bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial Baroreceptor-Cardiac Reflex Sensitivity in the Elderly
Authors: James Martin A. , Robinson Thompson G. , Panerai Ronney B. , Potter John F.
Published: June 2012

Uncertainty still remains regarding the differing effects of blood pressure and age on baroreceptor-cardiac reflex sensitivity in elderly individuals; these differences are at least partly due to the differing methods and subject groups used in previous studies. We sought to resolve these issues by examining baroreflex sensitivity in 54 subjects aged 70±1 years (mean±SE; range, 60 to 81) divided into groups with combined systolic-diastolic hypertension (CH group, n=16), isolated systolic hypertension (ISH group, n=16), or normotension (NT group, n=22). Baroreflex sensitivity was quantified from the pulse interval and blood pressure responses to the Valsalva maneuver and pressor (phenylephrine) and depressor (sodium nitroprusside) stimuli. Baroreflex sensitivity was significantly reduced in the two hypertensive groups but did not differ between them (Valsalva maneuver: CH group, 1.9±0.3 ms/mm Hg; ISH group, 2.8±0.5; NT group, 4.4±0.4; phenylephrine: CH group, 3.1±0.6; ISH group, 3.5±0.7; NT group, 7.7±1.0; sodium nitroprusside: CH group, 2.1±0.3; ISH group, 3.6±0.8; NT group, 5.4±0.3; all
P
<.05 for comparison with the NT group). Thus, this study demonstrated reductions in baroreflex sensitivity with hypertension in elderly subjects consistent across all methods but with no difference between subjects with combined hypertension and isolated systolic hypertension matched for similar systolic pressure. Baroreflex sensitivity was related only to the level of systolic pressure independent of diastolic pressure or age. If elderly subjects with isolated systolic hypertension have a greater reduction in large-artery compliance than combined hypertensive subjects with similar systolic pressure, this does not appear to lead to further reductions in baroreflex sensitivity in these individuals.
Superiority of Brain Natriuretic Peptide as a Hormonal Marker of Ventricular Systolic and Diastolic Dysfunction and Ventricular Hypertrophy
Authors: Yamamoto Kazuhiro , Burnett John C. , Jougasaki Michihisa , Nishimura Rick A. , Bailey Kent R. , Saito Yoshihiko , Nakao Kazuwa , Redfield Margaret M.
Published: June 2012

Atrial and brain natriuretic peptides (ANP and BNP) are produced by the heart, and their plasma concentrations are increased in human chronic congestive heart failure. Although separate studies have suggested that circulating levels of the biologically active C-terminal ANP, the biologically inactive N-terminal ANP, and BNP may have diagnostic utility in the detection of left ventricular systolic dysfunction or left ventricular hypertrophy, no studies have directly assessed the relative value of these peptides prospectively. We therefore designed this study to compare the relative ability of the different natriuretic peptides to detect abnormal left ventricular systolic and diastolic function and left ventricular hypertrophy. Using a prospective study design, we investigated 94 patients referred for cardiac catheterization and 15 age-matched normal subjects. The diagnostic abilities of elevated plasma C-terminal ANP, N-terminal ANP-(1-30), and BNP concentrations to identify systolic dysfunction (ejection fraction <45%), diastolic dysfunction (time constant of left ventricular relaxation >55 milliseconds, left ventricular end-diastolic pressure >18 mm Hg), and left ventricular hypertrophy (left ventricular mass index >120 g/m
2
) were objectively compared by receiver operating characteristic analysis. The areas under the receiver operating characteristic curve of BNP for detecting each of these abnormalities ranged from 0.715 to 0.908 and were significantly greater than those of C-terminal ANP or N-terminal ANP-(1-30). The sensitivity and specificity of an elevated plasma BNP, which we defined as greater than the mean+3 SD of the 15 age-matched normal subjects, were 0.83 and 0.77, respectively, for detecting ejection fraction less than 45%, 0.85 and 0.70 for detecting the time constant of left ventricular relaxation greater than 55 milliseconds, 0.63 and 0.76 for detecting left ventricular end-diastolic pressure greater than 18 mm Hg, and 0.81 and 0.85 for detecting left ventricular mass index greater than 120 g/m
2
. The use of BNP and one other peptide increased sensitivity (0.90 to 0.96), albeit with lower specificity (0.56 to 0.71). An elevated plasma BNP was a more powerful marker of left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and left ventricular hypertrophy than C-terminal ANP or N-terminal ANP-(1-30) in this population of patients with suspected cardiac disease. Measurement of BNP alone or in combination with C-terminal ANP or N-terminal ANP-(1-30) has potential utility for the detection of altered left ventricular structure and function in a patient population at risk for cardiovascular disease.
Differential Human Renal Tubular Responses to Dopamine Type 1 Receptor Stimulation Are Determined by Blood Pressure Status
Authors: O'Connell Damian P. , Ragsdale N. Virginia , Boyd David G. , Felder Robin A. , Carey Robert M.
Published: June 2012

We performed the present studies to determine whether a proximal renal tubular dopamine D
1
-like receptor defect exists in human essential hypertension. Twenty-four subjects were studied (13 normotensive and 11 hypertensive) in a randomized, double-blind, vehicle-controlled study using fenoldopam, a selective D
1
-like receptor agonist. Subjects were studied in sodium metabolic balance at 300 mEq/d, after which the salt sensitivity of their blood pressure was determined. Fenoldopam at peak doses of 0.1 to 0.2 μg/kg per minute decreased mean arterial pressure in hypertensive subjects but did not change mean pressure in normotensive subjects. Fenoldopam increased renal plasma flow to a greater extent in hypertensive than normotensive subjects. Fenoldopam increased both urinary and fractional sodium excretions in the hypertensive and normotensive groups. In normotensive but not hypertensive subjects, fenoldopam increased the fractional excretion of lithium and distal sodium delivery. In contrast, both distal fractional sodium reabsorption and sodium-potassium exchange fell significantly in hypertensive subjects. We conclude that human essential hypertension is associated with a reduction in the proximal tubular response to D
1
-like receptor stimulation compared with normotensive subjects. Hypertensive subjects appear to have a compensatory upregulation of renal vascular and distal tubular D
1
-like receptor function that offsets the proximal tubular defect, resulting in an enhanced natriuretic response to D
1
-like receptor stimulation.
Aging, Acculturation, Salt Intake, and Hypertension in the Kuna of Panama
Authors: Hollenberg Norman K. , Martinez Gregorio , McCullough Marji , Meinking Terri , Passan Diane , Preston Mack , Rivera Alicio , Taplin David , Vicaria-Clement Maureen
Published: June 2012

The indigenous Kuna who live on islands in the Panamanian Caribbean were among the first communities described with little age-related rise in blood pressure or hypertension. Our goals in this study were to ascertain whether isolated island-dwelling Kuna continue to show this pattern, whether migration to Panama City and its environs changed the patterns, and whether the island-dwelling Kuna have maintained their normal blood pressure levels despite partial acculturation, reflected in an increased salt intake. We enrolled 316 Kuna participants who ranged in age from 18 to 82 years. In 50, homogeneity was confirmed by documentation of an O+ blood group. In 92 island dwellers, diastolic hypertension was not identified and blood pressure levels were as low in volunteers over 60 years of age as in those between 20 and 30 years of age. In Panama City, conversely, hypertension prevalence was 10.7% and exceeded 45% in those over 60 years of age (
P
<.01), blood pressure levels were higher in the elderly, and there was a statistically significant positive relationship between age and blood pressure (
P
<.01). In Kuna Nega, a Panama City suburb designed to maintain a traditional Kuna lifestyle but with access to the city, all findings were intermediate. Sodium intake and excretion assessed in 50 island-dwelling Kuna averaged 135±15 mEq/g creatinine per 24 hours, exceeding substantially other communities free of hypertension and an age-related rise in blood pressure. Despite partial acculturation, the island-dwelling Kuna Indians are protected from hypertension and thus provide an attractive population for examining alternative mechanisms.
Influence of Nitric Oxide and Angiotensin II on Renal Involvement in Hypertension
Authors: Frohlich Edward D.
Published: June 2012

Remarkable advances have been made with prolonged antihypertensive therapy in reversing cardiovascular morbidity and mortality. Deaths from stroke have been reduced by 70% and from coronary heart disease by 35%. In contrast, endstage renal disease resulting from hypertension continues to increase. The explanations for this seeming paradox remain unresolved even though experimental models have demonstrated that certain antihypertensive agents may have beneficial renal and intrarenal hemodynamic effects; but reversal of the intrarenal pathological lesions have not been shown to improve. This discussion summarizes recent studies from our laboratory in aged (73- and 85-week-old) spontaneously hypertensive rats (SHR) with naturally occurring end-stage renal disease and in a model of aged SHR employing nitric oxide inhibition in younger, adult (20-week-old) SHR. Our findings demonstrated that the systemic and whole renal hemodynamics, intrarenal glomerular dynamics, proteinuria, and renal pathological lesions can be prevented or reversed with angiotensin-converting enzyme inhibition therapy but not with hydrochlorothiazide (at similar levels of arterial pressure reduction). The implications and possible mechanisms involved in the development of both naturally occurring and nitric oxide-exacerbated SHR are multifactorial, involving the endothelial nitric oxide system and its interaction with angiotensin II (and possibly bradykinin) among other factors. Moreover, these pathophysiological cellular mechanisms may be shared by the aging process as well as in naturally occurring spontaneous hypertension in the rat and, perhaps, in humans with essential hypertension. Thus, antihypertensive therapy seems to be specific in its ability to prevent and even reverse the pathophysiological derangements of renal involvement in hypertension. Thus, prevention and reversal of end-stage renal disease do not seem to require greater reduction of arterial pressure than with other target-organ involvement. However, they do require specific inhibition of the arteriolar and glomerular lesions produced by the disease.
Prediction of Cardiac Structure and Function by Repeated Clinic and Ambulatory Blood Pressure
Authors: Fagard Robert H. , Staessen Jan A. , Thijs Lutgarde
Published: June 2012

We performed imaging echocardiography, Doppler velocimetry, and repeated clinic and ambulatory blood pressure measurements in 74 hypertensive individuals to clarify why reports differ on the strength of the relationships of left ventricular characteristics with clinic blood pressure, on the superiority of ambulatory over clinic pressure, and on the importance of daytime and nighttime pressures. Clinic pressure was measured five times with an automated device and five times with the conventional technique on 2 different days. The partial correlation coefficients of left ventricular mass and wall thickness with the first automated systolic and diastolic clinic pressures amounted to .38 to .45 (
P
<.001), improved with increasing numbers of measurements, and reached .56 to .58 for the average of 10 automated pressure determinations. Similar trends were observed for conventional clinic pressures. Average 24-hour pressures were significantly related to mass and wall thickness (partial
r
=.50 to .61,
P
<.001) and explained 3% to 6% (systolic) and 5% to 12% (diastolic) of the variance of cardiac structure in addition to the first automated or conventional clinic pressure (
P
<.05). However, when 10 clinic measurements were averaged, only diastolic 24-hour pressure added information over and above clinic pressure (
P
<.05); the additional explained variance was larger with regard to the conventional (+4% for mass and +7% for wall thickness) rather than the automated (+3% for wall thickness only) pressures. Mass and wall thickness were more closely related to daytime than nighttime pressures and were not independently related to day-night differences in pressure, except when men and women were considered separately; the results were similar when four different definitions of day and night were applied. Finally, the weak association of left ventricular diastolic function with blood pressure did not improve on repeated clinic or ambulatory blood pressure measurements. In conclusion, increasing numbers of measurements strengthen the relationships of clinic pressure with left ventricular mass and wall thickness and, conversely, diminish the additional predictive power of 24-hour blood pressure. The importance of nighttime pressure and of the nighttime pressure fall does not seem to depend on the definition of day and night but differs in men and women.
Afferent and Efferent Arteriolar Vasoconstriction to Angiotensin II and Norepinephrine Involves Release of Ca
2+
From Intracellular Stores
Authors: Inscho Edward W. , Imig John D. , Cook Anthony K.
Published: June 2012

Renal vascular responses to angiotensin II (Ang II) and norepinephrine (NE) are reported to involve both mobilization of calcium from intracellular stores and activation of calcium influx pathways. The present study was conducted to determine the contribution of calcium release from intracellular stores to afferent and efferent arteriolar responses to Ang II and NE. Experiments were performed in vitro using the blood-perfused, juxtamedullary nephron technique combined with videomicroscopy. The responses of afferent and efferent arterioles to Ang II and NE were determined before and after depletion of intracellular calcium pools with 1 μmol/L thapsigargin. Positive control responses were obtained with 55 mmol/L KCl. Ang II concentrations of 0.1, 1.0, and 10 nmol/L decreased afferent arteriolar diameter by 10±4%, 17±4%, and 29±6%, respectively (
P
<.05; n=8). NE also decreased afferent diameter by 5±1%, 13±1%, and 57±9% at concentrations of 10, 100, and 1000 nmol/L, respectively (
P
<.05; n=6). Thapsigargin treatment shifted the afferent arteriolar concentration-response curves for both Ang II and NE significantly to the right. Nevertheless, KCl evoked a pronounced vasoconstriction and decreased afferent diameter by 56±7% (
P
<.05; n=6). Postglomerular responses to Ang II and NE were abolished by thapsigargin. During the control period, efferent diameter decreased by 3±1%, 7±2%, and 14±4% for the three Ang II concentrations and 3±1%, 5±1%, and 15±4% in response to the three NE concentrations, respectively. These responses were completely eliminated in the presence of thapsigargin, whereas KCl evoked an efferent arteriolar vasoconstriction of 57±9% (
P
<.05). These data demonstrate that agonist-induced calcium release from intracellular stores represents an essential component in the afferent and efferent arteriolar response to Ang II and NE. Furthermore, they suggest that efferent arteriolar responses to these agents may rely more heavily on calcium release from this store, whereas afferent responses may include activation of other pathways.
Intrarenal Dopamine Production and Distribution in the Rat
Authors: Wang Zhi-Qin , Siragy Helmy M. , Felder Robin A. , Carey Robert M.
Published: June 2012

Dopamine (DA), produced by the renal proximal tubule, has been demonstrated as an intrarenal paracrine hormone mediating diuresis and natriuresis. The precise mechanism by which DA exerts its cell-to-cell action is not fully understood. In the present study, renal interstitial fluid (RIF) DA (by in vivo microdialysis) and urinary DA excretion (U

da

V) were compared in anesthetized rats on either normal (0.28% NaCl, NS) or high (4.0% NaCl, HS) sodium balance and in response to acute γ-
l
-glutamyl-
l
-dopa (gludopa) administration. Urine flow (UV) and sodium excretion (U

n
a

V) in HS were greater than in NS rats. U

da

V was increased in HS compared with NS rats. RIF DA was significantly lower in HS than NS rats. Gludopa at 3, 5, and 7.5 nmol/kg (IV bolus) produced a larger increase in U

da

V than RIF DA. Only the highest dose of gludopa (7.5 nmol/kg), which resulted in a 7.3-fold increase in U

da

V and 1.7-fold increase in RIF DA, was associated with significant diuresis and natriuresis. Cortical and medullary blood flow remained unchanged after gludopa (7.5 nmol/kg) administration, while angiotensin II (100 ng·kg
−1
·min
−1
) induced significant reduction in cortical and medullary blood flow. Prior bilateral renal denervation did not have a significant effect on basal DA levels (RIF DA and U

da

V) or gludopa-induced DA production or natriuresis and diuresis. These data demonstrated that both chronic sodium loading and acute gludopa administration stimulated renal DA production and release predominantly into the tubule lumen, where DA had a direct tubule action in the control of U

n
a

V. Renal DA production and its renal effects were not significantly regulated by renal sympathetic nerve activity.
Inhibition of 20-HETE Production Contributes to the Vascular Responses to Nitric Oxide
Authors: Alonso-Galicia Magdalena , Drummond Heather A. , Reddy K. Kishta , Falck John R. , Roman Richard J.
Published: June 2012

Nitric oxide (NO) inhibits a variety of heme-containing enzymes, including NO synthase and cytochrome P4501A1 and 2B1. The present study examined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10
−5
, 10
−4
, and 10
−3
mol/L) reduced the production of 20-HETE by renal microsomes incubated with arachidonic acid to 71±5%, 29±4%, and 4±2% of control, respectively (n=5). Similar results were obtained with the use of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n=3). To determine whether inhibition of 20-HETE contributes to the vasodilatory effects of NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selective inhibitor of the formation of 20-HETE, on the response to SNP (10
−7
to 10
−3
mol/L) were examined in rat renal arterioles preconstricted with phenylephrine (n=5). SNP increased vascular diameter in a concentration-dependent manner to 82±4% of control. After DDMS (25 μmol/L), SNP (10
−3
mol/L) increased vascular diameter by only 17±3%. The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to infusion of an NO donor and a synthase inhibitor were also examined in thiobutabarbital-anesthetized, Sprague-Dawley rats. Infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/min reduced MAP by 16±2, 30±3, 40±5, and 48±5 mm Hg and lowered renal vascular resistance (RVR) by 15±3%, 26±2%, 30±3%, and 34±4% of control. After DDMS (10 mg/kg, n=7 rats), the MAP and RVR responses to 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrohydrazino)
N
-methyl (MAHMA NONOate) averaged only 20% of those seen during control. In other experiments, MAP increased by 32±4% and RBF fell to 56±5% of control after administration of
N
-nitro-
l
-arginine (L-NArg) (10 mg/kg IV). After DDMS (10 mg/kg, n=7 rats), MAP increased by only 19±4% and RBF fell by only 7±4% after L-NArg. These results indicate that NO inhibits cytochrome P4504A enzymes and that inhibition of the production of 20-HETE contributes to the vasodilatory effects of NO.
High Human Renin Hypertension in Transgenic Rats
Authors: Bohlender Jürgen , Fukamizu Akiyoshi , Lippoldt Andrea , Nomura Tatsuji , Dietz Rainer , Ménard Joel , Murakami Kazuo , Luft Friedrich C. , Ganten Detlev
Published: June 2012

We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither transgenic strain was hypertensive. These strains were then crossed, producing a double transgenic strain. The double transgenic rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269±381 (±SD) ng angiotensin I (Ang I)/mL per hour, plasma renin activity of 177±176 ng Ang I/mL per hour, rat angiotensinogen concentration of 1.49±1 μg Ang I/mL, and human angiotensinogen concentration of 78±39 μg Ang I/mL (n=49). Control rats had plasma renin activity of 3.7±3.9 ng Ang I/mL per hour and rat angiotensinogen of 1.32±0.16 μg Ang I/mL. Angiotensinogen transgene expression by RNase protection assay was ubiquitously present but most prominent in liver. Renin transgene expression was high in kidney but absent in liver. The rats featured severe cardiac hypertrophy, with increased cross section of cardiomyocytes but little myocardial fibrosis. The kidneys showed atrophic tubules, thickened vessel walls, and increased interstitium. Both the angiotensin-converting enzyme inhibitor lisinopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gene expressions are similar. The specificity of rodent and human renin is similarly documented. Although many elegant physiological studies can now be done in mice, rats nevertheless offer flexibility, particularly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simultaneous investigation of genetic and pathophysiological aspects of renin-induced hypertension. The fact that human renin can be studied in the rat is a unique feature of this model.
Endothelin-1 Inhibits Nitric Oxide Synthesis in Vascular Smooth Muscle Cells
Authors: Ikeda Uichi , Yamamoto Keiji , Maeda Yoshikazu , Shimpo Masahisa , Kanbe Toshiko , Shimada Kazuyuki
Published: June 2012

We investigated the effects of endothelin-1 on nitric oxide synthesis in vascular smooth muscle cells. We measured the production of nitrite, a stable metabolite of nitric oxide, and the expression of inducible nitric oxide synthase mRNA and protein in cultured rat vascular smooth muscle cells. Incubation of the cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in nitrite production. Endothelin-1 significantly decreased the interleukin-1β–induced nitrite production by vascular smooth muscle cells in a dose-dependent manner (10
−11
to 10
−8
mol/L). Incubation with interleukin-1β for 24 hours induced expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells, whereas endothelin-1 showed a suppressive effect on their expressions. Addition of the endothelin type A receptor antagonist BQ-485, but not the endothelin type B receptor antagonist BQ-788, dose-dependently inhibited the effect of endothelin-1. After protein kinase C activity was functionally depleted by treatment of cells with phorbol 12-myristate 13-acetate for 24 hours, the effect of endothelin-1 was abolished. These results indicate that endothelin-1 acts on endothelin type A receptors and inhibits nitric oxide synthesis in interleukin-1β–stimulated vascular smooth muscle cells at least partially through a protein kinase C–dependent pathway.
The Angiotensinogen T235 Variant and the Use of Antihypertensive Drugs in a Population-Based Cohort
Authors: Schunkert Heribert , Hense Hans-Werner , Gimenez-Roqueplo AnnePaule , Stieber Jutta , Keil Ulrich , Riegger Günter A.J. , Jeunemaitre Xavier
Published: June 2012

Variants of the angiotensinogen gene may increase the risk of developing arterial hypertension, but their effect on the use of antihypertensive medication in the general population remains unclear. Thus, we determined T174M and M235T allele status and angiotensinogen plasma levels in a cross-sectional sample of 634 middle-aged subjects (48.4% men) from the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort study. We found no association between T174M allele status and angiotensinogen levels, blood pressure, or use of antihypertensive drugs. In contrast, multivariate analysis revealed that individuals who carried at least one copy of the T235 allele (n=418) had higher systolic and diastolic pressures (
P
=.007 and .008, respectively) and were more likely to use an antihypertensive drug (1.6-fold risk,
P
=.04) than homozygotes for the M235 allele (n=216). The likelihood of taking two or more antihypertensive medications was 2.1-fold higher in carriers of the T235 allele (
P
=.02). Overall, 22.5% of all antihypertensive drugs taken appeared to be attributable to the excess risk associated with this allele. These associations were replicated in two previous surveys carried out on the same individuals over 10 years. Furthermore, the T235 allele was related to higher angiotensinogen plasma levels [15.5±0.31 versus 16.5±0.15 (nmol/L)/L in homozygotes for the M235 and T235 alleles, respectively;
P
<.01], which were also related to systolic pressure (
P
=.03) and more intensive antihypertensive medication (
P
=.03). We conclude that the angiotensinogen T235 allele accounts for a substantial proportion of antihypertensive drug use in this middle-aged, population-based group of white subjects.
Heme Oxygenase-1 Is Regulated by Angiotensin II in Rat Vascular Smooth Muscle Cells
Authors: Ishizaka Nobukazu , Griendling Kathy K.
Published: June 2012

Recently, heme oxygenase-1 (HO-1) has been shown to be present in vascular smooth muscle cells. In the present study, we examined the effect of angiotensin II (Ang II) on HO-1 in rat vascular smooth muscle cells. After treatment with 100 nmol/L Ang II, HO-1 mRNA levels were decreased, with a nadir at 2 hours (39±9% of the control level,
P
<.01). This downregulation was completely blocked by the Ang II type 1 receptor antagonist losartan. Western blot analysis showed that HO-1 protein is also significantly downregulated, with a nadir at 4 hours (52±6% of the control level,
P
<.01). Heme oxygenase activity was also significantly decreased at 4 hours (control, 0.35±0.86 nmol bilirubin/mg per hour; Ang II, 0.10±0.06). This downregulation was observed in serum-starved cells to a similar extent as in serum-supplemented cells. Inhibitors of protein kinase C, lipoxygenase, cyclooxygenase, cytochrome P450 monooxygenase, and phospholipase A
2
did not block this downregulation. However, this effect was not observed in the absence of calcium and presence of EGTA (2 mmol/L). Furthermore, a 2-hour incubation with calcium ionophore or arginine vasopressin decreased HO-1 mRNA levels, suggesting that an increase of intracellular calcium mediates the downregulation. In conclusion, Ang II decreases HO-1 mRNA in a calcium-dependent manner in vascular smooth muscle cells, which may provide a novel mechanism for the modulation of vascular tone and oxidative stress.
Baroreflex Impairment by Low Sodium Diet in Mild or Moderate Essential Hypertension
Authors: Grassi Guido , Cattaneo Bianca Maria , Seravalle Gino , Lanfranchi Antonio , Bolla Giambattista , Mancia Giuseppe
Published: June 2012

Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1±3.3 years [mean±SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (
P
<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1±5.2% (
P
<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9±5.7% (
P
<.01) reduction in the sensitivity of the baroreceptor–muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.
Pregnancy-Induced Hypertension in Rats With Adriamycin Nephropathy Is Associated With an Inadequate Production of Nitric Oxide
Authors: Podjarny Eduardo , Ben-Chetrit Sidney , Rathaus Mauro , Korzets Zeev , Green Janice , Katz Bernard , Bernheim Jacques
Published: June 2012

Abstract
Hypertensive complications are relatively common in pregnancy, particularly in the presence of preexisting renal disease. Although the pathogenesis of such complications is still unknown, recent animal studies have suggested that it may be related to impaired synthesis of nitric oxide (NO). Rats with adriamycin nephropathy develop a “preeclamptic-type” pregnant state characterized by elevated blood pressure, lack of hyperfiltration, and enhanced proteinuria. Preliminary studies with this model have implicated inadequate NO synthesis in the development of preeclamptic-like pregnancy. The aim of the present study was to confirm this hypothesis. Pregnant rats, both normal (PREG) and those with adriamycin nephropathy (AN-PREG), received 100 mg/L
N
ω
-nitro-
l
-arginine methyl ester PO from the middle of gestation to term (day 11, term approximately 22 days). One group of AN-PREG rats received either
l
-arginine or
d
-arginine (2 g/L) from midpregnancy. At term, systolic pressure, mean arterial pressure, urinary metabolites of NO, creatinine clearance, and urinary protein were assessed. At term, compared with virgin rats with adriamycin nephropathy, untreated AN-PREG rats had increased systolic pressure, mean arterial pressure, and proteinuria (mean arterial pressure, 124±2.5 versus 99.7±1.6 mm Hg [
P
<.05]; proteinuria, 434±58 versus 216±63 mg/d [
P
<.05]). Creatinine clearance did not change (1.68±0.23 versus 1.35±0.09 mL/min,
P
=NS). In PREG rats, urinary metabolites of NO increased approximately threefold at term pregnancy compared with control. By contrast, in AN-PREG rats, excretion of urinary metabolites of NO increased only by approximately 1.7-fold (
P
<.01) versus PREG rats. With the exception of AN-PREG rats, inhibition of NO synthesis with
N
ω
-nitro-
l
-arginine methyl ester enhanced blood pressure and decreased creatinine clearance but did not influence proteinuria. Excretion of urinary metabolites of NO was similarly inhibited in all rats. In AN-PREG rats,
l
-arginine normalized blood pressure (91±2.15 mm Hg) and lowered proteinuria partially but significantly.
d
-Arginine had no effect. In summary, AN-PREG rats are unable to adequately increase NO synthesis when physiologically required. Correction of this deficit by
l
-arginine treatment induced a significant clinical improvement.
Association of the Angiotensinogen Gene to Serum Angiotensinogen in Blacks and Whites
Authors: Bloem Laura J. , Foroud Tatiana M. , Ambrosius Walter T. , Hanna Mark P. , Tewksbury Duane A. , Pratt J. Howard
Published: June 2012

Abstract
A variant of the angiotensinogen gene (
AGT
) that encodes for threonine at codon 235 (
T235
) has been associated with a higher serum angiotensinogen concentration and with hypertension in white subjects. The frequency of
T235
is about two times higher in blacks than whites, suggesting that
AGT
may contribute to the susceptibility to hypertension in blacks more than it does in whites. However, an association of
T235
with angiotensinogen level or blood pressure has not been observed in blacks, possibly because the high prevalence of
T235
makes it insufficiently informative as a marker. For this reason, we undertook to further differentiate the
T235
carrier state by constructing haplotypes with alleles in the 5′ upstream region of
AGT
. One such haplotype,
−1074t;T235
, showed a significant association with angiotensinogen level in a cohort of black and white children and adolescents (76 blacks, mean age= 12.3±2.0 [SD] years; 139 whites, mean age=12.4±1.8 years). With a linear regression model, the level of serum angiotensinogen was significantly related to body mass index (
P
=.0017) and the haplotype (
P
=.0001). Within specific race groups, the haplotype was significantly related to serum angiotensinogen in both the blacks (
P
=.0277) and whites (
P
=.0001). The mean level of angiotensinogen was higher in the blacks carrying a single copy of the haplotype than in those without the haplotype (1472.2±68.4 versus 1274.9±46.7 nmol angiotensin I/L), a difference that was marginally significant (
P
=.0609). In the whites, the level of angiotensinogen was also higher in carriers of a single copy than in those with no copy (1527.9±71.2 versus 1099.2±20.1 nmol angiotensin I/L) (
P
=.0003). Serum angiotensinogen level did not increase with two copies of the haplotype, but in each racial group, there were only four individuals who were homozygous. The haplotype showed a marginally significant relation (
P
=.0757) to the mean of longitudinally determined diastolic pressures adjusted for body mass index, race, sex, and age. In summary, using a haplotype to differentiate further the
T235
carrier state, we observed an association of genotype with serum angiotensinogen level and blood pressure in blacks and whites. The findings suggest that
AGT
may play an important role in blood pressure regulation in both racial groups.
Confirmation or Exclusion of Stage I Hypertension by Ambulatory Blood Pressure Monitoring
Authors: Moore Carlton R. , Krakoff Lawrence R. , Phillips Robert A.
Published: June 2012

Abstract
Criteria for the diagnosis or exclusion of hypertension using ambulatory blood pressure monitoring have not been agreed upon. We designed this study to provide a statistically based guide for using results of ambulatory blood pressure monitoring to resolve this issue. To generate this information, we used a database of 228 subjects (135 men, 93 women; average age, 45 years) referred by their primary physicians over the past 7 years for evaluation of borderline or stage I hypertension (average blood pressure, 148/92 mm Hg; SD, ±17.5/12.2 mm Hg). In this population, the pooled SDs of systolic and diastolic ambulatory blood pressures were 13.8 and 11.6 mm Hg, respectively. Using the pooled SD, we calculated the probability that a patient’s blood pressure falls within the hypertensive range (>140/90 mm Hg). The 95% confidence interval for each subject’s blood pressure was also determined. For example, if 40 ambulatory blood pressure measurements are performed on a subject and the average systolic ambulatory blood pressure is 137 mm Hg, then there is a 10% probability that the patient’s “true” average blood pressure is actually in the hypertensive range. By contrast, if the systolic pressure is 143 mm Hg, there is a 90% probability that the patient is hypertensive. This approach may be useful for clinical decision making and also for the design of clinical trials.
Neural Circulatory Responses to Carbon Monoxide in Healthy Humans
Authors: Hausberg Martin , Somers Virend K.
Published: June 2012

Abstract
The contribution of carbon monoxide (CO) to the acute cardiovascular effects of smoking is not clear. Using a double-blind, randomized, vehicle-controlled study design, we examined the sympathetic and vascular responses to modest increases in carboxyhemoglobin in 10 healthy humans. We measured muscle sympathetic nerve activity (microneurography), forearm blood flow (plethysmography), heart rate, blood pressure, and minute ventilation at baseline and during 60 minutes of CO inhalation (1000 ppm during the first 30 minutes and 100 ppm during the last 30 minutes). The same measurements were made in a vehicle session (room air inhalation) on a separate day. During the first 30 minutes of CO inhalation, carboxyhemoglobin levels increased progressively from 0.2±0.1% to 8.3±0.5% and were maintained at about this level for a further 30 minutes. Forearm vascular resistance did not change with CO but increased slightly with vehicle; the effects of CO on muscle sympathetic nerve activity, forearm blood flow, blood pressure, heart rate, and minute ventilation were not significantly different from the effects of vehicle. Modest increases in carboxyhemoglobin levels equivalent to those resulting from cigarette smoking are unlikely to contribute to the acute sympathetic and hemodynamic effects of smoking in healthy humans.
Cardiovascular Effects of Anandamide in Anesthetized and Conscious Normotensive and Hypertensive Rats
Authors: Lake Kristy D. , Martin Billy R. , Kunos George , Varga Károly
Published: June 2012

Abstract
We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of Δ
9
-tetrahydrocannabinol (THC). The prolonged depressor but not the pressor response was reduced after α-adrenergic receptor blockade or cervical spinal cord transection and was inhibited by the cannabinoid type 1 (CB
1
) receptor antagonist SR141716A, suggesting CB
1
receptor–mediated sympathoinhibition as the underlying mechanism. Here we examined the relationship between sympathetic tone and the cardiovascular effects of anandamide by testing these effects in both conscious and anesthetized, normotensive and spontaneously hypertensive rats. In urethane-anesthetized normotensive rats, SR141716A inhibited the prolonged depressor and bradycardic effects of anandamide and THC with similar potency, whereas it did not affect the pressor response to either agent. Anandamide caused similar hypotension in spontaneously breathing and in paralyzed, mechanically ventilated rats, suggesting that the hypotension is not secondary to respiratory effects. In conscious normotensive rats, anandamide elicited transient vagal activation and a brief pressor response, but the prolonged hypotensive component was absent. SR141716A potentiated and prolonged the brief pressor response to anandamide, suggesting that the depressor response may have been masked by an increased pressor response. All three phases of the anandamide response were present in both anesthetized and conscious spontaneously hypertensive rats, and the hypotensive component, inhibited by SR141716A in both, was more prolonged in the absence (>50 minutes) than the presence (10 to 15 minutes) of anesthesia. We conclude that anandamide causes a non–CB
1
receptor–mediated pressor and a CB
1
receptor–mediated prolonged depressor response. The depressor response can be elicited in both conscious and anesthetized animals, but its magnitude depends on preexisting sympathetic tone.
Plasma norepinephrine in essential hypertension. A study of the studies.
Authors: Goldstein D S
Published: June 2012

Of 32 studies comparing plasma norepinephrine concentrations in hypertensive and normotensive groups, 28 (88%) reported higher levels in the hypertensive group. However, only 13 (41%) of the studies reported statistically significant hypertensive-normotensive differences in norepinephrine, leading the present attempt to identify factors differentiating "positive" studies (those reporting significant hypertensive-normotensive differences) from "negative" studies (those reporting nonsignificant differences). Hypertensive norepinephrine levels were similar in positive and negative studies (281 vs 288 pg/ml), but normotensive levels were lower in the positive studies (177 vs 269 pg/ml). When compared with the fluorimetric technique, the radioenzymatic type of assay was associated both with a lower frequency of positive results (25% vs 100%) and greater intrastudy standard deviations (152 vs 72 pg/ml). Hypertensive-normotensive differences varied inversely with age (r = -0.37). Resolution of the persisting controversy about norepinephrine levels in essential hypertension will require more attention to the causes of variability associated with the assay technique, to the sources, characteristics, and treatment of the normotensive controls, and to the age of the patient population.
Blood pressure response to hemodialysis.
Authors: Chaignon M , Chen W T , Tarazi R C , Nakamoto S , Bravo E L
Published: June 2012

Blood pressure response to hemodialysis was investigated in 15 patients with end-stage kidney disease; mean arterial pressure was unchanged in five (Group 1) and reduced 10 mm Hg in 10 (Group 2). The two groups did not differ significantly with regard to either biochemical values or hemodynamic indices before dialysis, and both sustained comparable reduction in body weight, total blood volume, and cardiac output following dialysis. Heart rate remained unchanged in both. The only significant difference between the two was the response of total peripheral resistance (TPR) to fluid depletion. TPR rose adequately in Group 1 but was unchanged in Group 2 (7.5 +/- 2.2 (SE) vs 0.7 +/- 1.1 units, p less than 0.025) despite equal fall in cardiac output in both (881 +/- 212 vs 890 +/- 173 ml/m, p less than 0.10). Thus, differences in arterial pressure response to fluid loss by hemodialysis could be due to impaired autonomic control of resistance vessels; this abnormality might not be revealed by tests of baroreceptor activity that depend only on heart rate responses to blood pressure variations.
Isolation and activation of inactive renin from human kidney and plasma. Plasma and renal inactive renins have different molecular weights.
Authors: Chang J J , Kisaragi M , Okamoto H , Inagami T
Published: June 2012

Inactive renin and active renin from human kidney and human plasma were prepared in highly purified forms by three steps of chromatography on Octyl-Sepharose, immunoaffinity chromatography, and pepstatin-amino hexyl Sepharose CL-4B. The inactive renin and active renin from human kidney had molecular weights of 51,000 and 44,000 as measured by a calibrated gel filtration column run with internal molecular weight standards. Molecular weights of plasma inactive renin and active renin were 56,000 and 51,000 respectively. Both inactive and active renins were found to be heterogeneous, consisting of several components with different isoelectric points. Renal inactive renin has higher pI values of 6.40, 6.10, 5.90, 5.61, and 5.40. Renal active renin has pI values of 5.73, 5.40, 5.25, and 5.13. The pI values of plasma inactive renin were 6.37, 6.08, 5.77, 5.36, and 5.25; of plasma active renin, 5.68, 5.40, 5.33, and 5.25. Trypsin activation and plasmin activation of plasma inactive renin produced an active enzyme with similar molecular weight but lower pI values. Acid activation of inactive renin did not change the molecular weight and pI values.
Cardiac involvement in adolescent hypertension. Echocardiographic determination of myocardial hypertrophy.
Authors: Zahka K G , Neill C A , Kidd L , Cutilletta M A , Cutilletta A F
Published: June 2012

We measured left ventricular chamber dimension and wall thickness using M-mode echocardiography in 61 adolescents with systolic or diastolic blood pressures above the 90th percentile for age and sex and in 49 normotensive adolescents. Left ventricular posterior wall and ventricular septal thickness indexed to body surface area were significantly greater (p less than 0.001) in the hypertensive group than in the normotensive controls. Left ventricular chamber diastolic and systolic dimensions were not different in the hypertensive group when compared to normotensive adolescents with comparable body size. Left ventricular diastolic and systolic volumes as well as left ventricular function did not differ between the hypertensive and control groups. Calculated parameters of left ventricular hypertrophy, namely, the radius-to-wall-thickness ratio, cross-sectional muscle area, and left ventricular mass, in the hypertensive adolescents were all significantly different (p less than 0.001) from those in the control groups. The finding of myocardial hypertrophy in young, mildly hypertensive subjects suggests early myocardial involvement in the hypertensive process.
Angiotensin-converting enzyme inhibitor resets baroreceptor reflexes in conscious dogs.
Authors: Hatton R , Clough D , Faulkner K , Conway J
Published: June 2012

The present experiments investigate whether the absence of tachycardia during lowering of blood pressure (BP) with an angiotensin-converting enzyme inhibitor (CEI) in salt-depleted dogs is due to an alteration in the activity of the baroreflex. Baroreflex activity was measured after pharmacological manipulation of BP using intravenous nitroglycerin or phenylephrine, and the heart period (R-R interval) relative to the arterial pressure pulse was recorded. The slope of the relationship between BP and R-R interval is a measure of the sensitivity of the baroreceptor reflex and displacement of the line indicates a change in the setpoint of BP. On normal sodium diet, the sensitivity and setpoint of the baroreflex were unaltered by the nonapeptide CEI given both intravenously and into a lateral cerebral ventricle. During salt depletion. however, intravenously but not centrally administered CEI altered the setpoint of the baroreflex without modifying the sensitivity. The alteration in the setpoint that occurred following intravenous CEI in the salt-depleted dog could well account for the fact that the fall in BP induced by CEI does not cause reflex tachycardia. These results indicate that circulating but not brain angiotensin II is essential for the maintenance of baroreflex function during sodium depletion and provide further evidence for the important interactions between angiotensin and the autonomic nervous system.
Altered in vitro uptake of norepinephrine by cardiovascular tissues of spontaneously hypertensive rats. Part 2. Portal-mesenteric veins and atria.
Authors: Rho J H , Newman B , Alexander N
Published: June 2012

Norepinephrine (NE) incorporation by portal-mesenteric veins (P-M) veins) and atria of spontaneously hypertensive rats (SHR) were compared with that of age-matched Wistar Kyoto controls (WKY). Tissues were incubated in the presence of tritiated norepinephrine (3H-NE), and fractions were isolated by means by differential and sucrose density gradient centrifugation. The peak of radioactivity was located in the 0.4-0.5 M sucrose region that contained vesicular materials, as shown by electron micrography. NE incorporation (picomoles/mg tissue) into the P3 subfraction of SHR atria and P-M veins was reduced; in atria, the reduction was statistically significant. These results contrasted with the enhanced 3H-NE incorporation by SHR mesenteric artery, and point out regional differences in this process.