ANP release by incubating left and right atrial sections with 10
−6
mol/L ST-91 in the presence and absence of efaroxan, a selective imidazoline I
1
receptor antagonist, for 30 minutes at 37°C. ST-91 significantly stimulated ANP release, and the effect was inhibited by 10
−6
mol/L efaroxan. Further studies using heart perfusion with the imidazoline drugs with and without antagonists over 30 minutes revealed that both clonidine and ST-91 gradually stimulated ANP release. Also, perfusion with these compounds resulted in a gradual decrease in heart rate, but bradycardia was significant only with clonidine. The effects of ST-91 were inhibited by 10
−6
mol/L efaroxan and to a lesser extent by 10
−6
mol/L yohimbine, implying that the actions of ST-91 were mainly mediated by I
1
receptors. On the other hand, the actions of clonidine were inhibited by 10
−5
mol/L efaroxan and by 10
−6
mol/L yohimbine, an α
2
-adrenoceptor antagonist, which may suggest that the actions of clonidine were preferentially mediated by α
2
-adrenoceptors in the heart. These results indicate that the peripheral actions of clonidine are probably mediated by α
2
and imidazoline receptors and may involve direct stimulation of ANP release by the cardiac atria—an effect that may account for the increase in plasma ANP levels and diuresis and natriuresis observed in vivo after administration of clonidine and its analogues.
Role of Natriuretic Peptide Receptor Type C in Dahl Salt-Sensitive Hypertensive Rats
Authors: Nagase Miki , Ando Katsuyuki , Katafuchi Takeshi , Kato Akira , Hirose Shigehisa , Fujita Toshiro
Published: June 2012

Abstract
The natriuretic peptide system is suggested to be involved in the pathogenesis of salt-sensitive hypertension; a recent report indicated that disruption of the atrial natriuretic peptide precursor gene caused salt-sensitive hypertension. However, natriuretic peptide receptor (NPR)-A knockout mice did not show enhanced salt sensitivity of blood pressure. The aim of the present study was to investigate the role of NPR-C, the other receptor for atrial natriuretic peptide, in increased salt sensitivity of blood pressure. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were placed on a 0.3% or 8% NaCl diet for 4 weeks. Blood pressure was elevated by salt loading only in DS rats. RNase protection assay demonstrated that NPR-C transcript level in the kidney was reduced by chronic salt loading in both DR and DS rats, whereas expression of NPR-A and NPR-B was not altered. The reduction of NPR-C mRNA in response to salt loading was enhanced in DS compared with DR rats. In situ hybridization indicated that the salt-induced NPR-C change was attributed mainly to suppressed expression of NPR-C in the podocytes. NPR-C gene expression was regulated by salt loading in a tissue-specific manner; the marked decrease in NPR-C mRNA by salt loading was seen only in the kidney. These data suggest that the exaggerated salt-induced reduction of NPR-C in the kidney of DS rats may play an important role in the pathogenesis of salt hypertension in this animal, possibly related to impaired renal sodium excretion.