bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambulatory Blood Pressure
Authors: Schettini Carlos , Bianchi Manuel , Nieto Fernando , Sandoya Edgardo , Senra Hugo
Published: June 2012

Abstract
—Previous studies have reported results on 24-hour ambulatory blood pressure (ABP) in Europe and Japan, but no data exists from South America. In this study, we conducted a population survey to identify reference values and to compare ambulatory blood pressure with clinic, home, and self-measured values. A random sample of 2650 adults was selected among 190 000 people covered by our prepaid healthcare institution. Clinic (physician and nurse) and home (nurse) blood pressure measurements were performed 3 times each, with semiautomatic electronic equipment. Self-measurements were performed by the subjects manually activating the ambulatory device. We analyzed 1573 individuals who were not receiving antihypertensive therapy from 1921 participants. Self-measurement was available in a subgroup of 577 participants younger than the whole sample. Normal ambulatory blood pressure limits were estimated as those that best correlated with 140/90 mm Hg at clinic. Estimated values were 125/80 mm Hg for 24-hour ambulatory (range: 122 to 128 and 77 to 83 mm Hg) and 129/84 mm Hg for daytime ambulatory (range: 127 to 132 and 81 to 86) blood pressure, depending on gender and age. Ambulatory and clinic blood pressures increased with age. The age-dependent increase in ABP was similar in women and men. Average blood pressure at clinic was 124/79 mm Hg by physician and 123/78 mm Hg by nurse. Nurse measurement at home was 125/78 mm Hg, daytime ambulatory was 121/77 mm Hg, and 24-hour ambulatory was 118/74 mm Hg. The values of the subgroup with self-measurement were physician 119/77 mm Hg; nurse at clinic 118/77 mm Hg; nurse at home 121/78 mm Hg; self-measured 115/72 mm Hg; daytime ambulatory 119/77 mm Hg; and 24-hour ambulatory 115/73 mm Hg. This study shows that a 24-hour ABP average value of 125/80 mm Hg and a daytime ABP average value of 129/84 mm Hg are suitable upper limits for normality. Higher limits would yield an artificially higher prevalence of white coat hypertension. Most subjects showed higher blood pressure levels when measurements were performed by healthcare personnel at a clinic or at home than when self-measured at home.
Kinin B2 Receptors Mediate Blockade of Atrial Natriuretic Peptide Natriuresis Induced by Glucose or Feeding in Fasted Rats
Authors: Croxatto Héctor R. , Figueroa Xavier F. , Roblero Juan , Boric Mauricio P.
Published: June 2012

Abstract
—We have shown previously that the kininogen-derived peptides bradykinin, prokinins, and PU-D1, given intravenously or into the duodenal lumen, block the atrial natriuretic peptide (ANP)-induced diuretic-natriuretic effect in fasting, anesthetized rats infused with isotonic glucose. HOE-140, an inhibitor of bradykinin B2 receptors, completely suppresses this ANP blockade. When intravenous glucose infusion is omitted, the above-described inhibition of ANP does not take place. Therefore, to clarify the role of glucose and/or feeding in this phenomenon, we used fasted, anesthetized rats to test how the ANP excretory response was affected by (1) short-term feeding before anesthesia, (2) 1 mL of isotonic glucose introduced into the stomach, and (3) the interaction of HOE-140 with these treatments. In addition, we tested the effects of 1 mL of intragastric glucose administration and HOE-140 on urinary excretion in awake rats. In anesthetized rats, both glucose administration and feeding significantly inhibited the diuretic-natriuretic effect of ANP for up to 90 minutes. Similarly, intragastric glucose delayed spontaneous sodium and water excretion for 90 minutes in awake rats. In all 3 cases, pretreatment with HOE-140 (2.5 μg IV) fully prevented the inhibition of ANP excretory action, ruling out osmotic effects as the cause of reduced diuresis. These results indicate that the presence of glucose in the digestive tract triggers an inhibitory effect on ANP renal actions that requires activation of kinin B2 receptors, providing strong support to our hypothesis that during the early prandial period, gastrointestinal signals elicit a transient blockade of renal excretion with a mechanism involving the kallikrein-kinin system.
Responses to Acute Changes in Arterial Pressure on Renal Medullary Nitric Oxide Activity in Dogs
Authors: Majid Dewan S. A. , Said Karim E. , Omoro Sophia A.
Published: June 2012

Abstract
—A direct relationship between renal arterial pressure (RAP) and cortical tissue nitric oxide (NO) activity in the canine kidney was reported earlier. We have conducted further experiments to evaluate medullary NO responses to alterations in RAP with the use of a NO-selective microelectrode inserted into the renal medulla of 6 anesthetized, sodium-replete dogs. Graded reductions in RAP (from 140 to 80 mm Hg) elicited decreases in medullary tissue NO concentration, with a slope of 10.2±4.5 nmol · L
−1
· mm Hg
−1
. These changes in NO levels were associated with decreases in urinary excretion rate of nitrate and nitrite (U
NOx
V; control value, 1.7±0.03 nmol · min
−1
· g
−1
; slope, 0.02±0.004 nmol · min
−1
· g
−1
· mm Hg
−1
) and sodium excretion (U
Na
V; control, 3.2±0.7 μmol · min
−1
· g
−1
; slope, 0.06±0.02 μmol · min
−1
· g
−1
· mm Hg
−1
) without changes in glomerular filtration rate control (0.84±0.06 mL · min
−1
· g
−1
). Intra-arterial administration of the NO synthase inhibitor
N
ω
-nitro-
l
-arginine (NLA; 50 μg · kg
−1
· min
−1
) decreased medullary NO concentration by 218±55 nmol · L
−1
(n=5) and attenuated the relationship between RAP and NO concentration (slope, 2.7±2.2 nmol · L
−1
· mm Hg
−1
). NLA infusion decreased U
NOx
V (0.8±0.06 nmol · min
−1
· g
−1
) and U
Na
V (1.1±0.2 μmol · min
−1
· g
−1
) without changes in glomerular filtration rate and attenuated RAP versus U
Nox
V and U
Na
V relationships. Total and regional blood flows, as measured by electromagnetic and laser Doppler needle flow probes, respectively, remained autoregulated both before and during NLA infusion. These data support the hypothesis that acute changes in RAP elicit changes in intrarenal NO production, which may participate in the mediation of pressure natriuresis.
Cyclooxygenase-2 Modulates Afferent Arteriolar Responses to Increases in Pressure
Authors: Ichihara Atsuhiro , Imig John D. , Navar L. Gabriel
Published: June 2012

Abstract
—This study was designed to examine the contribution of cyclooxygenase-2 (COX-2) in the afferent arteriolar autoregulatory responses to increases in perfusion pressure and its relationship with neuronal nitric oxide synthase (nNOS). In rat kidneys, afferent arteriolar diameter responses to increases in perfusion pressure were assessed in vitro with the blood-perfused juxtamedullary nephron technique. Basal afferent arteriolar diameter at 100 mm Hg averaged 21.0±1.2 μm (n=7), and the vasoconstrictor response to increasing perfusion pressure to 160 mm Hg averaged 18.4±1.2%. Superfusion with the COX-2 inhibitor NS398 (10 μmol/L) did not influence basal diameters, but it did significantly enhance the vasoconstrictor response to the increase in perfusion pressure (32.9±4.0%). In contrast to previous findings that the nNOS inhibitor
S
-methyl-
l
-thiocitrulline (10 μmol/L) enhanced afferent arteriolar autoregulatory responses in normal rat kidneys, in this study, administration of 10 μmol/L
S
-methyl-
l
-thiocitrulline did not further modulate the vasoconstrictor response to increases in perfusion pressure in the NS398-treated kidneys of normal rats (31.8±4.7%). When tubuloglomerular feedback activity was interrupted by papillectomy and the addition of 50 μmol/L furosemide to the blood perfusate (n=5 for each), the afferent arteriolar constrictor responses to increasing perfusion pressure to 160 mm Hg averaged 7.9±0.9% and 10.7±0.7%, respectively, and they were significantly attenuated compared with the responses observed in control kidneys. NS398 treatment did not modulate the afferent arteriolar autoregulatory responses in papillectomized or furosemide-treated kidneys. These results indicate that COX-2–derived metabolites contribute to the nNOS modulation of pressure-mediated afferent arteriolar autoregulatory responses.
Protective Effects of Captopril Against Ischemic Stress
Authors: Barbagallo Mario , Dominguez Ligia J. , Resnick Lawrence M.
Published: June 2012

Abstract
—Magnesium (Mg) deficiency enhances tissue sensitivity to ischemic damage, an effect reversed not only by Mg, but also by sulfhydryl (SH)-containing compounds. We therefore created an in vitro model of red blood cell ischemia to investigate whether the protective effects of these compounds might be related to effects on intracellular free Mg (Mg
i
) content.
31
P-nuclear magnetic resonance (NMR) spectroscopy was used to measure the high-energy metabolites ATP and 2,3-diphosphoglycerate (DPG) and Mg
i
and inorganic phosphate (P
i
) levels in erythrocytes before and for 6 hours after progressive oxygen depletion in the presence or absence of SH-compounds, including captopril,
N
-acetyl-
l
-cysteine (NAC), penicillamine, and
N
-(2-mercaptopropionyl)-glycine (MPG). Under basal aerobic conditions, captopril increased Mg
i
in a dose- and time-dependent fashion (174.5±5.3 to 217.1±5.1 μmol/L,
P
<0.05 at 100 μmol/L, 60 minutes). The SH compounds NAC, penicillamine, and MPG but not the non-SH compound enalaprilat also significantly raised Mg
i
in erythrocytes (
P
<0.05). With oxygen deprivation, a consistent decrease occurred in both ATP and 2,3-DPG levels associated with a rise in P
i
and in the P
i
/2,3-DPG ratio used as an index of high-energy metabolite depletion. Captopril, compared with control, retarded the rise in P
i
and reduced the P
i
/2,3-DPG ratio (
P
<0.008 and
P
<0.025 at 4 and 6 hours, respectively). Furthermore, the higher the initial Mg
i
and the greater the captopril-induced rise in Mg
i
, the greater the metabolite-protective effect (
r
=0.799 and
r
=0.823, respectively;
P
<0.01 for both). Altogether, the data suggest that Mg influences the cellular response to ischemia and that the ability of SH compounds such as captopril to ameliorate ischemic injury may at least in part be attributable to the ability of such compounds to increase cytosolic free Mg levels.
Cardiovascular Effects of Angiotensin-(1–7) in Conscious Spontaneously Hypertensive Rats
Authors: Widdop Robert E. , Sampey Donella B. , Jarrott Bevyn
Published: June 2012

Abstract
—In the present study, we reassessed whether angiotensin (Ang)-(1–7) can exert short- and long-term cardiovascular effects because there has been a resurgence of interest in this N-terminal heptapeptide fragment of Ang II. In particular, we studied 3 aspects relating to the reported cardiovascular effects of Ang-(1–7): does this peptide (1) potentiate the hypotensive effect of bradykinin in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHR), (2) cause a depressor effect after long-term treatment in SHR, and (3) contribute to the antihypertensive effects of angiotensin-converting enzyme inhibitors? In the first series of experiments, Ang-(1–7) failed to enhance the dose-related hypotensive responses evoked by bradykinin in SHR (n=11) and Wistar-Kyoto (n=5) rats. In the second series of experiments, a 7-day intravenous infusion of Ang-(1–7) (24 μg · kg
−1
· h
−1
) decreased blood pressure in SHR (n=12) on days 4 and 5, although this effect waned despite continual Ang-(1–7) infusion. However, a new finding was that the Ang-(1–7) antagonist A-779 (24 μg · kg
−1
· h
−1
for 7 days) attenuated the depressor effect of Ang-(1–7) when given concurrently in a separate group of SHR (n=8). In the third series of novel experiments, the angiotensin-converting enzyme inhibitor perindopril was given in drinking water for 7 days (0.3 mg · kg
−1
· day
−1
), either alone (n=6) or combined with an intravenous infusion of A-779 (24 μg · kg
−1
· h
−1
for 7 days, n=8). Although this dose of A-779 attenuated the depressor effect of Ang-(1–7), it did not alter the antihypertensive effect caused by perindopril. Thus, the present results contrast with a number of previous studies and argue against Ang-(1–7) playing a major role in blood pressure regulation.
Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells
Authors: Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Intracellular signaling events that mediate the long-term effects of Ang II in vascular smooth muscle cells are unclear, but oxidative stress may play an important role. This study examined the ability of Ang II to generate reactive oxygen species and investigated the putative role of phospholipase D (PLD)–dependent signaling pathways for its production in human vascular smooth muscle cells. In addition, we assessed whether redox-sensitive pathways influence Ang II–stimulated cell growth. Primary and low-passage cells (passages 1 to 4) derived from resistance arteries of subcutaneous gluteal biopsies from healthy subjects were studied. Oxidative stress was measured with the fluorescent probe 5-(and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H
2
DCFDA) (8 μmol/L), and the role of PLD was assessed with the PLD inhibitor
d
-
erythro
-sphingosine, dihydro (sphinganine) (10 μmol/L). To determine whether NADH/NADPH oxidase contributes to production of reactive oxygen species, Ang II–stimulated cells were pretreated with the specific flavoprotein inhibitor diphenylene iodinium (DPI) (10 μmol/L). DNA and protein synthesis were determined by [
3
H]thymidine and [
3
H]leucine incorporation, respectively. Ang II increased CM-H
2
DCFDA fluorescence, and this was inhibited by catalase (350 U/mL), indicating that the fluorescence signal was derived predominantly from H
2
O
2
. Ang II dose-dependently increased H
2
O
2
production (E
max
=57.6±1.7 nmol/L, pD
2
=7.7±0.06) and PLD activation (E
max
=207±3.3% of control, pD
2
=7.7±0.5). H
2
O
2
effects were evident within 1 hour, and maximal PLD activation occurred within 40 minutes after stimulation. DPI inhibited (
P
<0.01) Ang II–stimulated responses. PLD inhibition significantly attenuated (
P
<0.05) Ang II–elicited H
2
O
2
production (E
max
=29±5 nmol/L). DPI and sphinganine inhibited Ang II–induced DNA and protein synthesis. These data indicate that in vascular smooth muscle cells from human peripheral resistance arteries, Ang II increases H
2
O
2
generation via PLD-dependent, NADH/NADPH oxidase–sensitive pathways. These cascades may function as second messengers in long-term Ang II–mediated growth-signaling events.
Influence of Verapamil and Diclofenac on Leukocyte Migration in Rats
Authors: Martinez Luis Lopez , Aparecida de Oliveira Maria , Fortes Zuleica Bruno
Published: June 2012

Abstract
—Nonsteroidal anti-inflammatory drugs and calcium channel blockers can reduce inflammatory responses. Leukocytes play an important role in these responses. An increased expression of adhesion molecules may increase leukocyte migration. Verapamil and diclofenac are known to reduce leukocyte-endothelium interaction. To investigate a possible synergism between these drugs that could be beneficial in cardiovascular diseases, we studied leukocyte behavior by using intravital microscopy. Venules of the spermatic fascia of anesthetized Wistar rats were observed with a closed-circuit TV coupled to an optical microscope. The number of leukocytes rolling along the venular endothelium (“rollers”), sticking after application of a stimulus such as leukotriene B
4
or zymozan-activated plasma (“stickers”), or migrating after a carrageenan stimulus was reduced by verapamil at the dose of 10 mg/kg IP and by diclofenac at the dose of 2.5 mg/kg IP. The combination of both did not augment the effect of each agent alone. Verapamil, diclofenac, or their combination did not interfere with vessel diameter, number of circulating leukocytes, blood pressure levels, or heart rate. Verapamil alone or together with diclofenac reduced venular blood flow velocity and in consequence, the venular shear rate. Our data allow us to suggest that these drugs might interfere with the expression of adhesion cell molecules to reduce cell migration in inflammation. The lack of synergism between the drugs might be explained by the reduction in venular shear rate induced by verapamil, which might not be sufficient to hinder the effect of verapamil alone but hindered the summation effects of both.
Effects of Transdermal 17β-Estradiol on Left Ventricular Anatomy and Performance in Hypertensive Women
Authors: Modena Maria Grazia , Muia Nicola , Aveta Pietro , Molinari Rosella , Rossi Rosario
Published: June 2012

Abstract
—To reduce cardiovascular complications, antihypertensive therapy should not only normalize blood pressure but also induce a regression of structural abnormalities, which are the expression of end-organ damage. We investigated the effects of transdermal 17β-estradiol, combined with standard antihypertensive therapy, on the modification of left ventricular anatomy and systolic performance in hypertensive postmenopausal women. In a randomized, double-blind, placebo-controlled study, we enrolled 169 postmenopausal women with mild or moderate hypertension. Eighty-six patients (group 1) received transdermal 17β-estradiol (50 μg/d) and norethisterone acetate (2.5 mg/d, orally), and 83 patients (group 2) received placebo. At baseline, all women underwent M-mode and 2-D echocardiogram, which was repeated after 6, 12, and 18 months of follow-up. After 18 months of treatment, we observed a significant decrease in left ventricular diastolic septal and posterior wall thickness and mass in both groups. Furthermore, after 18 months, left ventricular mass was significantly less than in the estrogen-treated group. No significant modifications were observed in left ventricular systolic and diastolic dimensions or in systolic performance, as expressed by left ventricular fractional shortening. In conclusion, transdermal 17β-estradiol, which is associated with antihypertensive therapy, may contribute in the reduction of left ventricular mass in hypertensive postmenopausal women.
Elements of a Paracrine Tubular Renin-Angiotensin System Along the Entire Nephron
Authors: Rohrwasser Andreas , Morgan Terry , Dillon Harrison F. , Zhao Ling , Callaway Christopher W. , Hillas Elaine , Zhang Shuhua , Cheng Tong , Inagami Tadashi , Ward Kenneth , Terreros Daniel A. , Lalouel Jean-Marc
Published: June 2012

Abstract
—The renin-angiotensin system is a major regulator of body sodium, predominantly through the actions of intrarenal angiotensin II of unclear origin. We show that polarized epithelium of the proximal tubule synthesizes and secretes angiotensinogen at its apical side and that the protein can be detected in urine as a function of dietary sodium. Furthermore, we demonstrate that renin is expressed and secreted in a restricted nephron segment, the connecting tubule, also in a sodium-dependent fashion. A paracrine renin-angiotensin system operating along the entire nephron may contribute to long-term arterial pressure regulation by integrating distant tubular sodium-reabsorbing functions.
New β-Blocker
Authors: Clare Zhang Yuan , Kimura Birgitta , Shen Leping , Phillips M. Ian
Published: June 2012

Abstract
—β-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel β-blocker by targeting β
1
-adrenergic receptor (β
1
-AR) mRNA with antisense oligodeoxynucleotides (β
1
-AS-ODN). A single intravenous injection of β
1
-AS-ODN significantly reduced cardiac contractility and blood pressure (38±5 mm Hg,
P
<0.05) in spontaneously hypertensive rats for 3 weeks. In the present study, we improved the antihypertensive effect of β
1
-AS-ODN by delivery with the cationic liposomes DOTAP/DOPE and studied its impact on the peripheral renin-angiotensin system. Five charge ratios (±) of liposome/ODN from 0 to 3.5 were tested to deliver 0.5 mg/kg β
1
-AS-ODN intravenously in spontaneously hypertensive rats (n=30). On the basis of the magnitude and duration of hypotension, 2.5 was determined to be the optimal charge ratio, which decreased blood pressure by up to 35 mm Hg for 20 to 33 days (
P
<0.05). The effects were specific for β
1
-AR, because radioligand binding assay and quantitative autoradiography showed a 35% reduction in β
1
-AR levels in kidney but no change in β
2
-AR. β
1
-AS-ODN diminished the preprorenin mRNA levels in renal cortex by 37% 4 days after administration. This transient effect was followed by a delayed yet marked diminution of plasma renin activity and plasma angiotensin II levels on days 10 and 17 (
P
<0.01). The results show that β
1
-AS-ODN has an effective long-term antihypertensive effect up to 33 days with a single intravenous injection. The mechanism appears to be through reduced β
1
-AR number specifically and reduced cardiac contractility. The inhibition of the renin-angiotensin system is probably a second mechanism to produce the sustained antihypertensive effect of β
1
-AS-ODN.
G-Protein–Coupled Receptor Kinase Activity in Hypertension
Authors: Gros Robert , Chorazyczewski Jozef , Meek Murray D. , Benovic Jeffrey L. , Ferguson Stephen S. G. , Feldman Ross D.
Published: June 2012

Abstract
—Impaired receptor-stimulated adenylyl cyclase activation has been observed in lymphocytes from hypertensive subjects and has been linked to an increase in lymphocyte G-protein receptor kinase-2 (GRK-2) protein expression. However, whether the increase in lymphocyte GRK-2 reflected an increase in vascular GRK-2 was unknown. Therefore, we compared GRK-2 protein expression in lymphocytes and aortas obtained from normotensive Wistar rats, Wistar-Kyoto rats (WKY), and spontaneously hypertensive rats (SHR) and from aortas of Dahl rats. Impaired β-adrenergic responsiveness was observed in lymphocytes and vascular tissues obtained from hypertensive SHR (10 and 15 weeks old) but not in those obtained from prehypertensive SHR (5 weeks old). Immunodetectable lymphocyte GRK-2 protein expression was increased in 10-week-old SHR (143±10% of the expression in 10-week-old Wistar rats and 131±11% of the expression in 10-week-old WKY, n=5 in each group). Immunodetectable vascular smooth muscle cell GRK-2 was comparably increased (169±14% of the expression in Wistar rats and 138±7% of the expression in WKY, n=5 in each group). Also, in hypertensive Dahl salt-sensitive rats, vascular GRK-2 protein expression was increased (185±14% of the expression in Dahl salt-resistant rats, n=5 in each group) compared with Dahl salt-resistant controls. These studies support a generalized defect in vascular GRK-2 protein expression in hypertension, which could be an important factor in the impairment of β-adrenergic–mediated vasodilation, characteristic of the hypertensive state.
High- or Low-Salt Diet From Weaning to Adulthood
Authors: Prada Patrícia de O. , Okamoto Maristella M. , Furukawa Luzia Naôko S. , Machado Ubiratan Fabres , Heimann Joel C. , Dolnikoff Miriam Sterman
Published: June 2012

Abstract
—Because of conflicting results in the literature, further studies are needed to confirm an association between the degree of salt consumption and insulin sensitivity. The aim of this study was to measure insulin sensitivity in rats fed from weaning to adulthood with a low (LSD), normal (NSD), or high (HSD) salt diet. Body weight, carcass lipid content, blood glucose, nonesterified fatty acids, plasma insulin, plasma renin activity, and a glucose transporter (GLUT4) were measured. A euglycemic hyperinsulinemic clamp was used in 52 anesthetized rats. Body weight was higher in rats on LSD than in those on NSD (
P
<0.05) or HSD (
P
<0.001). Percentage fat carcass content was higher (
P
<0.05) in rats on LSD than in those on NSD. Basal plasma insulin and glucose levels were not altered (
P
>0.05) by salt consumption. Nonesterified fatty acids were lower in rats on HSD than in those on LSD (
P
<0.05) or NSD (
P
<0.01). Glucose uptake was lower in rats on LSD than in those on NSD (
P
<0.05) or HSD (
P
<0.001). When a euglycemic hyperinsulinemic clamp was used on pair-weight rats, similar results were obtained, which suggests that the effect of LSD on insulin sensitivity was not due to higher body weight. GLUT4 in insulin-sensitive tissues was increased in rats on HSD except in the cardiac muscle. Captopril treatment partially reversed low insulin sensitivity in LSD rats, whereas losartan did not change it, which indicates that the effect of LSD on insulin sensitivity is angiotensin independent. In conclusion, the present results demonstrate that chronic dietary salt restriction induces a decrease in insulin sensitivity not associated with renin-angiotensin system activity or body weight changes.
A Nonpeptide Mimic of Bradykinin Blunts the Development of Hypertension in Young Spontaneously Hypertensive Rats
Authors: Majima Masataka , Hayashi Izumi , Inamura Naoya , Fujita Tomoe , Ogino Michiko
Published: June 2012

Abstract
—We tested whether
FR190997
, a nonpeptide B
2
agonist, prevented the development of hypertension in young spontaneously hypertensive rats (SHR), which secrete less kallikrein into the urine than do Wistar-Kyoto rats. An intra-arterial (IA) injection of
FR190997
(0.3 to 30 nmol/kg) caused dose-dependent hypotension in conscious Sprague-Dawley rats. Although the maximum hypotensive potency of
FR190997
equaled that of bradykinin, its action lasted ≈10 times as long. Hoe140 (100 nmol/kg IA) significantly blocked the hypotensive response induced by
FR190997
(10 nmol/kg). Atropine (100 nmol/kg IA) did not affect this response. A selective infusion of
FR190997
into the renal artery induced natriuresis and diuresis in anesthetized rabbits. A continuous infusion (2 nmol · 10 mL
−1
· h
−1
per rat) of
FR190997
into the abdominal aorta of young SHR (6 weeks old, n=6) for 6 days significantly (
P
<0.05) reduced mean blood pressure to 114±6 (day 2) and 110±6 (day 5) mm Hg, from 149±7 and 162±6 mm Hg, respectively, in vehicle-infused rats (n=6). At 8 days after continuous infusion (day 14), mean blood pressure (148±5 mm Hg) in
FR190997
-infused rats remained significantly (
P
<0.05) lower than that in vehicle-infused rats (190±6 mm Hg), almost the peak value. The mesenteric artery isolated from
FR190997
-treated rats (day 14) had lower contractile sensitivity to norepinephrine than that from vehicle-treated rats. These results suggested that the continuous infusion of a nonpeptide B
2
agonist may prevent hypertension if performed in the critical phase.
Microalbuminuria and Pulse Pressure in Hypertensive and Atherosclerotic Men
Authors: Pedrinelli Roberto , Dell’Omo Giulia , Penno Giuseppe , Bandinelli Simona , Bertini Alessio , Di Bello Vitantonio , Mariani Mario
Published: June 2012

Abstract
—To identify the biological covariates of microalbuminuria (albuminuria ≥15 μg/min) in nondiabetic subjects, brachial blood pressure, echocardiographic left ventricular mass, and other cardiovascular and metabolic parameters were evaluated in 211 untreated males (38 normal controls, 109 uncomplicated stage 1 to 3 essential hypertensives, and 64 patients with clinically stable atherosclerotic peripheral vascular disease either with [n=44] or without [n=20] essential hypertension) with normal cardiac and renal function. Compared with normoalbuminuric subjects, microalbuminuric subjects (n=67) were characterized by higher systolic blood pressure, comparable diastolic blood pressure, and, therefore, wider pulse pressure. Greater prevalence of hypertension, peripheral vascular disease, left ventricular hypertrophy, and reduced HDL cholesterol values further distinguished microalbuminuric from normoalbuminuric subjects in univariate comparisons. The risk of microalbuminuria increased by ascending pulse pressure quintiles in age-corrected logistic regression models, in which pulse pressure was more predictive than systolic pressure and was independent of mean pressure. When microalbuminuric status was regressed against a series of dichotomous (vascular and active smoker status) and continuous (age, pulse and mean pressure, left ventricular mass index, and HDL and LDL cholesterol) variables, only pulse pressure, left ventricular mass index, and smoking status were independent predictors. The association of increased albuminuria with wider pulse pressure, a correlate of the pulsatile hemodynamic load and conduit vessel stiffness as well as an important cardiovascular risk factor, may explain why microalbuminuria predicts cardiovascular events in nondiabetic subjects. The independence from concomitant vascular disease also suggests that wider pulse pressure, rather than representing a simple marker for atherosclerotic disease, influences albuminuria directly.
Socioeconomic Status and Blood Pressure Reactivity in Healthy Black Adolescents
Authors: Wilson Dawn K. , Kliewer Wendy , Plybon Laura , Sica Domenic A.
Published: June 2012

Abstract
—Adolescents in low-socioeconomic-status environments are more susceptible to illnesses, such as hypertension and cardiovascular diseases. This study examined the influence of both neighborhood- and family-level socioeconomic status (SES) on blood pressure (BP) reactivity in a healthy sample of 76 black adolescents. It was hypothesized that a higher level of parental education and/or income would reduce the elevated BP reactivity associated with living in poorer neighborhoods. Census-derived data were obtained using each participant’s address. Neighborhood level of SES was based on percentage of households below the poverty line, female-headed households, owner-occupied housing, percentage vacant housing, and average number of persons per household. Family level of SES was based on self-reported level of parental education and annual family income. Adolescents participated in a competitive video game to establish their BP reactivity scores. As predicted, adolescents who lived in poorer neighborhoods had lower diastolic BPs if their parents were more (versus less) educated (
P
<0.05; 7±8 versus 13±6 mm Hg). Adolescents who lived in poorer neighborhoods also had significantly lower diastolic BP reactivity (
P
<0.05) if their family had a higher (versus lower) annual income (7±7 versus 12±8 mm Hg). These data are the first to demonstrate the buffering effect of family SES on the negative health consequences of living in low-SES neighborhoods in healthy black adolescents.
Pranidipine Enhances the Action of Nitric Oxide Released From Endothelial Cells
Authors: Yang Jin , Fukuo Keisuke , Morimoto Shigeto , Niinobu Tadaaki , Suhara Toshimitsu , Ogihara Toshio
Published: June 2012

Abstract
—Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. Calcium antagonists have been shown to improve endothelial function in hypertensive patients. Here we report that pranidipine, one of the latest long-acting calcium antagonists in the dihydropyridine group, enhances the actions of NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP accumulation in vascular smooth muscle cells cocultured with ECs, whereas amlodipine and nifedipine had no significant effects. In addition, pranidipine also suppressed basal and thrombin-stimulated endothelin-1 production from ECs. Pranidipine also enhanced cGMP accumulation in rat aortic segments with endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had no effect in the presence of
N
G
-monomethyl-
l
-arginine, an inhibitor of NO synthesis. Pranidipine did not affect the basal expression of endothelial NO synthase in ECs. However, pranidipine upregulated the activity of superoxide dismutase in ECs. These findings suggest that pranidipine enhances NO action through inhibition of superoxide-induced NO decomposition in the vessel wall. Thus, pranidipine may be useful in the treatment of impaired endothelial function in patients with hypertension.
Heritability of Central Systolic Pressure Augmentation
Authors: Snieder Harold , Hayward Christopher S. , Perks Ursula , Kelly Raymond P. , Kelly Paul J. , Spector Tim D.
Published: June 2012

Abstract
—Less than 50% of the variance in left ventricular mass is explained by conventional factors such as age, blood pressure, and body size. Genetic influences may account for part of the unexplained variance. The central (aortic) pressure augmentation index has been suggested as a noninvasive measure of pulsatile load, which is a likely determinant of left ventricular mass. We quantified the genetic influence on augmentation index and determined the extent to which this influence is dependent on the effects of age, height, heart rate, and blood pressure. We performed a classical twin study composed of 225 monozygotic and 594 dizygotic female white twin pairs aged 18 to 73 years. Augmentation index and mean arterial pressure were based on the central pressure wave derived from the radial waveform as measured by applanation tonometry. Quantitative genetic modeling techniques were used to analyze the data. The heritability of augmentation index was 37%, whereas heritabilities for blood pressure traits varied between 13% and 25%. Most of the variance in augmentation index could be explained by genetic and environmental factors specifically influencing augmentation index. Only a relatively small part of the total variance in augmentation index could be attributed to genes in common with height (3.1%), heart rate (4.6%), and mean arterial pressure (5.6%). Age explained 19% of the total variation in augmentation index. In conclusion, augmentation index has a significant heritable component, which is largely independent of the influence of blood pressure, heart rate, height, and age. Finding genes for the augmentation index could help to unravel pathophysiological mechanisms causing left ventricular hypertrophy and lead to improvements in prevention, diagnosis, and treatment of at-risk populations.
Elevated Perfusion Pressure Upregulates Endothelin-1 and Endothelin B Receptor Expression in the Rabbit Carotid Artery
Authors: Lauth Manfred , Berger Marc-Moritz , Cattaruzza Marco , Hecker Markus
Published: June 2012

Abstract
—To investigate the hypothesis that high blood pressure activates the endothelin system in the vessel wall, isolated segments of the rabbit carotid artery were subjected to different levels of perfusion pressure. Both preproendothelin-1 (ppET-1) mRNA abundance and intravascular ET-1 peptide content were strongly upregulated on raising the intraluminal pressure from 90 to 160 mm Hg for 3 to 12 hours, and this increase in ppET-1 mRNA occurred predominantly in the endothelial cells. Endothelin-converting enzyme-1 and endothelin A receptor (ET
A
-R) expression were pressure-insensitive, whereas that of the ET
B
-R in the smooth muscle cells was also significantly enhanced. Both the pressure-induced increase in ppET-1 and ET
B
-R expression required RNA synthesis because they were abolished by actinomycin D. The nuclear signaling mechanisms involved therein, however, appeared to be different. Thus, the pressure-induced expression of ppET-1 and activation of CCAAT-enhancer binding proteins β and δ were blocked by the tyrosine kinase inhibitor herbimycin A, whereas ET
B
-R expression and the nuclear translocation of activator protein-1 were abolished by the protein kinase C inhibitor Ro 31-8220. One consequence of these presumably deformation-induced changes in gene expression was an increased rate of apoptosis of the smooth muscle cells in the media that if transferable to the situation in human blood vessels may contribute to hypertension-induced arterial remodeling.
Effect of Salt on Insulin Sensitivity Differs According to Gender and Degree of Salt Sensitivity
Authors: Melander Olle , Groop Leif , Hulthén U. Lennart
Published: June 2012

Abstract
—The aim of the present study was to investigate the effect of salt intake on insulin sensitivity and the relation between salt sensitivity and insulin sensitivity in genetically hypertension-prone individuals. Twenty-eight healthy subjects (13 men and 15 women) with a family history of hypertension were examined at baseline, after 1 week of salt restriction (10 mmol/d), and after 1 week of salt loading (240 mmol/d). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp after the low- and high-salt diets. Salt sensitivity was defined as the difference in mean arterial blood pressure between the high-salt and the low-salt diets. There was no significant relationship between insulin sensitivity and salt sensitivity after either of the 2 diets. In the men, salt sensitivity was inversely related to plasma renin activity (
r
=−0.61,
P
=0.03) and plasma aldosterone (
r
=−0.74,
P
=0.004), whereas salt sensitivity in women was directly correlated with the salt-induced increase in body weight (
r
=0.68,
P
=0.005). In men, the high-salt diet induced a change in glucose disposal that was strongly correlated with the degree of salt sensitivity (
r
=0.83,
P
=0.0004), plasma renin activity (
r
=−0.82,
P
=0.0006), and plasma aldosterone concentrations (
r
=−0.87,
P
=0.00009) (eg, the greater the salt sensitivity and the lower the activity of the renin-angiotensin-aldosterone system, the greater improvement in insulin sensitivity). No such relationships were observed in women. In conclusion, increased salt sensitivity and decreased activity of the renin-angiotensin-aldosterone system predict improved insulin sensitivity with high-salt intake compared with low-salt intake in men, suggesting an interaction among salt intake, salt sensitivity, the renin-angiotensin-aldosterone system, and insulin action.
Elevated Intraluminal Pressure Inhibits Vascular Tissue Plasminogen Activator Secretion and Downregulates Its Gene Expression
Authors: Sjögren Lena Selin , Doroudi Roya , Gan Li-ming , Jungersten Lennart , Hrafnkelsdóttir Thórdís , Jern Sverker
Published: June 2012

Abstract
—We recently discovered that patients with essential hypertension have a markedly impaired capacity for stimulated release of tissue plasminogen activator (tPA) from vascular endothelium. This defect may reduce the chance of timely spontaneous thrombolysis in case of an atherothrombotic event. We now investigated whether increased intraluminal pressure as such may depress vascular tPA release or downregulate its gene expression. Segments of human umbilical veins were studied in a new computerized vascular perfusion model under steady laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear stress (10 dyne/cm
2
). Quantitative immunohistochemical evaluation of cellular tPA immunoreactivity was performed on paraffin-embedded 5-μm vascular sections. tPA mRNA in endothelial cells was quantified with reverse transcription real-time TaqMan polymerase chain reaction with GAPDH as endogenous control. Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western blotting, followed by densitometric quantification. High-pressure perfusion downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (
P
=0.01) compared with vessels perfused under normal intraluminal pressure. tPA release into the perfusion medium was markedly suppressed by high pressure (
P
<0.01 ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3 hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein expression and inhibits its release from the endothelium independently of shear stress. The defective capacity for stimulated tPA release that we demonstrated in patients with essential hypertension might thus be an effect of the elevated intraluminal pressure per se.
Department of Veterans Affairs Hypertension Meeting
Authors: Perry H. Mitchell , Freis Edward D. , Frohlich Edward D.
Published: June 2012

Abstract
—A major invitational hypertension meeting was hosted by the Department of Veterans Affairs (VA) in Washington, DC, on May 26 to 28, 1999. It followed a report that only 25% of hypertensive veterans had adequate levels of treated blood pressure and focused on how control of hypertension could be improved both immediately and in the future. After the presentation of brief outlines of 5 unresolved basic science questions, 2 general topics were considered: (1) 30 years of change in hypertension and its treatment and (2) current healthcare delivery mechanisms and how to improve them. Since 1970, the severity of hypertension has decreased, malignant hypertension has disappeared, and the prognostic roles of systolic and diastolic blood pressure have been reversed as hypertension became milder. Five VA Cooperative Studies have provided important data: the 1970 Freis Trial report demonstrated the value of treatment, 2 trials showed that some controlled patients can decrease or even discontinue pharmacological treatment without recrudescent hypertension, a blinded trial was performed on the efficacy of different antihypertensive drugs, and an unblinded trial showed that diuretics and β-blockers are the most effective agents when caregivers choose the agent and dose. Two healthcare models were considered: (1) the patient-friendly VA Hypertension Screening and Treatment Program that was introduced in 1972, which controls 80% of patients at the goal of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure with diuretics and keeps patients in the program an average of 7.5 years, and (2) the newer primary care health maintenance organization–like model in the VA and throughout the United States. Choosing a regimen and monitoring control of blood pressure and compliance with therapy were discussed. The meeting was closed with 6 general recommendations for improving the care of hypertensive patients.
Shear Stress–Induced Release of Prostaglandin H
2
in Arterioles of Hypertensive Rats
Authors: Huang An , Sun Dong , Koller Akos
Published: June 2012

Abstract
—The nitric oxide–mediated portion of shear stress–induced dilation of rat gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive rats (SHR). Because shear stress–induced dilation is primarily mediated by endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized that in the cremasteric vascular bed the mediation of shear stress–induced dilation by prostaglandins is altered in hypertension. At a constant intraluminal pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0±3.1 and 51.7±3.6 μm, respectively, whereas their passive diameters were 109.4±4.4 and 101.9±6.7 μm, respectively. Dilations to increases in shear stress elicited by increases in intraluminal flow (from 0 to 25 μL/min) were significantly less (
P
<0.05) in cremasteric arterioles isolated from SHR than from WKY. Arachidonic acid (10
−5
mol/L) elicited constrictions in SHR arterioles but dilations in WKY arterioles. The prostaglandin H
2
/thromboxane A
2
(PGH
2
/TxA
2
) receptor antagonist SQ 29,548 (10
−6
mol/L) significantly increased basal diameter by 11% and normalized the attenuated shear stress–induced dilation in SHR, whereas it did not affect basal diameter and arteriolar responses of WKY. Furegrelate, a specific inhibitor of TxA
2
synthase, did not affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid–induced constriction to dilation in SHR arterioles, whereas it did not affect the dilator response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619 (a PGH
2
/TxA
2
receptor agonist) were not different. These results demonstrate that in cremasteric arterioles of hypertensive rats, shear stress elicits an enhanced release of PGH
2
, resulting in a reduced shear stress–dependent dilation. Thus, augmented hemodynamic forces can alter the shear stress–induced synthesis of prostaglandins, which may contribute to the elevated vascular resistance in hypertension.
Estimation of Skeletal Muscle Interstitial Adenosine During Forearm Dynamic Exercise in Humans
Authors: Costa Fernando , Heusinkveld John , Ballog Robert , Davis Stephen , Biaggioni Italo
Published: June 2012

Abstract
—It has been proposed that adenosine is a metabolic signal that triggers activation of muscle afferents involved in the exercise pressor reflex. Furthermore, exogenous adenosine induces sympathetic activation that mimics the exercise pressor reflex, and blockade of adenosine receptors inhibits sympathetic activation induced by exercise. Thus, we hypothesize that adenosine is released locally by the muscle during exercise. We used microdialysis probes, placed in the flexor digitorium superficialis muscle, to estimate muscle interstitial adenosine levels in humans. We estimated resting in vivo muscle interstitial adenosine concentrations (0.292±0.058 μmol/L, n=4) by perfusing increasing concentrations of adenosine to determine the gradient produced in the dialysate. Muscle interstitial adenosine concentrations increased from 0.23±0.04 to 0.82±0.14 μmol/L (n=14,
P
<0.001) during intermittent dynamic exercise at 50% of maximal voluntary contraction. Lactate increased from 0.8±0.1 to 2.3±0.3 mmol/L (
P
<0.001). Lower intensity (15% maximal voluntary contraction) intermittent dynamic exercise increased adenosine concentrations from 0.104±0.02 to 0.42±0.16 μmol/L (n=7). The addition of ischemia to this low level of exercise produced a greater increase in adenosine (from 0.095±0.02 to 0.48±0.2 μmol/L) compared with nonischemic exercise (0.095±0.02 to 0.25±0.12 μmol/L). These results indicate that microdialysis is useful in estimating adenosine concentrations and in reflecting changes in muscle interstitial adenosine during dynamic exercise in humans.
Comparison of Hearts With 2 Types of Pressure-Overload Left Ventricular Hypertrophy
Authors: Saupe Kurt W. , Lim Chee Chew , Ingwall Joanne S. , Apstein Carl S. , Eberli Franz R.
Published: June 2012

Abstract
—Comparisons of myocardium remodeled by the 2 most common causes of left ventricular hypertrophy (LVH), hypertension and aortic constriction, are limited. We hypothesized that important differences may exist in the myocardium of hearts with these 2 origins of “pressure overload” LVH. Accordingly, we studied isolated hearts from 3 groups of Dahl salt-sensitive rats, controls, and hearts with matched amounts of LVH secondary to either hypertension or aortic constriction. Isovolumic LV function and myocardial energetics (
31
P nuclear magnetic resonance spectroscopy) were measured as coronary flow was lowered to 16% of baseline for 48 minutes. During this low-flow ischemia, isovolumic end-diastolic pressure, a measure of LV stiffness, increased to 52±4 mm Hg in controls and 51±6 mm Hg in aortic banded hearts but to only 35±5 mm Hg in hearts with hypertensive LVH. In all hearts, the P
i
resonance in the
31
P nuclear magnetic resonance spectrum, whose position indicates myocardial pH, split into 2 peaks during low-flow ischemia, which indicates distinct regions of pH 6.9 (moderate acidosis) and pH 6.2 (severe acidosis). Concentrations of ATP, PCr, P
i
, and H
+
of the moderately acidotic region were not different among groups. However, the size of the severely acidotic region was smallest in the hypertensive LVH hearts, and in all 3 groups, the size of this region correlated (
r
2
=0.65 to 0.80) with the degree of LV stiffening. We conclude that in Dahl rats, LVH secondary to hypertension protects against ischemia-induced diastolic dysfunction by minimizing the size of the region of severe acidosis.