bluuebunny/crossref_metadata_2025 huggingface dataset:
Steroidogenic characteristics of a new aldosterone-stimulating factor (ASF) isolated from normal human urine.
Authors: Saito I , Bravo E L , Zanella T , Sen S , Bumpus F M
Published: June 2012

The steroidogenic properties of a glycoprotein fraction (urinary ASF), isolated from normal human urine, were studied in collagenase-dispersed rabbit adrenal capsular cells in 1) define the requirements for its steroidogenic activity, and 2) assess its site and mode of action. When incubated with adrenal cell suspension at 37 degrees C for 2 hours, urinary ASF induced dose-related increases in both aldosterone and corticosterone production. However, urinary ASF was less potent (ED50 = 10(-9) M) than either angiotensin II (ED50 = 8 x 10(-11) M) or ACTH (ED50 = 4 x 10(-11) M). Increases in cyclic AMP accompanized the steroidogenic response to ACTH but not to either urinary ASF or AII. Deprivation of potassium in incubation media or the addition of ouabain (1 mM) during incubation completely inhibited the steroidogenic response to either urinary ASF, ACTH, or AII. Like ACTH and AII, urinary ASF increased conversion of corticosterone to aldosterone. Specific competitive antagonist of AII (Sar1, Thr8, AII) and ACTH ([I1e9]ACTH1-24) did not prevent the ASF-induced increase in aldosterone production. These results suggest that urinary ASF is readily distinguishable from ACTH. Although it shares similar steroidogenic properties with AII, the inability of AII antagonist to block its effects suggests that it acts at a separate receptor site.
Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.
Authors: Meier A , Weidmann P , Grimm M , Keusch G , Glück Z , Minder I , Ziegler W H
Published: June 2012

The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 +/- 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p less than 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.
Cerebrospinal fluid and plasma dopamine-beta-hydroxylase activity in human hypertension.
Authors: Cubeddu L X , Davila J , Zschaeck D , Barbella Y R , Ordaz P , Dominguez J
Published: June 2012

Cerebrospinal fluid (CSF) and plasma dopamine-beta-hydroxylase (DBH) activity was measured in 22 normotensive (NT), 31 essential hypertensive (EH), and 11 renal hypertensive (RH) patients. Although no differences were observed in their plasma DBH, the mean CSF-DBH activity and specific activity of EH were significantly lower than those of NT and RH patients. Very low CSF-DBH (less than 0.15 units/ml of CFS or less than 0.5 units/mg of CSF protein) was found only in EH (26% of EH). Of the 31 EH patients, 19(60%) had CSF-DHB activities lower than 0.5 units/ml, whereas only 5 of 22 NT (23%) and no RH fell within this range. Nevertheless, 20% of EH, 55% of NT, and 40% of RH patients had CSF-DBH activities above the mean value for NT (less than 0.9 units/ml). NT subjects with very low plasma DBH (less than 50 units/ml) had CSF-DBH activities that fell within normal range. With the exception of these subjects, the specific activity of CSF-DBH was always lower than that of the plasma enzyme. The concentration of albumin, alpha 1, beta, and gamma globulins was measured in plasma and CSF obtained from the last five NT, four EH, and two RH patients. A positive linear relationship was obtained when the log of the plasma/CSF concentration ratio for these proteins was plotted against their molecular weight. Similar slopes and intercepts were obtained for these patients, suggesting that no major differences seem to exist in their blood-brain-barrier permeability to proteins. The results suggest that measurements of CSF-DBH could be of help in the differential diagnosis of human hypertension and in the neurochemical characterization of EH. If CSF-DBH reflects central noradrenergic activity, its reduction might indicate the existence of a central catecholaminergic defect in a subgroup of EH patients.
Effect of cross-transplantation on normotensive and spontaneously hypertensive rat arterial muscle membrane.
Authors: Campbell G R , Chamley-Campbell J , Short N , Robinson R B , Hermsmeyer K
Published: June 2012

Transplantation of arteries into the anterior eye chamber of rats for 8 weeks was used to test the hypothesis that the neurohumoral environment is important in establishing the altered membrane potential (observable during electrogenic ion transport inhibition) of vascular muscle in hypertension. When caudal arteries from 12- to 16-week-old spontaneously hypertensive rats (SHR) or genetically matched Kyoto-Wistar normotensive rats (KNR) were transplanted into the opposite strain, there was no change in the transport inhibited membrane potential (Em) of the arterial muscle cells from that found in freshly excised donor arteries. However, when caudal arteries from 2-week-old animals were transplanted into the anterior eye chamber, the arteries always developed the appropriate Em for the host animal. In other words, a genetically KNR artery developed the Em of an SHR artery in an SHR host; conversely, a genetically SHR artery developed the Em of a KNR artery in the KNR host. These results provide evidence that: 1) the differences between th Em of caudal arteries from SHR and KNR are not inherent in those muscle cells; 2) the change in Em is triggered in young animals preceding development of hypertension, but not after hypertension is established; and 3) the Em alteration of the caudal artery is independent of structural changes that occur in the artery as a result of increased blood pressure (because KNR transplants were not connected in series with the host anterior eye chamber vasculature and subject to the elevated blood pressures). We conclude that the arterial muscle cells up to a certain age respond to an external factor that regulates their Em and presumably their sensitivity to vasopressor agents.
Acute and chronic intrarenal alpha- and beta- adrenergic receptor stimulation of renin release in the conscious dog.
Authors: Ayers C R , Katholi R E , Carey R M , Yancey M R , Morton C L
Published: June 2012

The effect of continuous intrarenal infusion of norepinephrine, isoproterenol, and methoxamine on renin release was studied in the uninephrectomized conscious dog. Chronic intrarenal infusion of norepinephrine produced a biphasic curve of plasma renin activity (PRA) and a sustained 25 mm Hg increase in mean arterial pressure (MAP). The initial increase in PRA peaked at 3 hours, after which PRA returned to control levels. Alpha- or beta-adrenergic antagonists did not attenuate the initial rise in PRA. The PRA increased again after 48 hours of chronic intrarenal norepinephrine infusion and remained elevated thereafter. The second rise in PRA was increased by 30% with alpha-adrenergic blockade. Chronic intrarenal isoproterenol administration produced a similar increase in PRA, which peaked at 3-5 hours and then returned to control levels. In contrast to norepinephrine, chronic isoproterenol administration did not result in a second increase in PRA. At the end of the chronic isoproterenol infusion period, beta-adrenergic receptor refractoriness was demonstrated, as PRA did not increase significantly in response to a fourfold increase in the dose of isoproterenol. An increase in PRA was produced by acute intrarenal infusion of methoxamine. This increase in PRA was blocked by phentolamine, suggesting a vascular alpha-adrenergic receptor-mediated release of renin.
Endothelin-1–Induced Vasopressor Responses in Essential Hypertension
Authors: Kaasjager Karin A. H. , Koomans Hein A. , Rabelink Ton J.
Published: June 2012

Abstract
The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5±0.4 to 11.6±1.0 pmol/L (
P
<.05). Blood pressure rose by approximately 10 mm Hg (
P
<.05). Cardiac index decreased by 21±2%, whereas calculated systemic vascular resistance increased by 27±6% (
P
<.05). Renal blood flow decreased from 1051±94 to 707±60 mL/min at the end of the ET-1 infusion (
P
<.05), and calculated renal vascular resistance increased from 118±19 to 189±19 mm Hg·min/L (
P
<.05). Sodium excretion decreased from 227±39 to 111±15 μmol/min (
P
<.05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119±132 to 701±75 mL/min,
P
<.05) and increased renal vascular resistance (from 111±16 to 187±28 mm Hg·min/L,
P
<.05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1–induced fall in renal blood flow (from 1088±93 to 907±68 mL/min) and increase in renal vascular resistance (from 105±9 to 133±10 mm Hg·min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (
P
<.05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1.
Safety of Nifedipine in Patients With Hypertension
Authors: Stason William B. , Schmid Christopher H. , Niedzwiecki Donna , Whiting Gregory W. , Luo Donghan , Ross Susan D. , Chalmers Thomas C.
Published: June 2012

Abstract
Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading “hypertension” and the text word “nifedipine” to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (
P
=.02 for definitive events and
P
=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.
Plasma Epinephrine and Norepinephrine Concentrations of Healthy Humans Associated With Nighttime Sleep and Morning Arousal
Authors: Dodt Christoph , Breckling Ulrike , Derad Inge , Fehm Horst Lorenz , Born Jan
Published: June 2012

Abstract
We assessed the activity of the sympathetic nervous system during undisturbed nocturnal sleep and periods of wakefulness directly before and after sleep in healthy young men. Changes induced by periods of rapid eye movement and by morning awakening, both periods reported to demonstrate an enhanced risk for the onset of cardiovascular diseases, were of particular interest. In 13 healthy men (age, 18 to 35 years), blood for determination of epinephrine and norepinephrine was drawn every 7 minutes between 9:30
pm
and 8:30
am
with the subjects resting in a strictly horizontal position. Lights were switched off at 11
pm
until awakening at 7
am
. At 8:30
am
, subjects stood up and a final blood sample was drawn. Sleep was monitored somnopolygraphically, and heart rate and blood pressure were continuously measured. Average epinephrine but not norepinephrine concentrations were significantly lower during nocturnal sleep than during wakefulness before and after sleep. In parallel, heart rate and blood pressure declined significantly during sleep. During rapid eye movement sleep, both epinephrine and norepinephrine concentrations were significantly lower than during sleep stages 1 and 2 and slow-wave sleep. Whereas epinephrine concentrations gradually began to increase after morning awakening, norepinephrine levels were not significantly enhanced. However, standing up at the end of the experiment sharply increased norepinephrine concentrations by 180%, whereas epinephrine levels were less enhanced (46%) by the change of body position. This study suggests that the decrease in the activity of the sympathoadrenal branch of the sympathetic nervous system is probably due to an entrainment to the sleep-wake cycle, whereas the low activity of the noradrenergic branches depends mainly on horizontal body position during nocturnal sleep. The activities of the sympathoadrenal and noradrenergic branches of the sympathetic nervous system seem to be downregulated during rapid eye movement sleep. Awakening itself selectively enhances epinephrine levels. Subsequent orthostasis activates both the sympathoadrenal and, most prominently, the noradrenergic branches of the sympathetic nervous system.
Prolonged Reduction of High Blood Pressure With Human Nitric Oxide Synthase Gene Delivery
Authors: Lin Kuei-Fu , Chao Lee , Chao Julie
Published: June 2012

Abstract
Endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. We explored the effect of a continuous supply of human endothelial NO synthase (eNOS) on the blood pressure of spontaneously hypertensive rats (SHR) by somatic gene delivery. A DNA construct containing the human eNOS gene fused to the cytomegalovirus promoter/enhancer was injected into SHR through the tail vein. A single injection of the naked eNOS plasmid DNA caused a significant reduction of systemic blood pressure for 5 to 6 weeks in SHR, and the effect continued for up to 10 to 12 weeks after a second injection. The differences were significant from 2 to 12 weeks postinjections (n=6,
P
<.01). In a separate experiment,
l
-arginine, the substrate of eNOS, was supplied in drinking water at a concentration of 7.5 g/L for 11 weeks after eNOS gene delivery. A maximal blood pressure reduction of 21 mm Hg in SHR was observed with eNOS DNA compared with that of control SHR injected with vector DNA (181.9±1.46 versus 202.7±2.79 mm Hg, mean±SEM, n=6,
P
<.01). Human eNOS gene delivery induces significant increases in urinary and aortic cGMP levels and urinary and serum nitrite/nitrate content (
P
<.05), while no significant differences in body weight, heart rate, water intake, food consumption, or urine excretion were observed. These results indicate that somatic delivery of the human eNOS gene induces a prolonged reduction of high blood pressure and raises the potential of using eNOS gene therapy for hypertension and cardiovascular diseases.
Reduced Plasma Concentrations of Nitrogen Oxide in Individuals With Essential Hypertension
Authors: Node Koichi , Kitakaze Masafumi , Yoshikawa Hiromichi , Kosaka Hiroaki , Hori Masatsugu
Published: June 2012

Abstract
Patients with essential hypertension exhibit blunted endothelium-dependent vasodilator responses, which may be largely attributable to reduced bioactivity of nitric oxide (NO). Therefore, we measured the end product of NO, nitrate plus nitrite (nitrogen oxide), and examined the relationship between the degree of hypertension and plasma nitrate plus nitrite levels in patients with essential hypertension. The combined plasma concentration of nitrate plus nitrite, end products of NO metabolism, was reduced in individuals with essential hypertension relative to that in control subjects (15.7±1.1 versus 22.8±1.4 mmol · L
−1
,
P
<.001); individuals with borderline hypertension showed values that were intermediate between those of the other two groups (18.2±1.2 mmol · L
−1
,
P
<.001). The plasma nitrogen oxide concentration showed significant inverse correlations with both systolic and diastolic blood pressures. The basal concentration of nitrogen oxide in the plasma was reduced, at least in the peripheral circulation, in individuals with essential hypertension.
Angiotensin-Converting Enzyme Gene Polymorphism Adds Risk for the Severity of Coronary Atherosclerosis in Smokers
Authors: Hibi Kiyoshi , Ishigami Tomoaki , Kimura Kazuo , Nakao Masayuki , Iwamoto Tamio , Tamura Kouichi , Nemoto Toyoji , Shimizu Tomoaki , Mochida Yasuyuki , Ochiai Hisao , Umemura Satoshi , Ishii Masao
Published: June 2012

Abstract
To investigate the relation between the angiotensin-converting enzyme (ACE) gene polymorphism and acute coronary syndromes with respect to environmental factors, we analyzed the association of genotype with the coronary angiographic findings of patients with acute myocardial infarction or unstable angina pectoris, and we examined the linkage of each genotype with established risk factors for coronary artery disease. We determined the ACE genotype in 152 Japanese patients with acute coronary syndromes and 399 healthy individuals. The genotype distributions were not different between the two groups (
P
=.74, χ
2
test). In the former group, coronary angiograms were evaluated by criteria based on the number of diseased vessels, the number of stenotic lesions (≥50%), and the relative abnormal arterial portion (extent index). Although the number of stenotic lesions was higher in patients with the
DD
genotype than in those with the
ID
or
II
genotype (
P
=.006), there were no differences in the number of diseased vessels or the extent index. When only smokers were analyzed, the number of diseased vessels (
P
=.032), number of stenotic lesions (
P
=.003), and extent index (
P
=.019) were all higher in patients with the
DD
genotype than in those with the
ID
or
II
genotype. In contrast, these differences in the respective parameters did not exist in nonsmokers. The results indicate smoking-associated effects of the ACE genotype on the severity of coronary atherosclerosis.
Overweight and Hypertension
Authors: Arroyo Pedro , Fernandez Victoria , Avila-Rosas Hector
Published: June 2012

Abstract
Data of the 1992-1993 Mexican Survey of Chronic Diseases in the Urban Adult Population were analyzed to investigate the effects of age and sex on the association between overweight and hypertension. Blood pressure, body weight, and height were measured in a group of 13 945 Mexicans aged 20 to 69 years living in towns and cities larger than 15 000 people. Hypertension was defined following the recommendations of the Joint National Committee for Detection, Evaluation, and Treatment of High Blood Pressure-V. Overweight was defined following the recommendations of the National Institutes of Health Consensus on Health and Obesity. The prevalence of types of hypertension was higher in men than in women, particularly in the groups of 20 to 39 years of age. Cross-classification of subjects according to the presence of hypertension and overweight confirmed the association between both variables. The odds ratio and 95% confidence intervals indicated that overweight was associated with systolic and diastolic hypertension and with isolated diastolic hypertension in women and, to a lesser extent, in men. This association was not found in the 60- to 69-year group in both sexes. Overweight did not show significant association with isolated systolic hypertension in both sexes. Results of a multiple logistic regression analysis of overweight on hypertension, controlling for age and sex, were consistent with these findings. It is suggested that other factors, independent of overweight, explain the observed gender-specific differences in the prevalence of hypertension in younger age groups. The hormonal environment of young women is one of the mentioned factors modifying the prevalence of hypertension in this group of the Mexican urban adult population.
Direct Magnetic Resonance Determination of Aortic Distensibility in Essential Hypertension
Authors: Resnick Lawrence M. , Militianu Daniela , Cunnings Amy J. , Pipe James G. , Evelhoch Jeffrey L. , Soulen Renate L.
Published: June 2012

Abstract
To investigate the contribution of vascular compliance to essential hypertension (EH), we developed magnetic resonance imaging (MRI) techniques to directly measure aortic distensibility (AD) in the ascending and descending thoracic and abdominal aorta of fasting normal (n=10) and EH (n=20) subjects. These results were compared with concurrent MR-based measurements of left ventricular mass index (LVMI) and abdominal subcutaneous and visceral fat and with
31
P-MR spectroscopic measurement of in situ intracellular free magnesium levels (Mgi) in brain and skeletal muscle. Aortic distensibility in EH was consistently and significantly reduced at all measured sites (2.5±0.4, 2.2±0.4, 2.3±0.4 versus 7.0±1.6, 5.1±0.3, 7.3±0.8 mm Hg
−1
×10
−3
,
P
<.05), as was Mgi in the brain (284±22 versus 383±34 μmol/L,
P
<.05) and skeletal muscle (397±10 versus 527±36 μmol/L,
P
<.05). For all subjects, systolic blood pressure (
r
=−.662,
P
<.0001) and LVMI (
r
=−.484,
P
<.01) were inversely related to AD. AD and brain Mgi were inversely related to age (AD,
r
=−.792,
P
<.0001; brain Mgi:
r
=−.673,
P
<.05). AD was inversely related to fasting blood glucose (
r
=−.413,
P
<.05) and to abdominal visceral fat (
r
=−.416,
P
<.05) but not to body mass index (BMI:
r
=−.328,
P
=NS) or subcutaneous fat (
r
=−.157,
P
=NS). AD was also significantly and positively related to in situ Mgi, both in the brain and skeletal muscle (brain:
r
=.712,
P
<.01; skeletal muscle:
r
=.632,
P
<.01). We conclude that (1) MR techniques can be used to coordinately and noninvasively assess cardiac, vascular, metabolic, and ionic aspects of hypertensive disease in humans; (2) increased systolic blood pressure and LVMI in EH may at least in part result from decreased AD; (3) decreased Mgi contributes to arterial stiffness in hypertension and may help to explain the characteristic age-related decreases in AD; and (4) decreased AD may be one mechanism by which abdominal visceral fat contributes to cardiovascular risk.
Pressure Natriuresis After Adrenomedullin in Anesthetized Spontaneously Hypertensive Rats
Authors: Kurashina Toshiaki , Patel Ami R. , Granger Joey P. , Kirchner Kent A.
Published: June 2012

Abstract
Adrenomedullin (ADM), a peptide with potent vasodilatory and natriuretic actions, is elevated in patients with essential hypertension. Because pharmacological doses of ADM result in renal vasodilation and natriuresis, it has been suggested that ADM may play a modulatory role in hypertension through potential actions on renal pressure natriuresis. However, it is unclear whether elevation of plasma ADM within the pathophysiological range has similar actions. To determine the effects of pathophysiological doses of ADM on blood pressure and on the relationship between renal perfusion pressure (RPP) and renal hemodynamics and sodium excretion, renal function was determined at RPPs of 80, 105, 130, and 155 mm Hg in spontaneously hypertensive rats (SHR) infused with ADM at 50 ng · kg
−1
· min
−1
(ADM-50, n=5) and at 100 ng · kg
−1
· min
−1
(ADM-100, n=5) and in control SHR (n=5). Decreasing RPP from 155 to 80 mm Hg in control SHR decreased (
P
<.05) absolute sodium excretion from 0.81±0.25 to 0.04±0.02 μEq/min, fractional sodium excretion from 0.32±0.11% to 0.06±0.04%, and urine flow rate from 11.5±2.8 to 1.03±0.31 μL/min. ADM infusion elevated (
P
<.05) plasma ADM levels in ADM-infused SHR (679±47 pg/mL in ADM-50, 858±79 in ADM-100) compared with control (79.5±27.8). However, although reduction of RPP from 155 to 80 mm Hg in ADM rats decreased absolute sodium excretion (ADM-50, 0.98±0.10 to 0.09±0.04 μEq/min; ADM-100, 0.95±0.09 to 0.07±0.02 μEq/min), fractional sodium excretion (ADM-50, 0.31±0.03% to 0.17±0.04%; ADM-100, 0.33±0.02% to 0.09±0.01%), and urine flow (ADM-50, 13.6±1.4 to 1.73±0.75 μL/min; ADM-100, 13.5±1.5 to 1.07±0.16 μL/min), these decreases were not different from values found in controls. Renal plasma flow and glomerular filtration rate were also similar in control and ADM-treated SHR at each level of RPP. Thus, acute increases in ADM to levels found in pathophysiological conditions have no effect on blood pressure, pressure natriuresis, or renal autoregulation in the SHR. These findings do not support the hypothesis that ADM serves as a modulating factor in hypertension, at least in the SHR.
Abnormal Endothelium-Dependent Responses in Early Radiation Nephropathy
Authors: Juncos Luis I. , Cornejo Juan C. , Gomes Joaquin , Baigorria Sandra , Juncos Luis A.
Published: June 2012

Abstract
While arterial hypertension and renal dysfunction are well recognized complications of renal irradiation, the mechanisms that trigger the development of these complications are unknown. Recently, it was reported that the endothelium is a major target in radiation injury. Because dysfunction of the endothelial cells may lead or contribute to the development of hypertension and renal dysfunction in radiation nephropathy, we tested the hypothesis that endothelium-dependent vasodilation is impaired in radiated kidneys prior to the onset of hypertension. To test this hypothesis, we used Long-Evans rats that had undergone left nephrectomy (3 weeks earlier) and irradiation (3000 r’s) to the right kidney 8 days earlier (mean blood pressures in the irradiated rats were not different than in the controls). We then measured the changes in renal blood flow (RBF) induced by endothelium-dependent (acetylcholine and bradykinin) and -independent (nitroprusside, norepinephrine, and angiotensin II) vasoactive agents. We found that the increases in RBF induced by the endothelium-dependent but not independent vasodilators were markedly impaired in the irradiated kidneys. Blocking nitric oxide synthesis with nitro
l
-arginine methyl ester in sham rats mimicked the blunted responsiveness of the irradiated rats, whereas indomethacin (an inhibitor of prostaglandin synthesis) had no effect on either sham or irradiated rats. Finally, the RBF responses to the endothelium-independent vasoconstrictors, norepinephrine and angiotensin II, were not altered in the irradiated kidneys. These results suggest that renal irradiation causes endothelial dysfunction (prior to the onset of hypertension) but spares the vascular smooth muscle cells.
Renal Identification of Cyclooxygenase-2 in a Subset of Thick Ascending Limb Cells
Authors: Vio Carlos P. , Cespedes Carlos , Gallardo Pedro , Masferrer Jaime L.
Published: June 2012

Abstract
The prostaglandin G2/H2 synthase (cyclooxygenase, COX) is a key regulatory enzyme of prostanoid synthesis pathway. The message-encoding COX isoenzymes (constitutive COX-1 and inducible COX-2) have been described in the rat kidney. However, there is scarce information on the localization of COX-2 in the kidney, although it has been recently reported to be localized in the macula densa. The present study was designed to evaluate the localization of COX-2 in adult rat kidneys. Normal rat kidneys (n=10) were fixed in Bouin and were immunostained with specific antibodies against COX-2 by the peroxidase method. The cellular origin of COX-2 was assessed by the immunostaining of serial consecutive sections with antibodies against Na-K-ATPase, Tamm-Horsfall glycoprotein, H-K-ATPase, kallikrein, and macrophages. COX-2 was consistently observed in a subset of tubular cells located in the cortex and in the outer medulla. The staining of serial sections showed that the COX-2+ cells contained both Na-K-ATPase and Tamm-Horsfall, indicating that they corresponded to thick ascending limb (TAL) cells. They were observed at a considerable distance from the corresponding macula densa, although occasionally they were observed close to glomeruli. The COX-2 staining in the TAL cells was not abolished by dexamethasone treatment (1 to 20 mg/kg), suggesting its constitutive expression in normal kidneys. The presence of COX-2 in TAL (a tubular segment postulated to be devoid of COX-1) may contribute to the handling of ions through local production of prostaglandins.
A Descriptive and Quantitative Light and Electron Microscopy Study of the Aortic Depressor Nerve in Normotensive Rats
Authors: Fazan Valéria P. S. , Salgado Helio C. , Barreira Amilton A.
Published: June 2012

Abstract
There is no literature report of a detailed morphologic study of the aortic depressor nerve. The aim of this study was to describe the general morphological aspects and to obtain morphometric parameters for the aortic depressor nerve of normotensive Wistar rats (n=12). Before the morphologic studies, nerves were isolated and pressure-nerve activity curves were obtained. Basal mean arterial pressure was 117±5 mm Hg, the systolic pressure threshold was 100±7 mm Hg, and mean arterial pressure at 50% of maximal activity was 115±5 mm Hg and the baroreceptor gain 1.99±0.09%/mm Hg. Semithin and thin sections of proximal and distal nerve segments were then examined by light and electron microscopy, respectively. The main nerve components were (1) unmyelinated and myelinated axons; (2) Schwann cells; (3) capillary wall endothelial cells and pericytes; (4) collagen fibers in the epineurium and endoneurium and between perineurial cell layers; and (5) fibroblasts and mast cells. The depressor nerves were found to contain 204-996 axons per nerve, 80% of which, on average, were unmyelinated, with a 4:1 unmyelinated/myelinated axon ratio. The unmyelinated axon histogram was unimodal, with a mean diameter of 0.5±0.02 μm. Myelinated fibers had axons averaging 1.3±0.06 μm in diameter and representing 53% of the total fiber diameter. The ratio between axonal and total fiber diameter of myelinated fiber ranged from 0.4 to 0.8 and tended to increase with axon size. Proximal and distal segments were morphologically similar. In conclusion, the morphologic description of the depressor nerve provides important data for further investigations of the structural basis of altered baroreflex responses in conditions such as arterial hypertension, aging, atherosclerosis, and peripheral neuropathies.
Hemodynamic and Humoral Correlates in Essential Hypertension
Authors: Manolis Athanasios J. , Beldekos Demetrios , Hatzissavas John , Foussas Stephanos , Cokkinos Dennis , Bresnahan Margaret , Gavras Irene , Gavras Haralambos
Published: June 2012

Abstract
While evaluating 45 hypertensive patients with left ventricular hypertrophy (LVH) for enrollment in a clinical research protocol, we had the opportunity to compare anatomic and functional characteristics of those with LVH and ischemia on an exercise tolerance test (ETT), but without coronary artery disease by angiography (group I, n=8), versus those with a normal ETT (group II, n=37). There were no differences in age, sex, severity, and duration of hypertension between the two groups, but group I patients were significantly more overweight and had a worse lipid profile. Blood pressure at peak ETT was higher in group I despite shorter exercise duration, although resting and ambulatory pressures were similar. Group I patients had evidence of more pronounced cardiac enlargement and LVH by both ECG and echo criteria and a characteristic pattern of more pronounced thickening at the apex, but both groups had equally good systolic function and similar degrees of mild diastolic dysfunction. Analysis of 24-hour ambulatory ECG showed a significantly greater propensity to ventricular arrhythmias in group I, as shown by the presence of late potentials in 4 patients, the presence of couplets in 3, runs of ventricular tachycardia in 2 (while none of group II patients had late potentials or complex arrhythmias), and an average frequency of isolated premature ventricular contractions approximately three times higher in group I than group II patients. Our data demonstrate that hypertensives with LVH associated with myocardial ischemia at stress but with normal coronary arteriograms tend to be more overweight, attain a higher systolic blood pressure at ETT despite a shorter duration, have a higher propensity for severe arrhythmias, and have an adverse lipid profile. LVH in these subjects is more pronounced by both ECG and echo criteria and is characterized by predominantly apical hypertrophy with left atrial and ventricular dilatation rather than overall LV wall thickening.
Essential Hypertension in African Caribbeans Associates With a Variant of the β
2
-Adrenoceptor
Authors: Kotanko Peter , Binder Alexander , Tasker Jacquie , DeFreitas Perry , Kamdar Sejal , Clark Adrian J. L. , Skrabal Falko , Caulfield Mark
Published: June 2012

Abstract
Populations of West African ancestry dwelling in Western communities exhibit greater prevalence of human essential hypertension and higher rates of end-organ damage. The sympathetic nervous system influences cardiac output, vascular tone, renal sodium reabsorption, and renin release and could be implicated in enhanced vascular responsiveness observed in African hypertensives. Such an effect could arise from genetic variants that alter agonist response of α-adrenoceptors, leading to enhanced vasoconstriction, or attenuate β
2
-adrenoceptor–mediated vasodilatation. Indeed, there is evidence of a blunted vasodilator response to the β-agonist isoprenaline in African Americans. A variant of the β
2
-adrenoceptor gene that encodes glycine rather than arginine at position 16 (Arg16→Gly) has been shown to confer exaggerated agonist-mediated receptor downregulation, which might attenuate vasodilator response. One hundred thirty-six unrelated hypertensives and 81 unrelated normotensives of African Caribbean origin were identified from primary care on the island of St Vincent. Genomic DNA from these subjects was analyzed for the presence of the Gly16 and Arg16 alleles by using an allele-specific polymerase chain reaction method. We report strong support for association of the prodownregulatory glycine 16 variant of the β
2
-adrenoceptor gene with hypertension in African Caribbeans from St Vincent and the Grenadines (χ
2
=18.9,
P
=.000014, 1
df
). This observation, coupled with reports of attenuated vasodilator responses to β-agonists among people of West African ancestry, may provide a mechanism for enhanced vascular reactivity and identify a candidate gene for hypertension in this ethnic group.
A Peptide Released by Pepsin From Kininogen Domain 1 Is a Potent Blocker of ANP-Mediated Diuresis-Natriuresis in the Rat
Authors: Croxatto Héctor R. , Silva Rosa , Figueroa Xavier , Albertini Renato , Roblero Juan , Boric Mauricio P.
Published: June 2012

Abstract
A 20–amino acid peptide, KYEIKEGDCPVQSGKTWQDC (PU-D1), released by pepsin hydrolysis of LMW kininogen domain 1 was tested for its ability to antagonize the diuretic and natriuretic effect of ANP
103-125
in anesthetized rats. A single dose of 10.8 or 21.6 pmol (25 or 50 ng) PU-D1 given intravenously or into the duodenal lumen suppressed the diuresis-natriuresis induced by 209 pmol (500 ng) ANP by 43% to 59% and 69% to 96%, respectively. None of the doses tested (2.16 to 432 pmol, 5 ng to 1 μg) modified systemic blood pressure. Strikingly, a single IV dose of 10.8 pmol PU-D1 blocked the action of ANP for more than 3 hours. ANP blockade by PU-D1 was annulled completely by the bradykinin (BK) B2 receptor inhibitor Hoe 140. On a molar basis, PU-D1 is more effective than BK and kinins of 15, 16, and 18 amino acids for blocking the ANP-mediated diuresis-natriuresis. As with BK and other kinins, the inhibitory effect of Pu-D1 on ANP is obtained only within a small range of picomol doses. A single dose of 2.16 or 4.32 pmol PU-D1 or 47 pmol (50 ng) BK is ineffective against ANP if injected alone. However, when both substances are administered concomitantly at these subthreshold doses, they totally suppress ANP-induced diuresis-natriuresis. These results raise the question of whether PU-D1, released from kininogen domain 1, either alone or associated with BK, may interact with ANP in the regulation of urinary water and electrolyte excretion in physiological and pathological conditions.
Impaired Nitric Oxide– and Prostaglandin-Mediated Responses to Flow in Resistance Arteries of Hypertensive Rats
Authors: Matrougui Khalid , Maclouf Jacques , Lévy Bernard I. , Henrion Daniel
Published: June 2012

Abstract
In human and experimental hypertension, flow (shear stress)–induced dilation in large arteries is attenuated and resistant to nitric oxide blockade. We tested the hypothesis that a defect in nitric oxide–and/or prostaglandin-dependent flow-induced dilation might occur in mesenteric resistance arteries from spontaneously hypertensive rats (SHR). We measured resistance mesenteric artery diameter in situ by intravital microscopy and simultaneously measured mesenteric arterial pressure in a collateral artery. The flow-diameter-pressure relationship was established in normotensive Wistar-Kyoto rats (WKY) and in SHR under control conditions and after endothelium removal, inhibition of nitric oxide synthesis with
N
ω
-nitro-
l
-arginine methyl ester (10 μmol/L), or inhibition of prostaglandin synthesis with indomethacin (10 μmol/L). Production of prostaglandins was determined in the perfusate. Endothelium removal decreased artery diameter by 14±1.6% in WKY and 5±0.5% (
P
<.01 versus WKY) in SHR at a flow rate of 400 μL/min. In WKY,
N
ω
-nitro-
l
-arginine methyl ester and indomethacin decreased resistance artery diameter by 12±3% (
P
<.001) and 5±2% (
P
<.01), respectively, at a flow rate of 400 μL/min; neither substance had any significant effect in SHR. In both strains, flow induced the production of 6-keto-prostaglandin F
1α
, the metabolite of prostacyclin; prostaglandin F
2α
; and thromboxane B
2
, the stable metabolite of thromboxane A
2
. Production of 6-keto-prostaglandin F
1α
and prostaglandin F
2α
was significantly lower in SHR than WKY, and TxB
2
production was significantly higher in SHR than WKY. The present findings suggest that in SHR mesenteric resistance arteries, dilation in response to increases in flow was resistant to nitric oxide and prostaglandin synthesis blockade. A modification of the ratio of vasodilator to vasoconstrictor prostaglandins might be at least partly responsible for the decreased dilator response to flow in SHR.
Attenuation of Neurogenic Vasoconstriction by Nitric Oxide in Hindlimb Microvascular Beds of the Rat In Vivo
Authors: Häbler Heinz-Joachim , Wasner Gunnar , Jänig Wilfrid
Published: June 2012

Abstract
There is evidence that sympathetic nerve activity leads to endothelium-derived nitric oxide release, which in turn attenuates neurogenic vasoconstriction. Here we tested in vivo (1) whether the magnitude of the vasoconstriction induced by
N
G
-nitro-
l
-arginine methyl ester given systemically is altered when ongoing sympathetic activity is abolished by sectioning the lumbar sympathetic trunk, and (2) whether hindlimb sympathetic vasoconstriction elicited by electrical stimulation of the lumbar sympathetic trunk is enhanced after inhibition of nitric oxide synthesis. Blood flow in the microvascular beds of hairless skin and skeletal muscle of the rat hindlimb was measured with laser Doppler flowmetry. Sectioning the lumbar sympathetic trunk resulted in an increase of blood flow in both tissues, indicating that tonic neurogenic vasoconstriction was abolished. Inhibition of nitric oxide synthesis resulted in vasoconstriction in both vascular beds. This vasoconstriction was more pronounced after abolition of sympathetic activity than with intact sympathetic supply in skin but was smaller in skeletal muscle. The vasoconstriction elicited by graded electrical stimulation of the centrally sectioned lumbar sympathetic trunk with frequencies less than 5 Hz was significantly enhanced after blockade of nitric oxide in skeletal muscle but not in skin microvasculature. These findings suggest that under physiological conditions, sympathetic nerve impulses directly promote the release of nitric oxide in skeletal muscle but not in cutaneous blood vessels. Therefore, basal nitric oxide release is probably in part dependent on sympathetic activity in skeletal muscle, whereas it appears to be mainly due to flow-dependent shear stress in hairless skin microvasculature.
A Newly Identified Peptide, Proadrenomedullin N-Terminal 20 Peptide, Induces Hypotensive Action via Pertussis Toxin–Sensitive Mechanisms
Authors: Shimosawa Tatsuo , Ando Katsuyuki , Fujita Toshiro
Published: June 2012

Abstract
Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) are novel hypotensive peptides. Although they are derived from the same gene product, proadrenomedullin, their hypotensive mechanisms are different; PAMP inhibits the release of norepinephrine from the peripheral sympathetic nerve endings, whereas AM fosters vasodilation by elevating intracellular cAMP, possibly via activation of cholera toxin–sensitive G proteins. In PC12 cells, PAMP inhibited N-type calcium channel via activation of pertussis toxin–sensitive mechanisms. To clarify the relationship between the hypotensive effect of PAMP and pertussis toxin−sensitive mechanisms, we administered pertussis vaccine intraperitoneally into rats for 3 consecutive days. By using mesenteric artery preparation, we showed that PAMP’s ability to decrease norepinephrine overflow was significantly attenuated in pertussis toxin−treated rat (−18.5±6.9%;
P
<.05 versus control rats). In electrically stimulated pithed rat, PAMP (20 and 40 nmol/kg) showed a hypotensive effect (−13±5 and −18±7 mm Hg, respectively;
P
<.05,
P
<.01), whereas in pertussis vaccine−treated rat it did not (−2±3 and −8±9 mm Hg, respectively;
P
=NS). Also, in pithed rat, plasma norepinephrine level was significantly elevated by electrical stimulation in both control (0.323±0.035 ng/mL) and pertussis vaccine− treated groups (0.355±0.079 ng/mL). After injection of PAMP (40 nmol/kg), plasma norepinephrine level significantly decreased in the control group (0.225±0.044 ng/mL;
P
<.01) but not in the pertussis vaccine−treated group (0.392±0.021 ng/mL;
P
=NS). Moreover, in conscious rats, intravenous administration of PAMP (40 nmol/kg) did not evoke hypotension after pertussis vaccine treatment, although untreated controls had significantly decreased arterial pressure (−5±2 versus −20±3 mm Hg;
P
<.01). In contrast to PAMP, the administration of AM (1 nmol/kg) significantly reduced the blood pressure of pertussis vaccine−treated as well as control rats (−20±5 versus −18±7 mm Hg;
P
=NS). These results demonstrate that the ability of PAMP to inhibit norepinephrine release from peripheral sympathetic nerve endings and to decrease blood pressure is pertussis toxin sensitive. Our findings thus suggest that despite being derived from the same gene, PAMP and AM apparently produce hypotension by activating different signaling pathways.
Identification of a Renin Threshold and Its Relationship to Salt Intake in a Patient With Pure Autonomic Failure
Authors: Hohenbleicher Henriette , Klosterman Fabian , Schorr Ulrike , Seyfert Sepp , Persson Pontus B. , Sharma Arya M.
Published: June 2012

Abstract
Animal studies have demonstrated a threshold below which renin release increases proportionally to a decrease in renal perfusion pressure. Demonstration of a similar mechanism in humans, however, has proved difficult, as any attempt to lower blood pressure below the putative renin threshold results in renin release mediated by reflex activation of the sympathetic nervous system. In this study, we report on our observations in a 71-year-old woman who presented with a 20-year history of faintness and syncope and was diagnosed as having pure autonomic failure. Graded head-up tilting resulted in a stepwise reduction in mean arterial blood pressure to a minimum of 54 mm Hg, with no signs of increased sympathetic activity. A fall in blood pressure below 80 mm Hg resulted in a distinct rise in plasma renin activity, and a similar threshold pressure was observed under both a 50- and a 100-mmol/d sodium chloride diet. Below the threshold, response to changes in perfusion pressure was proportionally greater under the 50-mmol/d diet than under a 100- or 200-mmol/d diet. These observations demonstrate that a pressure threshold for renin release at 10 to 15 mm Hg below ambient blood pressure, as described previously in animal studies, is also present in humans. The significance of this pressure-dependent mechanism of renin release for the long-term regulation of blood pressure and water and mineral balance in humans remains to be determined.