bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Stable Inhibitor of Endopeptidases EC 3.4.24.15 and 3.4.24.16 Potentiates Bradykinin-Induced Hypotension
Authors: Smith A. Ian , Lew Rebecca A. , Shrimpton Corie N. , Evans Roger G. , Abbenante Giovanni
Published: June 2012

Abstract
—We have developed a novel inhibitor of the metalloendopeptidases EC
3.4.24.15
(EP24.15) and EC
3.4.24.16
(EP24.16),
N
-[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-
p
-aminobenzoate (JA2), in which α-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0±2.7-fold and 1.5±0.3-fold, respectively, during the 30 minutes after JA2 administration (mean±SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24.16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.
Glucocorticoid-Remediable Aldosteronism and Pregnancy
Authors: Wyckoff Jennifer A. , Seely Ellen W. , Hurwitz Shelley , Anderson Bruce F. , Lifton Richard P. , Dluhy Robert G.
Published: June 2012

Abstract
—Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism that presents with hypokalemia and hypertension from childhood onward. GRA is characterized by the ectopic production of aldosterone in the cortisol-producing zona fasciculata under the regulation of adrenocorticotrophic hormone. Despite the early age of onset, no previous reports of pregnancy and GRA exist. Therefore, we set out to describe the maternal and fetal outcomes of pregnancy in women with GRA. Data regarding the blood pressure and pregnancy outcomes were collected in a retrospective chart review of prenatal and hospital records of 35 pregnancies in 16 women with genetically proven GRA. A total of 6% of pregnancies in women with GRA (GRA+) were complicated by preeclampsia. The published rates of preeclampsia in general obstetric populations vary from 2.5% to 10%. Despite the lack of an apparent increase in the rate of preeclampsia, GRA+ women with chronic hypertension had a high rate (39%) of pregnancy-aggravated hypertension. Starting with a higher baseline blood pressure, maternal blood pressure plotted over the time course of pregnancy followed a quadratic curve similar to that previously described in normal pregnancy. Mean gestational age at delivery was 39.1 weeks. Mean birth weight, excluding the 3 sets of twins, was 3219 g. However, infants of GRA+ mothers with pregnancy-aggravated hypertension tended to have lower birth weights than those that did not (3019 g versus 3385 g, respectively;
P
=0.08). The primary cesarean section rate was 32%, which is approximately double that seen in other general or hypertensive obstetric populations. In summary, GRA+ women did not seem to have an increased risk of preeclampsia. However, GRA+ women with chronic hypertension seem to be at an increased risk for an exacerbation of their hypertension during pregnancy.
Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats
Authors: Kim Shokei , Zhan Yumei , Izumi Yasukatsu , Iwao Hiroshi
Published: June 2012

Abstract
—The combination therapy with ACE inhibitors, angiotensin II type 1 (AT
1
) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal α-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-β receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-β receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT
1
receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT
1
receptor antagonist or monotherapy with each agent.
Sodium Sensitivity of Blood Pressure in Long-Term Detoxified Alcoholics
Authors: Di Gennaro Cristiana , Barilli Angela , Giuffredi Cristina , Gatti Claudio , Montanari Alberto , Vescovi Pier Paolo
Published: June 2012

Abstract
—To investigate whether sodium sensitivity of blood pressure participates in the relationship of arterial hypertension to chronic alcohol consumption, 30 alcoholics detoxified from 6 to 12 months and 30 teetotaler controls underwent a dietary sodium manipulation study. They received a daily 55 mmol sodium diet for 7 days, followed by a 260 mmol sodium diet for 7 days. Changes in 24-hour urinary sodium excretion between the end of each period were similar in alcoholics and controls (202±16 SEM mmol and 227±11, respectively). Plasma renin activity in alcoholics was lower than in controls at both low (2.4±0.4 ng angiotensin I/mL×h
-1
versus 3.7±0.2,
P
<0.003) and high sodium intake (0.47±0.10 versus 0.82±0.10, P<0.05), with smaller variations in alcoholics (−1.9±0.3 versus −2.9±0.2,
P
<0.009). In alcoholics, alteration in sodium intake was followed by greater changes in both systolic and mean blood pressure (ambulatory blood pressure monitoring), which rose by 10.6±2.2 mm Hg and 7.3±1.5 versus 4.7±1.4 and 3.9±1.0 in controls, respectively (
P
<0.03 for systolic and
P
<0.05 for mean blood pressure). The ratio of changes in mean blood pressure to those in 24-hour urinary sodium excretion was higher in alcoholics (0.044± 0.011 mm Hg×mmol
−1
versus 0.018±0.0041,
P
<0.005). Our data show that in detoxified alcoholics, there is an abnormal response of both blood pressure and plasma renin activity to variations in salt intake similar to that in sodium-sensitive arterial hypertension. The precise relationship between the sodium sensitivity of blood pressure in detoxified alcoholics and the long-term influence of alcohol on blood pressure remains to be elucidated.
Role of Citrate Synthase in Aldosterone-Mediated Sodium Reabsorption
Authors: Ullian Michael E. , Robinson Christopher J. , Evans Claudia T. B. , Melnick Joel Z. , Fitzgibbon Wayne R.
Published: June 2012

Abstract
—Aldosterone and other mineralocorticoids increase citrate synthase activity in the kidney and enhance renal sodium reabsorption, but it is unclear whether the increased citrate synthase activity is involved in renal sodium transport. We used the Wistar-Furth rat, an inbred strain found to be deficient in renal citrate synthase activity, as an experimental model to investigate this issue. We confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth rats was decreased compared with that from control Wistar rats (by 28%). Similarly, urinary citrate excretion was 23% lower in Wistar-Furth rats. Subnormal citrate formation in Wistar-Furth rats could not be accounted for by differences in systemic pH or circulating potassium levels. Because renal citrate synthase activity was reduced in Wistar-Furth rats, we hypothesized that renal sodium excretory responses to mineralocorticoids would be reduced as well. Four-hour sodium excretion after intraperitoneal injection of 5 μg of aldosterone was reduced by 56% in adrenalectomized Wistar rats and by 52% in adrenalectomized Wistar-Furth rats (both
P
<0.01 compared with vehicle injection). Similarly, the pattern of urinary sodium excretion in response to subcutaneous injections of deoxycorticosterone acetate over a 2-week period was similar in adrenalectomized Wistar and Wistar-Furth rats. In summary, acute and chronic antinatriuretic responses to mineralocorticoids are maintained in Wistar-Furth rats at the level of Wistar rats, despite the marked reduction in citrate synthase activity. These findings are not consistent with an important role for citrate synthase activity in mineralocorticoid-mediated renal sodium transport.
Long-Term Angiotensin II Type 1 Receptor Blockade With Fonsartan Doubles Lifespan of Hypertensive Rats
Authors: Linz Wolfgang , Heitsch Holger , Schölkens Bernward A. , Wiemer Gabriele
Published: June 2012

Abstract
— In this study, we investigated the outcome of lifelong treatment with the angiotensin II type 1 receptor (AT
1
) blocker fonsartan (HR 720) in young stroke-prone spontaneously hypertensive rats (SHR-SP). In addition to the primary end point, lifespan, and to determine the mechanisms involved in the treatment-induced effects, parameters such as left ventricular hypertrophy, cardiac function/metabolism, endothelial function, and the expression/activity of endothelial nitric oxide synthase and of angiotensin-converting enzyme (ACE) were also investigated. Ninety 1-month-old SHR-SP were allotted to 2 groups and treated via drinking water with an antihypertensive dose of fonsartan (10 mg · kg
−1
· d
−1
) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP, which was comparable to the lifespan of normotensive Wistar-Kyoto rats. After 15 months, a time when ≈80% of the placebo group had died, left ventricular hypertrophy was completely prevented in fonsartan-treated animals. Furthermore, cardiac function and metabolism as well as endothelial function were significantly improved. These effects were correlated with increased endothelial nitric oxide synthase expression in the heart and carotid artery and with markedly decreased tissue ACE expression/activities. Lifespan extension and cardiovascular protection by long-term AT
1
blockade with fonsartan led to similar beneficial effects, as observed with long-term ACE inhibition.
Angiotensin-(1-7) Attenuates Vasoconstriction Evoked by Angiotensin II but Not by Noradrenaline in Man
Authors: Ueda Shinichiro , Masumori-Maemoto Satoko , Ashino Kazuhiro , Nagahara Toshihiro , Gotoh Eiji , Umemura Satoshi , Ishii Masao
Published: June 2012

Abstract
—Angiotensin-(1-7) has been suggested to be a novel vasodilating peptide. We investigated the direct vascular effect of angiotensin-(1-7) in human forearm resistant vessels, particularly with regard to the interaction with angiotensin II, in healthy normotensive men by strain-gauge venous occlusion plethysmography with intra-arterial infusions of peptides. Intra-arterial infusion of angiotensin-(1-7) at 0.1 to 2000 pmol/min did not cause vasodilatation but rather reduced forearm blood flow by ≈10% at the highest dose. A placebo-controlled study showed that angiotensin-(1-7) at 0.5 to 40 nmol/min caused weak but significant vasoconstriction (
P
=0.0016 by ANOVA). Angiotensin-(1-7) at 100 pmol/min, but not at 10 pmol/min, significantly shifted the angiotensin II dose-response curve toward the right (mean±SD of percent changes in forearm blood flow: −19±17%, −33±22%, −55±12%, −63±10%, and −68±5% at 5, 10, 25, 50, and 100 pmol/min of angiotensin II, respectively, with saline; 5±13%, 0.9±18%, −40±16%, −54±9%, and −61±6% with angiotensin-(1-7),
P
=0.0021 by ANOVA). Angiotensin-(1-7) did not affect the dose-response curve of noradrenaline [3±12%, 5±16%, −20±22%, −31±18%, and −40±12% at 25, 50, 100, 300, and 600 pmol/min of noradrenaline, respectively, with saline; −4±15%, −2±23%, −29±22%, −34±16%, and −42±9% with angiotensin-(1-7)]. Our results suggest that angiotensin-(1-7) antagonizes vasoconstriction by angiotensin II in human resistant vessels and might act as an endogenous angiotensin II antagonist.
Influence of Diabetes and Type of Hypertension on Response to Antihypertensive Treatment
Authors: Brown Morris J. , Castaigne Alain , de Leeuw Peter W. , Mancia Giuseppe , Palmer Christopher R. , Rosenthal Talma , Ruilope Luis M.
Published: June 2012

Abstract
—The aim of our investigation was to determine whether the presence of additional risk factors or type of hypertension (diastolic or isolated systolic) influences blood pressure (BP) response to treatment. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study is a double-blinded outcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years. Dynamic randomization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure that approximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors. Patients with isolated systolic hypertension were also separately randomized. Atenolol or enalapril was the mandatory second-line drug. In 5669 patients who completed the 18-week titration, BP fell from 172±15/99±9 mm Hg (mean±SD) while receiving placebo to 139±12/82±7 mm Hg. Twenty-six percent of patients required 2 drugs, and 4% required 3 drugs. Patients with diabetes were the most resistant to treatment, requiring second and third drugs 40% and 100% more frequently than patients without diabetes and achieving marginally the highest final BP, for any risk group, of 141±13/82±8 mm Hg. Age, smoking, gender, hypercholesterolemia, left ventricular hypertrophy, and existing atherosclerosis had little (<1 mm Hg) or no influence on BP at the end of titration, but all except smoking slightly reduced the initial response of either systolic or diastolic BP. Patients with isolated systolic hypertension were slightly more responsive than average to treatment. Our findings suggest that in patients at high absolute risk of cardiovascular complications from hypertension, the risk factors themselves do not prevent the recommended BP targets from being achieved.
Angiotensin Type 2 Receptor Mediates Valsartan-Induced Hypotension in Conscious Rats
Authors: Siragy Helmy M. , de Gasparo Marc , Carey Robert M.
Published: June 2012

Abstract
—Inhibition of the renin-angiotensin system is associated with vasodilation and reduction in blood pressure. We hypothesized that angiotensin type 1 (AT
1
) receptor (AT
1
R) blockade is associated with increased production of renal nitric oxide (NO) mediated by release of bradykinin (BK). By use of a microdialysis technique, changes in renal interstitial fluid (RIF) BK, NO end products nitrite and nitrate (NOX), and cGMP were monitored in response to intravenous infusion of the AT
1
R blocker valsartan (10 mg/kg), the angiotensin type 2 (AT
2
) receptor (AT
2
R) blocker
PD123319
(50 μg · kg
−1
· min
−1
), and the BK B
2
receptor blocker icatibant (10 μg · kg
−1
· min
−1
) in conscious rats (n=10) during low sodium intake. RIF BK, NOX, and cGMP significantly increased during valsartan treatment, whereas AT
2
R blockade caused a significant decrease in these autacoids. During icatibant infusion, RIF NOX and cGMP decreased by 64% and 40%, respectively, whereas BK increased. Combined administration of valsartan and icatibant, of valsartan and
PD123319
, or of valsartan,
PD123319
, and icatibant prevented the increase in RIF cGMP and NOX in response to valsartan alone. These data demonstrate that AT
1
R blockade with valsartan is associated with release of renal BK, which in turn mediates NO production. The results suggest that increased angiotensin II, in response to sodium restriction and valsartan infusion, stimulates AT
2
R, which mediates a BK and NO cascade.
Local Angiotensin II and Transforming Growth Factor-β1 in Renal Fibrosis of Rats
Authors: Sun Yao , Zhang Jiakun , Zhang John Q. , Ramires Felix J. A.
Published: June 2012

Abstract
—Studies have demonstrated that local angiotensin II (Ang II) generation is enhanced in repairing kidney and that ACE inhibition or AT
1
receptor blockade attenuates renal fibrosis. The localization of ACE and Ang II receptors and their relationship to collagen synthesis in the injured kidney, however, remain uncertain. Using a rat model of renal injury with subsequent fibrosis created with chronic elevations in circulating aldosterone (ALDO), we examined the distribution and binding density of ACE and Ang II receptors in repairing kidneys, as well as their anatomic relationship to transforming growth factor-β1 (TGF-β1) mRNA, type I collagen mRNA, collagen accumulation, and myofibroblasts. Two groups of animals (n=7 in each group) were studied: (1) normal rats served as controls, and (2) uninephrectomized rats received ALDO (0.75 μg/h SC) and 1% NaCl in drinking water for 6 weeks. Compared with control rats, in ALDO-treated rats we found (1) significantly (
P
<0.01) increased blood pressure, reduced plasma renin activity, and increased plasma creatinine levels, (2) diffuse fibrosis in both renal cortex and medulla, (3) abundant myofibroblasts at these sites of fibrosis, (4) significantly increased (
P
<0.01) binding density of ACE and Ang II receptors (60% AT
1
, 40% AT
2
) at the sites of fibrosis, and (5) markedly increased (
P
<0.01) expression of TGF-β1 and type I collagen mRNAs at these same sites. Thus, in this rat model of renal repair, the enhanced expression of ACE, Ang II receptors, and TGF-β1 is associated with renal fibrosis. Ang II generated at the sites of repair appears to have autocrine/paracrine functions in the regulation of renal fibrous tissue formation alone or through its stimulation of TGF-β1 synthesis.
Weight Gain–Induced Blood Pressure Elevation
Authors: Masuo Kazuko , Mikami Hiroshi , Ogihara Toshio , Tuck Michael L.
Published: June 2012

Abstract
—This study was conducted to evaluate the mechanisms in weight gain–induced blood pressure (BP) elevation focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels. The study design was longitudinal with a cohort of 1897 men. BP, pulse rate, body mass index (BMI), fasting plasma norepinephrine (NE), insulin, and leptin were measured at 6 and 12 months in those 172 lean normotensive, 79 obese normotensive, 64 lean untreated hypertensive, and 38 obese untreated hypertensive men whose BMI increased >10% during the first 6 months. At entry, levels of BP, pulse rate, plasma NE, insulin, and leptin in obese subjects, regardless of BP status, were significantly greater than those in lean subjects. The levels of plasma NE, insulin, and leptin increased with weight gain in the 4 study groups. In the subjects with BP elevation, the increase in pulse rate and plasma NE was significantly greater than that in the subjects without BP elevation at both 6 and 12 months for each of the 4 study groups, although the increase in BMI was similar between the subjects with and without BP elevation. In obese but not lean subjects, whether normotensive or hypertensive, the increases in plasma insulin and plasma leptin with weight gain were greater in the subjects with accompanying BP elevation compared with the subjects without BP elevation. On the other hand, at 6 months in lean subjects, the increase in plasma insulin with weight gain in the subjects with BP elevation was actually lower than that in the subjects without BP elevation. These results suggest that weight gain–induced sympathetic overactivity is more tightly linked to weight gain–induced BP elevation than the changes in plasma insulin and leptin that also accompany weight gain. It is probable that sympathetic nervous activation with weight gain is a major mechanism of blood pressure elevation. Hyperinsulinemia and hyperleptinemia may be ancillary factors that contribute to sympathetic nervous stimulation with weight gain.
Relation Between Low Calcium Intake, Parathyroid Hormone, and Blood Pressure
Authors: Jorde Rolf , Sundsfjord Johan , Haug Egil , Bønaa Kaare H.
Published: June 2012

Abstract
—In a population health survey in 1995, serum parathyroid hormone (PTH) was measured in 1113 subjects, aged 30 to 79 years, and was found to be elevated (>6.9 pmol/L) in 118 subjects. In 1998, this group and 131 subjects with normal PTH levels were invited for reexamination, and 82 and 90 subjects from each respective group attended the follow-up. At the follow-up, 72 subjects had elevated and 100 had normal serum PTH levels. Those with elevated serum PTH levels (8 subjects with hyperparathyroidism were excluded) had significantly lower serum calcium levels and intake of calcium than those with normal PTH (2.24±0.09 and 2.29±0.10 mmol/L [mean±SD] and 400.3±227.3 and 592.1±459.6 mg/d, respectively;
P
<0.01). Serum levels or intake of vitamin D did not differ between the 2 groups. Subjects with elevated PTH in both 1995 and 1998 had significantly lower bone mineral content and bone mineral density in the lumbar spine than did those with persistently normal PTH levels (
P
<0.05). In the females, but not in the males, the systolic and diastolic blood pressures were significantly higher in those with elevated serum PTH (158.0±27.5 versus 141.5±19.2 mm Hg and 90.5±13.6 versus 82.6±8.6 mm Hg, respectively;
P
<0.01). This difference was even more pronounced when those with persistently elevated PTH were considered separately. In conclusion, reduced intake of calcium is frequently associated with high levels of serum PTH. This is associated with moderately reduced bone mineral content and bone mineral density in the lumbar spine. In women, high levels of serum PTH are also associated with markedly increased blood pressure.
Vasopeptidase Inhibition Has Potent Effects on Blood Pressure and Resistance Arteries in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Intengan Hope D. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—The antihypertensive agent omapatrilat represents a novel approach to antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 μm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230±2 mm Hg that was significantly reduced (
P
<0.05) by omapatrilat (145±3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10
−5
mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure–lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (
P
<0.05) by omapatrilat, and a trend (
P
=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.
Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System
Authors: Engeli Stefan , Negrel Raymond , Sharma Arya M.
Published: June 2012

Abstract
—The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.
A Genome-Wide Search For Susceptibility Loci to Human Essential Hypertension
Authors: Sharma Pankaj , Fatibene Jennie , Ferraro Franco , Jia Haiyan , Monteith Sue , Brown Chrysothemis , Clayton David , O’Shaughnessy Kevin , Brown Morris J.
Published: June 2012

Abstract
—We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with
P
<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (
P
<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.
8-Iso-Prostaglandin F
2α
Reduces Trophoblast Invasion and Matrix Metalloproteinase Activity
Authors: Staff Anne Cathrine , Ranheim Trine , Henriksen Tore , Halvorsen Bente
Published: June 2012

Abstract
—Preeclampsia is a common pregnancy complication in the latter half of gestation diagnosed by hypertension and proteinuria. A key feature of preeclampsia is an altered placentation with reduced trophoblast invasion. Normal placentation requires controlled invasion of trophoblasts into the maternal uterine wall, with secretion of specific proteolytic enzymes able to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). 8-Iso-prostaglandin F
2α
(8-iso-PGF
2α
) is a marker of oxidative stress in vivo and is biologically active. We have recently reported an elevated content of free 8-iso-PGF
2α
in preeclamptic gestational tissue at delivery. Assuming an elevated level of 8-iso-PGF
2α
during the invasion period of the pregnancy, we hypothesized that 8-iso-PGF
2α
could reduce invasion of JAR cells, a choriocarcinoma cell line. We investigated JAR cell invasion with 2 types of Transwell assays and demonstrated that 8-iso-PGF
2α
(10 μmol/L) resulted in reduced cell invasion in both the colorimetric and radioactivity Transwell assays (
P
<0.01). Zymograms revealed reduced MMP-2 and MMP-9 activity in conditioned media from JAR cells incubated with 8-iso-PGF
2α
(10 μmol/L) (
P
<0.02). 8-Iso-PGF
2α
(10 μmol/L) also reduced the collagenase type IV activity in the conditioned media of JAR cells (
P
=0.04). No effects on MMP-2 and MMP-9 mRNA levels were observed after incubation with 8-iso-PGF
2α
(10 μmol/L), whereas protein levels were significantly decreased (
P
<0.02), suggesting a posttranscriptional regulation. We hypothesize a potential role for 8-iso-PGF
2α
in the reduced trophoblast invasion in preeclampsia.
DNA Synthesis and Apoptosis in Smooth Muscle Cells From a Model of Genetic Hypertension
Authors: Devlin Alison M. , Clark James S. , Reid John L. , Dominiczak Anna F.
Published: June 2012

Abstract
—The present study was designed to assess vascular smooth muscle cell (VSMC) proliferation and apoptosis in primary cultured VSMCs prepared from the aortic tunica media of adult (4 to 5 months old) age- and gender-matched groups of stroke-prone spontaneously hypertensive rats (SHRSP) and the normotensive reference strain, Wistar-Kyoto (WKY) rats. In the present study, VSMC proliferation was assessed with measurement of DNA synthesis in response to stimulation of G
0
/G
1
arrested VSMCs with 10% serum, whereas apoptosis was measured in response to serum deprivation. Apoptosis in aortic VSMCs was assessed in vitro with the technique of Annexin V binding in combination with propidium iodide exclusion with bivariate flow cytometric analysis. The percentage of necrotic VSMCs in the cell populations was assessed simultaneously. The light-scattering properties of the cells were assessed to provide further information on cell shrinkage and chromatin condensation. Results of the present study have shown enhanced DNA synthesis in VSMCs from SHRSP (n=10; 5.2±0.9 cpm×10
3
/mg protein) compared with WKY (n=12; 2.4±0.7 cpm×10
3
/mg protein;
P
<0.05, 95% CI, −5271 to −296). In addition, the results of the present study have demonstrated the role of serum in the survival of VSMCs in vitro, because SHRSP VSMCs underwent significantly more apoptosis in response to insult by serum deprivation (n=13; 10.21±1.8%) than WKY VSMCs (n=7; 3.44±1.4%;
P
<0.01, 95% CI, −11.5 to −2.0). Thus, it appears that both proliferation and apoptosis are enhanced in synthetic phenotype aortic medial VSMCs from the SHRSP in vitro.
Effect of Angiotensin II Antagonist Eprosartan on Hyperglycemia-Induced Activation of Intrarenal Renin-Angiotensin System in Healthy Humans
Authors: Osei Suzette Y. , Price Deborah A. , Laffel Lori M. B. , Lansang Maria C. , Hollenberg Norman K.
Published: June 2012

Abstract
—We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria (≈8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76±7 mL · min
−1
· 1.73 m
−2
,
P
<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147±15 mL · min
−1
· 1.73 m
−2
,
P
<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.
Hypertension Risk Status and Effect of Caffeine on Blood Pressure
Authors: Hartley Terry R. , Sung Bong Hee , Pincomb Gwendolyn A. , Whitsett Thomas L. , Wilson Michael F. , Lovallo William R.
Published: June 2012

Abstract
—We compared the acute effects of caffeine on arterial blood pressure (BP) in 5 hypertension risk groups composed of a total of 182 men. We identified 73 men with optimal BP, 28 with normal BP, 36 with high-normal BP, and 27 with stage 1 hypertension on the basis of resting BP; in addition, we included 18 men with diagnosed hypertension from a hypertension clinic. During caffeine testing, BP was measured after 20 minutes of rest and again at 45 to 60 minutes after the oral administration of caffeine (3.3 mg/kg or a fixed dose of 250 mg for an average dose of 260 mg). Caffeine raised both systolic and diastolic BP (SBP and DBP, respectively;
P
<0.0001 for both) in all groups. However, an ANCOVA revealed that the strongest response to caffeine was observed among diagnosed men, followed by the stage 1 and high-normal groups and then by the normal and optimal groups (SBP
F
4
,
175
=5.06,
P
<0.0001; DBP
F
4,175
=3.02,
P
<0.02). Indeed, diagnosed hypertensive men had a pre-to-postdrug change in BP that was >1.5 times greater than the optimal group. The potential clinical relevance of caffeine-induced BP changes is seen in the BPs that reached the hypertensive range (SBP ≥140 mm Hg or DBP ≥90 mm Hg) after caffeine. During the predrug baseline, 78% of diagnosed hypertensive men and 4% of stage 1 men were hypertensive, whereas no others were hypertensive. After caffeine ingestion, 19% of the high-normal, 15% of the stage 1, and 89% of the diagnosed hypertensive groups fell into the hypertensive range. All subjects from the optimal and normal groups remained normotensive. We conclude that hypertension risk status should take priority in future research regarding pressor effects of dietary intake of caffeine.
Genetic Determinants of Hypertension
Authors: Kotchen Theodore A. , Kotchen Jane Morley , Grim Clarence E. , George Varghese , Kaldunski Mary L. , Cowley Allen W. , Hamet Pavel , Chelius Thomas H.
Published: June 2012

Abstract
—Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in >200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia.
Vascular Compression of the Rostral Ventrolateral Medulla in Sympathetic Mediated Essential Hypertension
Authors: Gajjar Digesh , Egan Brent , Curè Joel , Rust Philip , VanTassel Pamela , Patel Sunil J.
Published: June 2012

Abstract
—The pathophysiological factors of neurogenic or sympathetically mediated essential hypertension are unknown. Neurons close to the surface of the ventrolateral medulla (specifically, in the retro-olivary sulcus [ROS]) are integrally involved in the control of blood pressure by means of efferent connections to presympathetic neurons in the spinal cord. It is hypothesized that vascular contact with the ROS is pathogenically involved in neurogenically mediated hypertension. We evaluated that theory in 20 subjects with uncomplicated stage 1 to stage 2 essential hypertension (EHTN) (18 of whom completed the study). The baseline supine plasma norepinephrine level served as an index of central sympathetic outflow. The response of blood pressure to clonidine was used as a surrogate marker for neurogenically mediated hypertension. We also examined the relationship between those markers and evidence of anatomic abnormalities in the area of the ROS that was provided by magnetic resonance imaging. A vessel contacted the left ROS in 5 of the 18 subjects. Those 5 subjects had higher plasma norepinephrine concentrations than did the 13 subjects without this vascular contact (358±46 versus 76±43 pg/mL,
P
<0.001). These 5 subjects also exhibited a significant depressor response to clonidine that tended to be greater than that seen in the 13 subjects without vascular contact (−20.6±3.2 versus −13.6±9 mm Hg). Both race and baseline mean blood pressure had only an independent effect on the depressor response to clonidine. The findings are consistent with the theory that vascular contact with the left ROS may contribute to neurogenically mediated “essential” hypertension in some patients.
Definitive Molecular Evidence of Renin-Angiotensin System in Human Uterine Decidual Cells
Authors: Li Chunbiao , Ansari Rais , Yu Ziming , Shah Dinesh
Published: June 2012

Abstract
—The tissue renin-angiotensin system (RAS) has been suggested to be present in human gestational tissues, but uncertainty exists about the authenticity of this RAS, and the cellular origin of this RAS has not been defined. In the present study, we confirmed the presence of authentic renin and angiotensinogen in the prolactin-producing decidual tissue by sequencing the cDNAs generated through reverse transcription–polymerase chain reaction, confirming cDNA product sizes, and by performing Northern blot analysis of the RNA. Our comparative data demonstrate that prolactin has the highest expression in the decidual tissue, followed by renin, and that angiotensinogen has the least expression. We demonstrated with fluorescent in situ hybridization that prolactin-expressing endocrine decidual cells are the same cells that express both renin and angiotensinogen. These results have implications in regard to how the decidual RAS may be regulated and what potential role this local RAS may have in the pathogenesis of preeclampsia.
Effects of Exercise and Weight Loss on Mental Stress–Induced Cardiovascular Responses in Individuals With High Blood Pressure
Authors: Georgiades Anastasia , Sherwood Andrew , Gullette Elizabeth C. D. , Babyak Michael A. , Hinderliter Alan , Waugh Robert , Tweedy Damon , Craighead Linda , Bloomer Richard , Blumenthal James A.
Published: June 2012

Abstract
—The purpose of this study was to determine the effects of exercise and weight loss on cardiovascular responses during mental stress in mildly to moderately overweight patients with elevated blood pressure. Ninety-nine men and women with high normal or unmedicated stage 1 to stage 2 hypertension (systolic blood pressure 130 to 179 mm Hg, diastolic blood pressure 85 to 109 mm Hg) underwent a battery of mental stress tests, including simulated public speaking, anger recall interview, mirror trace, and cold pressor, before and after a 6-month treatment program. Subjects were randomly assigned to 1 of 3 treatments: (1) aerobic exercise, (2) weight management combining aerobic exercise with a behavioral weight loss program, or (3) waiting list control group. After 6 months, compared with control subjects, participants in both active treatment groups had lower levels of systolic blood pressure, diastolic blood pressure, total peripheral resistance, and heart rate at rest and during mental stress. Compared with subjects in the control group, subjects in the exercise and weight management groups also had greater resting stroke volume and cardiac output. Diastolic blood pressure was lower for the weight management group than for the exercise-only group during all mental stress tasks. These results demonstrate that exercise, particularly when combined with a weight loss program, can lower both resting and stress-induced blood pressure levels and produce a favorable hemodynamic pattern resembling that targeted for antihypertensive therapy.
Close Relationship of Abnormal Glucose Tolerance With Endothelial Dysfunction in Hypertension
Authors: Tomiyama Hirofumi , Kimura Yutaka , Okazaki Ryo , Kushiro Toshio , Abe Masayuki , Kuwabara Yoichi , Yoshida Hideo , Kuwata Shoji , Kinouchi Takashi , Doba Nobutaka
Published: June 2012

Abstract
—Hypertension is frequently accompanied by left ventricular hypertrophy, endothelial dysfunction, and abnormal glucose metabolism. However, no study has examined the relative pathological significance of left ventricular hypertrophy and abnormal glucose metabolism on endothelial dysfunction in hypertension. This study was conducted to evaluate whether abnormal glucose tolerance assessed by 75-g oral glucose tolerance test or left ventricular hypertrophy is more closely associated with endothelial dysfunction in never-treated hypertensive patients without elevated fasting blood glucose. We studied 107 unmedicated hypertensive patients (mean age, 54±10 years) whose fasting blood glucose was <7.0 mmol/L. Endothelial function was assessed by change in brachial artery diameter in response to reactive hyperemia, and left ventricular mass index was determined by ultrasonography. Simple linear regression analysis demonstrated that endothelial function significantly correlated with left ventricular mass index and 2-hour blood glucose in 75-g oral glucose tolerance test, but not with fasting blood glucose. Multiple linear regression analysis revealed that endothelial function significantly correlated with 2-hour blood glucose (β=−2.68,
P
<0.05) after we controlled for other clinical variables. Patients were divided into 3 groups according to 2-hour blood glucose levels. Endothelial function was more impaired in patients with diabetes (n=12; 4.7±1.8%) and in those with impaired glucose tolerance (n=31; 6.3±2.9%) than in those with normal glucose tolerance (n=64; 8.4±4.5%) (
P
<0.05), but left ventricular mass index was similar in these 3 groups. Abnormal glucose tolerance assessed by 75-g oral glucose tolerance test, rather than left ventricular hypertrophy, may have direct pathophysiological relevance to endothelial dysfunction in borderline to moderate hypertensive patients.
Nitric Oxide and Cardiac Autonomic Control in Humans
Authors: Chowdhary Saqib , Vaile Julian C. , Fletcher Janine , Ross Hamish F. , Coote John H. , Townend Jonathan N.
Published: June 2012

Abstract
—Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23±5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with
N
G
-monomethyl-
l
-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (Δ) in high-frequency (HF) indexes of heart rate variability were smaller with L-NMMA in comparison to an equipressor dose of the control vasoconstrictor phenylephrine (12 to 42 μg/kg per hour): Δroot mean square of successive RR interval differences (ΔRMSSD)=23±32 versus 51±48 ms (
P
<0.002); Δpercentage of successive RR interval differences >50 ms (ΔpNN50)=5±15% versus 14±12% (
P
<0.05); and ΔHF normalized power=−2±7 versus 9±8 normalized units (
P
<0.01), respectively. Relative preservation of these indexes was observed during unloading of the baroreflex with sodium nitroprusside compared with a matched fall in blood pressure produced by a control vasodilator, hydralazine (9 to 18 mg/h): ΔRMSSD=−8±8 versus −24±15 ms (
P
<0.001); ΔpNN50=−6±11% versus −15±19% (
P
<0.01); ΔHF normalized power=−7±13 versus −13±11 normalized units (
P
<0.05), respectively. The change in cross-spectral α-index calculated as the square root of the ratio of RR interval power to systolic spectral power in the HF band (although not α-index calculated in the same way for the low-frequency bands or baroreflex sensitivity assessed by the phenylephrine bolus method) was attenuated with L-NMMA compared with phenylephrine (Δ=4±8 versus 14±15 ms/mm Hg, respectively;
P
<0.02) and with sodium nitroprusside compared with hydralazine (Δ=−7±6 and −9±7 ms/mm Hg, respectively;
P
<0.05). In conclusion, these data demonstrate that NO augments cardiac vagal control in humans.