bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Mechanisms Subserving Central Angiotensinergic Influences on Plasma Renin in Sheep
Authors: McKinley M. J. , McBurnie M. I. , Mathai M. L.
Published: June 2012

Abstract
—The mechanisms and brain regions subserving the suppression of plasma renin concentration caused by intracerebroventricular (ICV) infusion of angiotensin II were studied in sodium-depleted sheep. Infusion of angiotensin II (3 μg/h for 1 hour) into the lateral ventricle reduced plasma renin from 4.3±0.4 to 1.6±0.2 pmol angiotensin I/mL per hour at 1 hour after the commencement of infusion. This change persisted for at least another 90 minutes and was blocked by concomitant ICV infusion of the AT
1
antagonist losartan (1 mg/h). Arterial pressure did not change, but plasma vasopressin secretion was increased. ICV infusion of losartan (1 mg/h) significantly increased plasma renin in sodium-depleted sheep. The reduction of plasma renin concentration in response to either ICV angiotensin II or hypertonic NaCl (0.75 mol/L at 1 mL/h) and the increase in response to ICV losartan was prevented in sheep in which the lamina terminalis of the brain had been ablated. Lesions in the median eminence (MEL), which blocked the increased plasma vasopressin levels, did not prevent suppression of plasma renin in response to ICV angiotensin II. However, bilateral renal denervation largely blocked this inhibition of plasma renin concentration but not the increased plasma renin resulting from ICV infusion of losartan in sodium-depleted sheep. The results show that AT
1
receptors, probably located in the lamina terminalis, mediate a central inhibitory influence of angiotensin II on renin secretion. This inhibition of renin release is probably due to a reduction in activity of renal sympathetic nerves innervating the juxtaglomerular apparatus of the kidney.
Effect of Insulin and Angiotensin II on Cell Calcium in Human Skin Fibroblasts
Authors: Ceolotto Giulio , Valente Roberto , Baritono Elisabetta , Reato Stefania , Iori Elisabetta , Monari Alessandra , Trevisan Roberto , Semplicini Andrea
Published: June 2012

Abstract
—We have recently shown that insulin attenuates angiotensin II–induced intracellular Ca
2+
mobilization in human skin fibroblasts from normotensive subjects. This study was designed to investigate the effects of angiotensin II and the interactions between insulin and angiotensin II on intracellular Ca
2+
mobilization in skin fibroblasts from patients with essential hypertension. Fibroblasts were obtained from 9 normotensives and 18 hypertensives. Spectrofluorophotometric free Ca
2+
measurement was performed in monolayers of 24-hour serum-deprived cells. Resting intracellular Ca
2+
level and angiotensin II–stimulated intracellular Ca
2+
peak were higher in fibroblasts from hypertensives compared with those from normotensives. The effect of acute insulin exposure was evaluated in fibroblasts from hypertensives subdivided on the basis of insulin sensitivity. In insulin-sensitive hypertensives, insulin significantly blunted the effects of angiotensin II on intracellular Ca
2+
response, whereas in insulin-resistant patients, insulin did not modify intracellular Ca
2+
response to angiotensin II. Pertussis toxin, a G
iα
-inhibitor, reduced angiotensin II–stimulated Ca
2+
peak in insulin-sensitive but not in insulin-resistant hypertensives. In conclusion, the effects of angiotensin II on intracellular Ca
2+
mobilization are more pronounced in fibroblasts from hypertensives compared with those from normotensives, and the inhibitory effect of insulin is blunted in insulin-resistant hypertensives by a G
iα
pertussis toxin–sensitive abnormality.
Prostaglandin I
2
/E
2
Ratios in Unilateral Renovascular Hypertension of Different Severities
Authors: Imanishi Masahito , Tsuji Tetsu , Nakamura Satoko , Takamiya Makoto
Published: June 2012

Differences between prostaglandins I
2
and E
2
in their renal synthesis and pathophysiological roles were investigated in unilateral renovascular hypertension of different severities in 18 patients: 6 with mild stenosis (<75% of the diameter) of the renal artery, 7 with moderate stenosis (75% to 90%), and 5 with severe stenosis (>90%). Before and after aspirin administration (10 mg/kg), renal venous and aortic plasma was assayed for 6-ketoprostaglandin F
1α
(instead of prostaglandin I
2
), prostaglandin E
2
, and renin activity. In mild or moderate stenosis, the mean 6-ketoprostaglandin F
1α
level in renal venous plasma from the stenotic side was not different from that from the normal side or from aortic plasma. Prostaglandin E
2
levels and renin activity in such patients were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited prostaglandin E
2
synthesis and suppressed renin release from stenotic kidneys and lowered blood pressure as the renin activity decreased in patients with mild or moderate stenosis. In severe stenosis, levels of 6-ketoprostaglandin F
1α
and prostaglandin E
2
were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited the synthesis of both prostaglandins and suppressed renin release from the stenotic kidney. In patients with unilateral renovascular hypertension with mild or moderate stenosis of the renal artery, prostaglandin E
2
, rather than I
2
, seems to contribute to further acceleration of renin release. Prostaglandin I
2
may increase and participate in further renin release when the stenosis is severe.
Expression Analysis Using Oligonucleotide Microarrays in Mice Lacking Bradykinin Type 2 Receptors
Authors: Monti Jan , Gross Volkmar , Luft Friedrich C. , Franca Milia Anna , Schulz Herbert , Dietz Rainer , Sharma Arya M. , Hübner Norbert
Published: June 2012

We ecently conducted detailed cardiovascular and blood pressure-related phenotypic studies of mice lacking the bradykinin-B
2
receptor and were unable to identify a phenotype despite insensitivity to infused bradykinin. We therefore used oligonucleotide microarray analysis of some 12 000 genes and expressed sequence tags to identify molecular mechanisms that might be involved in compensating for the lack of a functional B
2
receptor in the kidneys of the mice. We identified 2 gene families that may have an impact on cardiovascular regulation and the bradykinin pathway. A water transport channel in the kidney, AQP4, was downregulated in the mice, whereas other members of the gene family did not show differences in expression levels. In addition, a number of serine proteases were upregulated in B
2
receptor-deficient mice. These genes are all located within a gene cluster on mouse chromosome 7. The findings were verified by an independent method. We suggest that microarray analysis has usefulness in elucidating otherwise unappreciated compensatory signaling pathways.
Iron Supplementation Inhibits Cough Associated With ACE Inhibitors
Authors: Lee Sang-Chol , Park Seung Woo , Kim Duk-Kyung , Lee Sang Hoon , Hong Kyung Pyo
Published: June 2012

Dry cough is the most common limiting factor of ACE inhibitor (ACEI) use. Generation of NO, a proinflammatory substance on bronchial epithelial cells, is increased by ACEI. Using a randomized, double-blind, placebo-controlled trial, we tested the hypothesis that supplementing iron, an inhibitor of NO synthase, may reduce the cough associated with ACEI use. The subjects were 19 patients who had developed ACEI-induced cough. After a 2-week observation period, they were randomized to a daily morning dose of either 256-mg ferrous sulfate as a tablet or placebo for a treatment period of 4 weeks. The subjects were requested to fill out a cough diary by scoring the daily severity of the cough on a scale of 0 to 4. Mean daily cough scores for the last week of the observation and treatment period were compared. Changes in blood cell count and serum iron and ferritin concentration between the 2 periods were evaluated. Mean daily cough scores during the observation and treatment periods were 3.07±0.70 and 1.69±1.10, respectively, for the iron group and 2.57±0.80 and 2.35±1.22, respectively, for the placebo group, showing a significant reduction in cough scores with iron supplementation (
P
<0.01) but not with placebo. Three subjects in the iron group showed almost complete cough abolition. No significant changes in laboratory data were observed in either group. In conclusion, iron supplementation successfully decreases ACEI-induced cough. This effect may be related to the decrease of NO generation associated with the inhibition of NO synthase activity in bronchial epithelial cells.
Endogenous Natriuretic Peptides Participate in Renal and Humoral Actions of Acute Vasopeptidase Inhibition in Experimental Mild Heart Failure
Authors: Chen Horng H. , Lainchbury John G. , Matsuda Yuzuru , Harty Gail J. , Burnett, Jr John C.
Published: June 2012

Mild heart failure is characterized by increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11, which degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, urinary ANP excretion, and glomerular filtration rate (
P
<0.05 for OMA versus ACE inhibition). Plasma renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.
Effect of Dietary Sodium Intake on the Responses to Bicuculline in the Paraventricular Nucleus of Rats
Authors: DiBona Gerald F. , Jones S.Y.
Published: June 2012

The tachycardic, pressor, and renal sympathoexcitatory responses produced by administration of the γ-aminobutyric acid antagonist bicuculline into the paraventricular nucleus of the rat are attenuated by the administration of losartan, an angiotensin II type 1 receptor antagonist, into the ipsilateral rostroventrolateral medulla. Therefore, excitatory synaptic inputs to pressor neurons in the rostroventrolateral medulla that arise from activation of the paraventricular nucleus are mediated predominantly by the action of angiotensin II on angiotensin II type 1 receptors. To examine whether such responses are influenced by physiological changes in the activity of the renin-angiotensin system, we measured heart rate, arterial pressure, and renal sympathetic nerve activity responses to the administration of bicuculline in the paraventricular nucleus in normal rats that were fed low-, normal-, and high-sodium diets and in rats with congestive heart failure. The rank order of both plasma renin activity and renal sympathoexcitatory responses was congestive heart failure>low-sodium diet>normal-sodium diet>high-sodium diet. The rank order of pressor and tachycardic responses exhibited a similar trend, but the differences between the groups were smaller and not statistically significant. The results indicate that the renal sympathoexcitatory responses to activation of the paraventricular nucleus are modulated by physiological alterations in the activity of the renin-angiotensin system.
Nitric Oxide Attenuates the Expression of Transforming Growth Factor-β
3
mRNA in Rat Cardiac Fibroblasts via Destabilization
Authors: Abdelaziz Nadia , Colombo Federico , Mercier Isabelle , Calderone Angelino
Published: June 2012

Transforming growth factor-β (TGF-β) has been implicated in the development of interstitial fibrosis in cardiac hypertrophy. NO has been regarded as a potent inhibitor of cardiac fibroblast growth, albeit the modulation of cellular events associated with interstitial fibrosis remains undefined. In this regard, the regulation of TGF-β mRNA expression by the NO donor
S
-nitroso-
N
-acetyl-penicillamine (SNAP) was examined in neonatal rat cardiac fibroblasts. SNAP treatment for 4 hours decreased TGF-β
3
mRNA levels, an effect mimicked by 8-bromo-cGMP. TGF-β
3
mRNA, however, had returned to levels observed in the untreated cells after a 24-hour exposure to SNAP, whereas a decreased expression persisted with 8-bromo-cGMP. In contrast to TGF-β
3
, TGF-β
1
mRNA levels were modestly increased in response to cGMP-generating molecules. The treatment with actinomycin D for at least 8 hours did not appreciably alter TGF-β
3
mRNA levels. By contrast, SNAP treatment caused a rapid decrease of TGF-β
3
mRNA with a half-life of 3.3±0.2 hours, thereby supporting a mechanism of destabilization. The pretreatment with SNAP inhibited angiotensin II-stimulated protein synthesis and the concomitant expression of TGF-β
3
mRNA. These data reveal a disparate pattern of TGF-β
1
and TGF-β
3
mRNA regulation by NO and highlight a novel mechanism of destabilization contributing to the decreased expression of TGF-β
3
mRNA. The modulation of both basal and angiotensin II-stimulated TGF-β
3
mRNA expression provides a mechanism by which NO may influence the progression of interstitial fibrosis.
Effects of Chronic Clonidine Administration on Sympathetic Nerve Traffic and Baroreflex Function in Heart Failure
Authors: Grassi Guido , Turri Carlo , Seravalle Gino , Bertinieri Giovanni , Pierini Alberto , Mancia Giuseppe
Published: June 2012

Abstract—

Congestive heart failure is characterized by a sympathetic activation that is coupled with a baroreflex impairment. Whether these alterations are affected by clonidine is unknown. In 26 normotensive patients age 58.0±1.1 years (mean±SEM) affected by congestive heart failure (New York Heart Association functional class II or III) and treated with furosemide and enalapril, we measured mean arterial pressure, heart rate, venous plasma norepinephrine, and muscle sympathetic nerve traffic (microneurography) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were repeated after a 2-month administration of transdermal clonidine patch (14 patients) or placebo (12 patients) according to a double-blind, randomized sequence. Clonidine caused a slight, nonsignificant reduction in mean arterial pressure and heart rate without affecting exercise capacity and echocardiographically determined left ventricular ejection fraction. In contrast, both plasma norepinephrine and sympathetic nerve traffic were significantly reduced (−46.8% and −26.7%, respectively;
P
<0.01 for both). This reduction was coupled with no change in cardiac and sympathetic baroreflex responses. Transdermal placebo administration for a 2-month period did not affect any of the above-mentioned variables. Thus, in congestive heart failure patients who are undergoing conventional drug treatment, chronic clonidine administration exerts marked sympathoinhibitory effects without adversely affecting cardiac functions and clinical state. Whether this leads to further therapeutic benefits remains to be tested.
Role of Corticotrophin-Releasing Factor in Effects of Leptin on Sympathetic Nerve Activity and Arterial Pressure
Authors: Correia Marcelo L.G. , Morgan Donald A. , Mitchell Jennifer L. , Sivitz William I. , Mark Allyn L. , Haynes William G.
Published: June 2012

Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular α-helical corticotrophin-releasing factor
9–41
(corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin-releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with α-helical corticotrophin-releasing factor
9–41
. Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with α-helical corticotrophin-releasing factor
9–41
. Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions.
Cardioreparation in Hypertensive Heart Disease
Authors: Weber Karl T.
Published: June 2012

Abstract
—

— The normal myocardium is composed of a variety of cells. Cardiac myocytes, tethered within an extracellular matrix of fibrillar collagen, represent one third of all cells; noncardiomyocytes account for the remaining two thirds. Ventricular hypertrophy involves myocyte growth. Hypertensive heart disease (HHD) includes myocyte and nonmyocyte growth that leads to an adverse structural remodeling of the intramural coronary vasculature and matrix. In HHD, it is not the quantity of myocardium but rather its quality that accounts for increased risk of adverse cardiovascular events. Structural homogeneity of cardiac tissue is governed by a balanced equilibrium existing between stimulator and inhibitor signals that regulate cell growth, apoptosis, phenotype, and matrix turnover. Stimulators (eg, angiotensin II, aldosterone, and endothelins) are normally counterbalanced by inhibitors (eg, bradykinin, NO, and prostaglandins) in a paradigm of reciprocal regulation. To reduce the risk of heart failure and sudden cardiac death that accompanies HHD, its adverse structural remodeling must be targeted for pharmacologic intervention. Cardioprotective agents counteract the imbalance between stimulators and inhibitors. They include ACE and endopeptidase inhibitors and respective receptor antagonists. Cardioreparative agents reverse the growth-promoting state and regress existing abnormalities in coronary vascular and matrix structure. ACE inhibition has achieved this outcome with favorable impact on vasomotor reactivity and tissue stiffness. Today’s management of hypertension should not simply focus on a reduction in blood pressure, it must also target the adverse structural remodeling that begets HHD.
Activation and reinactivation of inactive renin in normal human plasma.
Authors: Matsunaga M , Morimoto K , Hara A , Pak C H , Kawai C
Published: June 2012

Various facets of activation of inactive renin by acidification or cold exposure were investigated in normal human plasma. The acid activation obtained by titration was usually less than that by dialysis method, but varied from 41% to 122% of the latter. The acid phase of acid activation accounted for about 70% of the total activation achieved by the combined effects of the acid and alkaline phases on the average, and was not affected by any of the inhibitors for serine, thiol or carboxyl protease, whereas serine protease inhibitors suppressed the activation of both renin and plasma kallikrein in the alkaline phase of acid activation. A different mode of plasma kallikrein activation suggested some difference in the mechanism between the alkaline phase of acid activation and the cryoactivation. A part of cryoactivation of renin was independent of the action of plasma kallikrein. The renin activated by either acidification or cold exposure without concomitant activation of plasma kallikrein was reinactivated by the removal of pH and temperature, but recovered by repeating acidification or cold exposure. When active plasma kallikrein had been produced, it activated inactive renin irreversibly. It appears unlikely that irreversible activation of inactive renin is taking place in the normal circulation where practically no active plasma kallikrein is present.
Nitroprusside-induced vascular relaxation in DOCA hypertensive rats.
Authors: Cohen D M , Webb R C , Bohr D F
Published: June 2012

Vascular responsiveness to nitroprusside and to norepinephrine was examined in two different preparations from DOCA hypertensive and normotensive control Sprague-Dawley rats. The blood-perfused renal vasculatures of DOCA hypertensive rats were significantly more sensitive than those of normotensive controls to the vasodilator action of low doses of nitroprusside. At high doses, responses in DOCA hypertensive and normotensive rats were similar. Since basal "structural" vascular resistances were greater in the hypertensive rats, It is possible that further vasodilation with nitroprusside was impeded more in DOCA-treated than in control rats. Nitroprusside produced a greater degree of vascular smooth muscle relaxation in tail artery strips from DOCA hypertensive rats than in those from normotensive controls. The current study is the first characterization of the effects of a vasodilator in mineralocorticoid hypertension. The two preparations gave divergent results with respect to vascular sensitivity to norepinephrine. When compared with control rats, the DOCA hypertensive rats showed a greater sensitivity to norepinephrine in tail arteries but a lesser renal vascular reactivity. It is evident that one must take a number of variables into consideration when characterizing changes in vascular responses that occur in a given model of hypertension: 1) the region of the vasculature (renal vs caudal artery);2) the level of the arterial tree (conduit vs resistance vessels);3) the technique employed for measurement of vascular changes (smooth muscle contraction vs vascular resistance changes);4) the initial vasoconstrictor tone of the preparation; and 5) the agonist used (nitroprusside vs norepinephrine).
Hypertensinogenic potencies of aldosterone and deoxycorticosterone in the rat.
Authors: Komanicky P , Melby J C
Published: June 2012

Hypertensinogenic potency and other effects of acetate salts of aldosterone (ALA) and deoxycorticosterone (DOCA) were evaluated in 50-day-old mononephrectomized and saline-drinking Sprague-Dawley CD male rats. The steroids were administered by continuous subcutaneous infusion in a dose of 100 microgram/24 hrs by means of Alzet osmotic minipumps implanted subcutaneously. Within 3 weeks of steroid treatment, systolic blood pressure, measured in the tail of conscious animals by a photoelectric cell method at 27 degrees C environmental temperature, increased significantly in ALA rats as compared to that in DOCA rats, which was not different from controls. ALA rats exhibited marked polydipsia, decreased body weight, hypernatremia, hypokalemia, cardiomegaly, and kidney enlargement, whereas DOCA rats exhibited only cardiomegaly when compared with controls. The degree of cardiomegaly in ALA and DOCA rats was statistically much greater than the differences in their respective blood pressure levels when compared to controls. Under the conditions of this study, it is concluded that: 1) the hypertensinogenic potency of ALA is greater than that of DOCA; 2) ALA and DOCA may induce cardiomegaly, independent of their effect on blood pressure; 3) Alzet osmotic minipumps are effective tools for the administration of steroids by continuous infusion.
The storage form of human renal renin.
Authors: Kawamura M , Akabane S , Ito K , Ogino K , Yutani C , Go S , Ikeda M
Published: June 2012

We isolated renin granules from cadaver kidneys using discontinuous sucrose density gradient centrifugation, and investigated the storage form of the renin from these granules. Approximately 23% of the total renin activity in the original homogenate was obtained from the surface phase between 1.6 and 1.7 M sucrose (Fraction 6). Granule renin extracted from the granules in Fraction 6 was separated into active and inactive renin using pepstatin affinity chromatography. Only the active renin had an affinity for pepstatin. The inactive renin, albeit activated by trypsin, was little activated by acidification. The proportion of inactive renin was about 25% of the total granule renin (active renin + inactive renin). Trypsin concentrations over 10 micrograms/ml resulted in a decrease in the renin activity of the trypsin-activated renin, but the enzymatic activity of active renin was decreased by trypsin. With gel filtration, the inactive renin revealed a single peak, and the molecular weight (MW) was 48,000. The active renin had a MW of 44,000. The inactive renin could be activated by trypsin without an apparent change in molecular weight.
Decreased release of norepinephrine in the isolated kidney of the adult spontaneously hypertensive rat.
Authors: Vanhoutte P M , Browning D , Coen E , Verbeuren T J , Zonnekeyn L , Collis M G
Published: June 2012

Renal resistance vessels of the mature spontaneously hypertensive rat (SHR) exhibit an increased reactivity to exogenous norepinephrine, but a normal response to renal nerve stimulation. This difference could be due either to depression of the exocytotic process or to accelerated disposition of the released transmitter. We compared the overflow of norepinephrine in isolated perfused kidneys from adult SHR and normotensive rats. After previous incubation with 3H-norepinephrine, renal nerve stimulation caused smaller increases in the overflow of intact tritiated transmitter and its metabolites in kidneys form SHR than in those from normotensive controls. A similar difference was found when the amounts of endogenous norepinephrine were measured radioenzymatically. The tissue content of norepinephrine was comparable in kidneys from both hypertensive and normotensive animals. The uptake of 3H-norepinephrine was comparable in kidneys from SHR and normotensive controls; cocaine caused a comparable depression of the 3H-uptake in which then explains the normal vasoconstrictor response to renal nerve stimulation despite the increased responsiveness of the vascular smooth muscle cells to norepinephrine.
Experimental aldosterone hypertension in the dog.
Authors: Pan Y J , Young D B
Published: June 2012

Sequential changes in arterial pressure, renal function, body fluid, and electrolyte balance, and several hemodynamic variables were examined during chronic intravenous infusion of aldosterone (14 micrograms/kg/day) in eight conscious dogs maintained on 250 mEq/day sodium and 140 mEq/day potassium intake. Arterial pressure gradually increased and stabilized at 132% +/- 3% (p less than 0.05) of the control value on the 16th day of aldosterone infusion, and cardiac output remained within the normal range. Coinciding with the rise in arterial pressure on the first 2 days of infusion was a marked retention of water and sodium and a rise in extracellular fluid volume and blood volume. Blood volume increased from a baseline value of 64.0 +/- 0.3 ml/kg to 70.7 +/- 1.9 ml/kg (p less than 0.05) on Day 4 and extracellular fluid volume increased from 318 +/- 5 ml/kg to 352 +/- 11 ml/kg (p less than 0.05) on Day 3 of infusion. Both blood volume and extracellular fluid volume remained elevated during infusion. Mean circulatory filling pressure increased from the baseline volume of 9.7 +/- 0.4 mm Hg to an average of 11.7 +/- 0.3 mm Hg (p less than 0.05) during the experimental period. The elevation of mean circulatory filling pressure suggested that this increase may be an essential component in the onset and maintenance of hypertension.
Effect of high and low sodium intake on norepinephrine turnover in the cardiovascular tissues and brain stem of the rabbit.
Authors: Tanaka T , Seki A , Fujii J
Published: June 2012

To assess the relationship between sympathetic nerve function and sodium intake, we examined norepinephrine (NE) turnover in several cardiovascular tissues and the brain stem of rabbits maintained for 3 weeks on high (86 mEQ), normal (14 mEQ), and low (0.2 mEQ/day) sodium diet. None of the diets changed the blood pressure significantly. Plasma renin activity became high in the low sodium group and low in the high sodium group at the end of the treatment. NE turnover was measured from the rate of decline of tissue NE concentration after administration of alpha-methyl-p-tyrosine. Variation of sodium intake exerted opposite effects on NE turnover in the periphery and in the central nervous system; increasing sodium intake caused an increase in NE turnover in the thoracic aorta, mesenteric vein, and left ventricle, and a decrease in the hypothalamus, midbrain, and pons medulla. But in the mesenteric vein, and left ventricle, and a decrease in the hypothalamus, midbrain, and pons medulla. But in the mesenteric artery and abdominal aorta it was not affected by dietary sodium manipulation. The results show the varying influence of sodium balance on the central and peripheral noradrenergic neuron activity.
Increased circulating levels of an endogenous digoxin-like factor in hypertensive monkeys.
Authors: Gruber K A , Rudel L L , Bullock B C
Published: June 2012

An endogenous, immunoreactive digoxin-like factor (endoxin) was measured in the plasma of nonhuman primates with hypertension. Both normotensive and hypertensive rhesus monkeys had levels of endoxin that significantly correlated with their systolic or diastolic blood pressure. Vervet monkeys with experimentally produced chronic Goldblatt hypertension had significantly elevated endoxin, but not plasma renin. These data suggest that increased plasma endoxin may be a contributing factor in the development of hypertension.
Blood pressure, body composition, and fat tissue cellularity in adults.
Authors: Siervogel R M , Roche A F , Chumlea W C , Morris J G , Webb P , Knittle J L
Published: June 2012

While total body mass has been recognized for many years as having a strong positive association with blood pressure, it is not known whether body mass per se is important in this association or if a component of total mass, such as lean body mass or total body fat, is responsible for the relationship. To determine the relative importance of these components, 217 healthy adults unselected with respect to blood pressure or body composition, who were 18 to 49 years of age (X +/- sd = 33.1 +/- 8.9 years) had body density measured by underwater weighing. Body density was used to estimate percent body fat from which lean body mass and total body fat mass were determined. In addition, an adipose tissue biopsy from the gluteal area was made, and average fat cell size was measured using the osmium tetroxide method; fat cell number was then estimated. In both males and females, after adjusting for age, there were highly significant, positive partial correlations (r = 0.2 to 0.3) between measures of blood pressure (systolic, diastolic, and mean arterial) and percent body fat, total body fat mass or fat cell number. No significant correlation existed between lean body mass or fat cell size and any measure of blood pressure. These findings suggest that fat mass as opposed to body mass, per se, may be an important etiological component in elevated blood pressure in adults.
Angiotensin-like immunoreactivity in the brain of the spontaneously hypertensive rat.
Authors: Weyhenmeyer J A , Phillips M I
Published: June 2012

Evidence for the brain renin-angiotensin system being involved in the hypertension of the spontaneously hypertensive rat (SHR) includes central administration of angiotensin II (AII) antagonists and converting enzyme inhibitors that lower blood pressure in SHR. Using the unlabeled antibody enzyme method, we have found a significant difference in the distribution of brain angiotensin in SHR and Wistar-Kyoto controls (WKY). Six rats of each group were perfused with buffered picric acid-paraformaldehyde, and their brains sectioned at 50 and 100 mu. The sections were reacted with a 1:1000 dilution of AII antiserum for 36 hours followed by goat antirabbit immunoglobulin G and rabbit peroxidase antiperoxidase. For controls, preabsorption with AII, arginine vasopressin or preimmune serum were evaluated. The results showed over twice as many cells and fibers staining for AII-like immunoreactivity in SHR. The AII immunoreactive cell bodies were localized, in the order of their relative preponderance, in supraoptic and paraventricular nuclei of the hypothalamus, hippocampus, and cortex. The most prominent demonstration of AII-like immunoreactivity was observed in fiber profiles containing densely stained varicosities, which were present in many neuroanatomical subdivisions of the brain and brain stem including anterior and middle hypothalamus, basal ganglia, thalamus, locus coeruleus, nucleus of the solitary tract, limbic structures, and reticular formation. The increased fiber staining in the SHR was particularly evident in the frontal hypothalamic region, medial preoptic, and stria terminalis. We conclude that the results support the hypothesis of brain AII involvement in hypertension.
Left ventricular hypertrophy and function in high, normal, and low-renin forms of essential hypertension.
Authors: Devereux R B , Savage D D , Drayer J I , Laragh J H
Published: June 2012

To assess the relative importance of the level of blood pressure (BP) and renin profile status as determinants of hypertensive left ventricular hypertrophy (LVH) and dysfunction, we studied, by quantitative echocardiography, 118 hypertensive patients off medication. The 19 high-renin patients were younger (31 +/- 13 years; p less than 0.01) but had hypertension of severity (152 +/- 13/95 +/- 11 mg Hg) similar to the 79 normal-renin patients (42 +/- 14 years; 152 +/- 17/98 +/- 12 mg Hg) and 20 low-renin patients (49 +/- 13 yrs; 157 +/- 17/95 +/- 11 mm Hg). Left ventricular (LV) mass index (normal = 70 +/- 25 g/m2) was similar in the high- (113 +/- 21 g/m2, p less than 0.001), normal = (114 +/- 31 g/m2, p less than 0.001), and low-renin patients (115 +/- 18 g/m2, p less than 0.01). End-diastolic relative wall thickness (nl = 0.32 +/- 0.05) was equally elevated in high- (0.41 +/- 0.09), normal (0.42 +/- 0.08) and low-renin groups (0.41 +/- 0.08) (all p less than 0.001). In the entire population, there was a closer correlation of relative wall thickness with total peripheral resistance (r = 0.54, p less than 0.001) than with mean blood pressure (r = 0.31, p less than 0.05). LV dysfunction (LV fractional systolic shortening less than 26%) occurred only in two high-renin patients, whereas LV fractional shortening was significantly increased in the low-renin subgroup (p less than 0.01). We conclude that the degree of LVH is similar in low-, normal-, and high-renin hypertensives and is proportional to the degree of hypertension, even though the high-renin patients were significantly younger; but that the low-renin patients with similar level of blood pressure, even though significantly older and with a longer duration of hypertension than the other patient groups, manifest increased LV function compared to normals.
Salt excretion and vascular resistance of perfused kidneys of Dahl rats.
Authors: Maude D L , Kao-Lo G
Published: June 2012

We used a cell-free, 5% albumin-containing bicarbonate saline solution to perfuse kidneys of salt-sensitive (S) and salt resistant (R) rats derived from Dahl's original strains. The animals had been maintained on diets whose salt content was either 8% ((+)Na) or 0.4% ((-)Na). On these regimens only S(+)Na rats become hypertensive. Glomerular filtration rate (GFR), urinary sodium excretion (NaE), renal vascular resistance (RVR), and filtration fraction were measured as perfusate pressure (P) was increased in stepwise fashion from the 80-100 to the 140-160 mm Hg range. Pressure-GFR and pressure-natriuresis curves for the S(-)Na kidneys were displaced to the right of R, so that for any given value of P both GFR and NaE were significantly less for S(-)Na than for R kidneys. Kidneys from hypertensive (S(+)Na) animals had even more markedly impaired filtration and salt excretion. Although R and S(-)Na kidneys had nearly the same RVR at the lowest perfusate pressures, only the S kidney showed an autoregulatory rise in RVR as perfusate pressure was increased. Filtration fraction did not change, so the rise in resistance probably reflects chiefly afferent arteriolar constriction. Thus, in comparison with R, perfused S kidneys show an intrinsic defect in salt excretion ascribable to a reduced filtered sodium load. The rightward shift of their pressure-GFR curves may be due to an exaggerated afferent arteriolar vasoconstrictor response to increase in perfusion pressure.
Effect of AV3V lesions on development of DOCA-salt hypertension and vascular Na+-pump activity.
Authors: Songu-Mize E , Bealer S L , Caldwell R W
Published: June 2012

We studied the effects of anteroventral third ventricle (AV3V) lesions on the vascular Na+-pump activity of deoxycorticosterone acetate-salt (DOCA-salt) treated rats. Blood pressures and Na+-pump activity of the isolated tail arteries, measured as ouabain-sensitive 86Rb-uptake, were determined in untreated control rats, DOCA-salt treated rats, rats with AV3V lesions, and rats with AV3V lesions which were treated with DOCA-salt. Control rats receiving DOCA treatment developed higher blood pressures than rats receiving no DOCA treatment. Placement of AV3V lesions prior to administration of DOCA prevented the increase in blood pressure. Vascular Na+-pump activity in the DOCA-treated group was reduced by 20% compared to all other groups. The AV3V lesions prevented the suppression of Na+-pump activity caused by DOCA treatment. Suppression of vascular Na+-pump activity was due to a humoral substance since Na+-pump activity of tail arteries from control rats incubated in plasma from DOCA-salt treated rats was suppressed by 25% when compared to those incubated in control plasma. Our findings support the hypothesis that a circulating pressor substance is at least partially responsible for the development of DOCA-salt hypertension and that the mechanism by which AV3V lesions prevent DOCA hypertension may be through the interruption of secretion, transport, or synthesis of this factor.
Modulation of brain angiotensin-converting enzyme by dietary sodium and chronic intravenous and intracerebroventricular fusion of angiotensin II.
Authors: Mendelsohn F A , Csicsmann J , Hutchinson J S , DiNicolantonio R , Takata Y
Published: June 2012

Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics with the substrate Hip-His Leu, the inhibitors SQ 20,881 and SQ 14,225, and iun its Cl- activation profile. Modification of dietary NaCl intake was associated with marked changes in brain ACE activity. Sodium-loaded rats had lower activity of ACE in hypothalamus, striatum, and midbrain, and higher activity in spinal cord compared to controls. In sodium-restricted rats, ACE was elevated in pituitary and depressed in spinal cord. Chronic intravenous infusion of angiotensin (AII) was associated with a pattern of changes partly resembling sodium loading: ACE was depressed in hypothalamus and striatum but elevated in midbrain. After chronic intracerebroventricular infusion of AII, ACE was elevated in striatum and hippocampus, and depressed in spinal cord; a pattern of changes quite different from those associated with intravenous AII. These results show that ACE in several brain regions is sensitive to dietary sodium intake and support the hypothesis that angiotensin-containing neurons in these areas might be responsive to NaCl status of the animal. The observed changes in brain ACE do not seem to be explained in any simple manner by changes in circulating or central angiotensin II.
Effects of chronic sodium depletion on canine brain renin and cathepsin D activities.
Authors: Brosnihan K B , Smeby R R , Ferrario C M
Published: June 2012

The activities of brain renin and cathepsin D were measured in brain regions of 10 dogs on a normal sodium intake (65 mEq Na+/day) and 10 other dogs placed on a low sodium diet (less than 4 mEq Na+/day) for 21 days and given a diuretic. The purpose of this study was twofold: to assess the effect of sodium depletion on brain renin activity; and to assess in the same regions alterations in brain renin and cathepsin D activities. Sodium depletion caused a ninefold increase in plasma renin activity, hemoconcentration, and hyponatremia. In the presence of marked hyperreninemia, the average cerebral renin activity was reduced significantly; the most pronounced changes occurred in the upper and lower brain-stem regions. Cerebrospinal fluid renin was increased by 30%, but this change was not significant in sodium-depleted dogs. There were no significant alterations in cathepsin D activity whether assessed in total or regional brain areas. These observations support the view that there is an inverse relationship between plasma and brain renin activity in chronically sodium-depleted dogs. Additionally, evidence is provided that brain renin activity is modified independently from cathepsin D activity.
Potentiation of bradykinin by captopril during suppression of prostacyclin synthesis.
Authors: Vandongen R , Tunney A , Barden A , Mahoney D
Published: June 2012

The effect of captopril on blood pressure and on the depressor responses to intravenously administered bradykinin was examined in anesthetized normotensive rats during inhibition of prostaglandin synthesis. The hypotensive action of captopril persisted after treatment with indomethacin in doses that markedly suppressed urinary excretion of the prostacyclin metabolite 6-keto prostaglandin F1 alpha. Captopril markedly potentiated the vasodepressor responses to intravenous bradykinin given by bolus injection or continuous infusion. Neither the magnitude nor the duration of the blood pressure fall were affected by treatment with indomethacin. It is concluded that in the anesthetized rat the hypotensive action of captopril and its augmentation of the depressor response to bradykinin is independent of prostacyclin synthesis.
Pressor factors and cardiovascular pressor responsiveness in lean and overweight normal or hypertensive subjects.
Authors: Boehringer K , Beretta-Piccoli C , Weidmann P , Meier A , Ziegler W
Published: June 2012

Several blood-pressure-regulating factors including exchangeable sodium, blood volume, plasma renin, aldosterone, norepinephrine (NE), and epinephrine (E) levels, urinary catecholamine excretion rates, and cardiovascular responsiveness to infused NE and angiotensin II (AII) were compared among age-matched subgroups of normal subjects (15 with normal weight, 15 with overweight) and patients with essential hypertension (15 with either normal weight, overweight, or obesity). Exchangeable sodium, blood volume, plasma and urinary sodium and potassium, plasma renin, aldosterone and epinephrine levels, and NE or E excretion rates did not differ significantly among the five subgroups. Minimal differences included a slightly higher heart rate in overweight patients than in overweight normal subjects (p less than 0.01) and a tendency for a higher plasma NE in overweight than in normal weight patients. Plasma NE obtained immediately before NE infusion as well as the plasma clearance of NE did not differ among the five subgroups except, however, for a somewhat low NE clearance in obese patients. The NE pressor dose tended to be lower in normal-weight hypertensive than in normal-weight normotensive subjects. No alteration was apparent in overweight or obese hypertensive patients. Pressor responses to AII were similar in the different subgroups. These findings suggest that overweight does not confer a unique aberration in the body sodium-volume state, circulating renin, aldosterone or catecholamines, or cardiovascular responses to NE or AII which result in hypertension.
Sustained blood pressure elevation to lower body compression in pigs and dogs.
Authors: Julius S , Sanchez R , Malayan S , Hamlin M , Elkins M , Brant D , Bohr D F
Published: June 2012

Inflatable suits were constructed for lower body compression in pigs and dogs. The suit for pigs encompassed hindquarters and part of the abdomen, and the smaller suit for dogs compressed only the hindquarters, leaving free the abdominal cavity. In conscious, diazepam-pretreated pigs, the compression lasted 30 minutes; during that period the blood pressure increased 50/38 mm Hg over the baseline. In chloralose-anesthetized dogs, the compression was extended to 3 hours; the blood pressure increase was 44/53 mm Hg. Blood pressure fell to the baseline immediately after decompression in both animals. In both species the substantial blood pressure increase was due to an increase of vascular resistance; this did not induced the expected baroreceptor-mediated bradycardia. In dogs, the blood pressure increase was accompanied by a large increase of plasma norepinephrine (from 179 to 975 pg/ml). To test whether the increase of vascular resistance reflected the mechanical compression of the vessels under the suit, animals were pretreated with trimethaphan. In pigs the trimethaphan substantially decreased the vascular resistance and the blood pressure response. This indicated that a portion of the vasoconstriction occurred in areas outside the suit. Lower body compression is a new model to cause prolonged blood pressure elevation by noninvasive and nonpharmacologic means. The mechanism of the blood pressure elevation requires further investigation.
Mechanisms for the elevation of blood pressure in human renal disease. Preliminary report.
Authors: Brod J , Bahlmann J , Cachovan M , Hubrich W , Pretschner P D
Published: June 2012

Detailed hemodynamic studies were carried out in 99 subjects with chronic nonuremic renal disease and 17 healthy subjects. The earliest hemodynamic abnormality found in normotensive renal patients was a raised circulating blood volume and an increased cardiac output. The blood pressure remained normal as long as the peripheral vascular bed (arteriolar and venous) adjusted to these conditions. When this adjustment ceased, hypertension developed and the blood volume normalized. It is suggested that a disturbed volume-homeostatic function of the kidney, leading to a rise of the circulating blood volume, is the proper starter of hemodynamic events leading eventually to hypertension in chronic parenchymatous renal disease.