bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of Insulin Sensitivity by Short-term Exercise Training in Hypertensive African American Women
Authors: Brown Michael D. , Moore Geoffrey E. , Korytkowski Mary T. , McCole Steve D. , Hagberg James M.
Published: June 2012

Abstract
African American women have a high prevalence of insulin resistance, non–insulin-dependent diabetes mellitus, obesity, and hypertension that may be linked to low levels of physical activity. We sought to determine whether 7 days of aerobic exercise improved glucose and insulin metabolism in 12 obese (body fat >35%), hypertensive (systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg) African American women (mean age 51±8 years). Insulin-assisted frequently-sampled intravenous glucose tolerance tests were performed at baseline and 14 to 18 hours after the 7th exercise session. There was no significant change in maximal oxygen consumption, body composition, or body weight after the 7 days of aerobic exercise. The insulin sensitivity index increased (2.68±0.45 · 10
−5
to 4.23±0.10 · 10
−5
[min
−1
/pmol/L],
P
=.02). Fasting (73±9 to 50±9 pmol/L,
P
=.02) and glucose-stimulated (332±58 to 261±45 pmol/L,
P
=.05) plasma insulin levels decreased. Additional measures related to the insulin resistance syndrome also changed with the 7 days of exercise: basal plasma norepinephrine concentrations were reduced (2.46±0.27 to 1.81±0.27 nmol/L,
P
=.02) and sodium excretion rate increased from 100±13 to 137±7 mmol/d (
P
=.03); however, there was no change in potassium excretion or 24-hour ambulatory blood pressure. We conclude that a short-term aerobic exercise program improves insulin sensitivity in African American hypertensive women independent of changes in fitness levels, body composition, or body weight. The present study indicates that short-term exercise can improve insulin resistance in hypertensive, obese, sedentary African American women and confirms previous reports that a portion of the exercise-induced improvements in glucose and insulin metabolism may be the result of recent exercise.
Effect on Blood Pressure of Potassium, Calcium, and Magnesium in Women With Low Habitual Intake
Authors: Sacks Frank M. , Willett Walter C. , Smith Angela , Brown Lisa E. , Rosner Bernard , Moore Thomas J.
Published: June 2012

Abstract
—In populations, dietary intakes of potassium, calcium, and magnesium each have been inversely associated with blood pressure. However, most clinical trials in normotensive populations have not found that dietary supplements of these minerals lowered blood pressure. We tested the hypothesis that normotensive persons who have low habitual intake of these minerals would be particularly responsive to supplementation. Three hundred normotensive women in the Nurses Health Study II (mean age, 39 years), whose reported intakes of potassium, calcium, and magnesium were between the 10th and 15th percentiles, received for 16 weeks’ duration daily supplements of either potassium 40 mmol, calcium 30 mmol (1200 mg), magnesium 14 mmol (336 mg), all three minerals together or placebos. At baseline, mean (±SD) 24-hour ambulatory blood pressures were 116±8 and 73±6 mm Hg systolic and diastolic, respectively, and mean dietary intakes of potassium, calcium, and magnesium were 62±20 mmol/d, 638±265 mg/d, and 239±79 mg/d, respectively. The mean differences (with 95% confidence intervals) of the changes in systolic and diastolic blood pressures between the treatment and placebo groups were significant for potassium, −2.0 (−3.7 to −0.3) and −1.7 (−3.0 to −0.4), but not for calcium, −0.6 (−2.2 to 1.0) and −0.7 (−2.0 to 0.6), or for magnesium, −0.9 (−2.6 to 0.8) and −0.7 (−2.2 to 0.8). The administration of calcium and magnesium with potassium did not enhance the effect of potassium alone; and the changes in blood pressure were not significant −1.3 (−3.0 to 0.4) and −0.9 (−2.2 to 0.4). In conclusion, potassium, but not calcium or magnesium supplements, has a modest blood pressure–lowering effect in normotensive persons with low dietary intake. This study strengthens evidence for the importance of potassium for blood pressure regulation in the general population.
Phospholipase A
2
Metabolites Regulate Inducible Nitric Oxide Synthase in Myocytes
Authors: LaPointe Margot C. , Sitkins Jodi R.
Published: June 2012

The proinflammatory cytokine interleukin-1β (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A
2
(PLA
2
), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA
2
and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in ≈200-fold and 15-fold increases in PGE
2
and 6-keto-PGF
1α
(the stable metabolite of PGI
2
), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA
2
inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA
2
products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.
Endothelin-A Receptor Antagonism Attenuates the Hypertension and Renal Injury in Dahl Salt-Sensitive Rats
Authors: Kassab Salah , Miller M. Todd , Novak Jacqueline , Reckelhoff Jane , Clower Ben , Granger Joey P.
Published: June 2012

The aim of this study was to examine the role of endothelin-A (ET
A
) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET
A
antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118±3 to 186±15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125±4 to 167±12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (
P
<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET
A
receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1±1.1 to 74.3±5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7±1.2 to 55.2±6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET
A
receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
Response of Proximal Tubules to Angiotensin II Changes During Maturation
Authors: Garvin Jeffrey L. , Beierwaltes William H.
Published: June 2012

The renin-angiotensin system changes with age, but it is unclear how renal responses to angiotensin II (Ang II) evolve as an animal matures. We hypothesized that Ang II exerts a greater effect on proximal nephron volume absorption (Jv), blood pressure (BP), renal blood flow (RBF), and renal vascular resistance (RVR) in young compared with adult rats. To test this hypothesis, we investigated the effects of Ang II on proximal nephron fluid absorption in response to 10
−10
mol/L Ang II in rats from three age groups: young (4 to 5 weeks old), intermediate (6 weeks old), and adult (7 weeks old). In proximal straight tubules from 7 young rats, Jv was 0.64±0.05 nL/mm per minute. Ang II in the bath increased Jv by 69±18% to 1.05±0.07 nL/mm per minute (
P
<.005). In tubules from five intermediate-aged rats, Jv was 0.60±0.10 nL/mm per minute and increased by 34±5% to 0.83±0.16 nL/mm per minute after Ang II (
P
<.02). In five adult rats, Jv was 0.69±0.06 nL/mm per minute and increased 20±6% to 0.85±0.13 nL/mm per minute after Ang II (
P
<.05). Next we tested whether the exaggerated effect of Ang II on proximal tubular Jv in young rats was due to Ang II-induced changes in cAMP. cAMP content of proximal tubules from eight young rats was 24.8±7.6 fmol/mm and fell by 29.7±9.8% (
P
<.025) after treatment with Ang II. In contrast, cAMP content of proximal tubules from nine adults was only 9.8±4.5 fmol/mm, 40% of baseline in young rats, and was unchanged by Ang II (9.2±4.5 fmol/mm). We finally determined whether the increased sensitivity to Ang II in tubules of young rats is mimicked by renal hemodynamics. Eleven adult rats had BP of 115±5 mm Hg, RBF of 6.99±0.42 mL/min per g kidney weight (kw), RVR of 16.82±0.95 mm Hg/mL per minute per g kw (resistance units), and plasma renin activity (PRA) of 11.2±2.3 ng Ang I/mL per hour. Seven young rats had BP of 98±7 mm Hg, 17 mm Hg lower than adults (
P
<.025). RBF was 4.94±0.23 mL/min per g kw, and RVR was 20.30±1.19 RU. 20% greater than in adults (
P
<.025). PRA was 9.2±2.2 ng Ang I/mL per hour. There were no differences between groups with regard to increased BP, decreased RBF, or increased RVR with graded doses of 8, 40, and 200 fmol Ang II/g body weight. Thus, Ang II increased Jv more in young rats but had a lesser effect in adults. This was coupled with a greater effect of Ang II on tubular cAMP in young rats, but no differences in systemic or renal hemodynamic responses to Ang II between adults and young. We conclude that during adolescent development, Ang II may be an important factor in the regulation of salt and water metabolism, but not renal hemodynamics.
Three-Dimensional Microcomputed Tomography of Renal Vasculature in Rats
Authors: Garcia-Sanz Agustin , Rodriguez-Barbero Alicia , Bentley Michael D. , Ritman Erik L. , Romero J. Carlos
Published: June 2012

Current microscopic methods to view renal microvasculature reveal only a very limited portion of the total renal volume. Identification of connectivity for postglomerular vessels in the cortex and the medulla during functional states related to changes in sodium excretion will help better to understand the coupling of renal vasculature to tubular function. The purpose of this study was to investigate the possibility of visualizing the continuity of pre- and postglomerular vasculature using three-dimensional micro-computed tomography (micro-CT). Kidneys from normal rats were perfusion fixed in situ at physiological pressure, filled with latex microfil containing lead chromate, and embedded in plastic. The micro-CT scans of the intact kidneys were carried out on a rotating stage illuminated either by a synchrotron x-ray source or a conventional x-ray spectroscopy tube. Images were reconstructed by a filtered backprojection algorithm and volume-rendering techniques were utilized to display the vasculature. The reconstructed images clearly showed the large distribution vessels and the venous drainage of the kidneys, while pre- and postglomerular vessels and their vascular connections throughout the kidney were displayed in great detail. Efferent arterioles showed the characteristics of their peritubular capillary beds in the cortical and medullary regions. The vascular volume of the cortex was 27%, the outer stripe of the outer medulla 18%, the inner stripe of the outer medulla 30%, and the inner medulla 18%. In conclusion, micro-CT is a promising method to evaluate renal vascular architecture relative to physiological and pathological alterations.
Localization of 2 11β-OH Steroid Dehydrogenase Isoforms in Aortic Endothelial Cells
Authors: Brem Andrew S. , Bina Robert B. , King Thomas C. , Morris David J.
Published: June 2012

11β-hydroxysteroid dehydrogenase (11β-HSD) is expressed in vascular smooth muscle cells (VSMC) but has not been reported to be present in vascular endothelial cells. This enzyme assists in regulating the cellular concentration of active endogenous glucocorticoids (GCs). We have observed that endothelium intact rat aortic rings express message for both Type 1 and Type 2 11β-HSD whereas primary cultures of VSMC express only mRNA for the Type I isoform. Since GCs diminish prostacyclin synthesis in endothelial cells, we hypothesized that 11β-HSD is present in vascular endothelial cells. In primary cultures of rat aortic endothelial (RAE) cells, mRNA from both isoforms of 11β-HSD could be detected by RT-PCR with higher levels of the Type 1 isoform. The oxo-reductase reaction “activating” 11-dehydro metabolites back to the parent steroid is the preferred enzyme direction (12:1 after a 120 minutes steroid incubation) in intact RAE cells. When RAE cells are grown in the presence of antisense oligonucleotides specific for Type 1 11β-HSD, oxo-reductase activity is decreased by approximately 50% but the dehydrogenase reaction, which inactivates endogenous GCs and is characteristic of the Type 2 isoform, is unaffected. Thus endothelial cells appear to express both isoforms of 11β-HSD; the Type 1 isoform dominates functioning in the oxo-reductase mode. Inhibition of the oxo-reductase reaction may lower the local concentrations of GC and indirectly allow for increased production of prostacyclin in endothelial cells.
ET
A
Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension
Authors: Barton Matthias , d’Uscio Livius V. , Shaw Sidney , Meyer Peter , Moreau Pierre , Lüscher Thomas F.
Published: June 2012

Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET
A
receptor antagonist
LU135252
for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190±4 versus 152±2 mm Hg,
P
<.05) and aortic ET-1 protein content (4.2-fold,
P
<.0001) and induced aortic hypertrophy as assessed by tissue weight (
P
<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49±4% versus 81±4%,
P
<.0001) and contractions to ET-1 (92±7 versus 136±8% of KCl,
P
=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (
r
=0.931,
P
<.0001) and contractions to ET (
r
=0.77,
P
=.0007).
LU135252
treatment reduced systolic blood pressure only in part (168±3 versus 190±4 mm Hg.
P
<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (
P
<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET
A
receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
Adenosine Inhibits Growth of Human Aortic Smooth Muscle Cells Via A
2B
Receptors
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Mi Zaichuan , Jackson Edwin K.
Published: June 2012

Adenosine inhibits rat vascular smooth muscle cell (SMC) growth. However, the effects of adenosine on human vascular SMC proliferation and synthesis of extracellular matrix proteins, such as collagen, are unknown. The objective of this study was to characterize the effects of exogenous and endogenous (SMC-derived) adenosine on human aortic SMC proliferation and collagen synthesis. Growth-arrested SMCs were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), and with agents that increase endogenous adenosine levels, including erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), dipyridamole, and iodotubericidin. All of these agents inhibited in a concentration-dependent manner FCS-induced SMC proliferation as assessed by DNA synthesis (
3
H-thymidine incorporation) and cell counting, as well as collagen synthesis (
3
H-proline incorporation). EHNA, dipyridamole, and iodotubericidin increased extracellular levels of adenosine by 1.7-fold to 18-fold when added separately to SMCs, and EHNA+iodotubericidin and EHNA+iodotubericidin+dipyridamole increased extracellular adenosine levels by more than 392-fold. Both KF17837 (selective A
2
antagonist) and DPSPX (A
1
/A
2
antagonist), but not DPCPX (selective A
1
antagonist), blocked the antimitogenic effects of 2-chloroadenosine, EHNA, and dipyridamole on DNA and collagen synthesis, suggesting the involvement of A
2A
and/or A
2B
, but excluding the participation of A
1
, receptors. The lack of effect of
CGS21680
(selective A
2A
agonist), excluded involvement of A
2A
receptors and suggested a major role for A
2B
receptors. A comparison of the inhibitory potencies of 2-chloroadenosine, N
6
-cyclopentyladenosine (selective A
1
agonist), NECA (A
1
/A
2
agonist), and MECA (A
1
/A
2
agonist) were consistent with an A
2B
receptor subtype mediating the inhibitory effects of adenosine on human aortic SMC proliferation. In conclusion, human aortic SMCs synthesize adenosine, and exogenous as well as endogenous (SMC-derived) adenosine inhibits SMC proliferation and collagen synthesis via activation of A
2B
receptors.
Baroreflex Control of Sympathetic Nerve Activity in Essential and Secondary Hypertension
Authors: Grassi Guido , Cattaneo Bianca M. , Seravalle Gino , Lanfranchi Antonio , Mancia Giuseppe
Published: June 2012

Abstract
—Studies performed in experimental animals and in humans have documented that high blood pressure markedly impairs baroreceptor control of heart rate. Whether a similar impairment also characterizes baroreceptor control of sympathetic activity modulating peripheral vasomotor tone is still unknown. In 28 untreated essential hypertensive subjects [14 of moderate and 14 of more severe degree, age 51.6±2.4 and 52.6±2.1 years (mean±SEM)] and in 13 untreated secondary hypertensives (renovascular or pheochromocytoma, age 50.1±4.6 years), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Data were compared with those obtained in 15 age-matched normotensive control subjects. Muscle sympathetic nerve activity (bursts per 100 heart beats) showed a progressive and significant (
P
<.01) increase from normotension (40.3±3.3) to moderate (55.6±4.1) and more severe essential hypertension (68.2±4.1), paralleling the progressive increase in blood pressure values. In contrast, muscle sympathetic nerve activity was not increased in secondary hypertensives (40.5±6.7) despite blood pressure values similar to or even greater than those of severe essential hypertensives. In both essential and secondary hypertensives, baroreceptor–heart rate control was displaced toward elevated blood pressure values and markedly impaired compared with normotensive subjects (average reduction, 38.5%). In contrast, the sympathoinhibitory and sympathoexcitatory responses to baroreceptor stimulation and deactivation were displaced toward elevated blood pressure values but similar in all groups. Thus, sympathetic activation characterizes essential but not secondary hypertension. Regardless of its nature, however, hypertension is not accompanied by an impairment of baroreceptor modulation of sympathetic activity.
Longitudinal Correlates of Change in Blood Pressure in Adolescent Girls
Authors: Daniels Stephen R. , McMahon Robert P. , Obarzanek Eva , Waclawiw Myron A. , Similo Shari L. , Biro Frank M. , Schreiber George B. , Kimm Sue Y. S. , Morrison John A. , Barton Bruce A.
Published: June 2012

Abstract
—The objective of this study was to assess the longitudinal changes in blood pressure in black and white adolescent girls and evaluate potential determinants of changes in blood pressure, including sexual maturation and body size. A total of 1213 black and 1166 white girls, ages 9 or 10 years at study entry, were followed up through age 14 with annual measurements of height, weight, skinfold thickness, stage of sexual maturation, systolic and diastolic blood pressures, and other cardiovascular risk factors. Average blood pressures in black girls were generally 1 to 2 mm Hg higher than in white girls of similar age over the course of the study. Age, race, stage of sexual maturation, height, and body mass index (kg/m
2
) were all significant univariate predictors of systolic and diastolic blood pressures in longitudinal regression analyses. Black girls had a significantly smaller increase in blood pressure for a given increase in body mass index compared with white girls. The predicted increases in blood pressure per unit increase in body mass index (mm Hg per kg/m
2
) were as follows: systolic, 0.65±0.04 in whites and 0.52±0.04 in blacks (
P
<.001); diastolic fourth Korotkoff phase, 0.31±0.04 in whites and 0.15±0.03 in blacks (
P
<.001); and diastolic fifth Korotkoff phase, 0.31±0.05 in whites and 0.16±0.04 in blacks (
P
<.001). Understanding of the determinants of the racial differences in blood pressure could provide the rationale for future interventions to reduce the excess cardiovascular mortality in black compared with white women.
Increased Urinary Free Cortisol
Authors: Litchfield W. Reid , Hunt Steven C. , Jeunemaitre Xavier , Fisher Naomi D. L. , Hopkins Paul N. , Williams Roger R. , Corvol Pierre , Williams Gordon H.
Published: June 2012

Abstract
—We evaluated urinary cortisol excretion as a potential intermediate phenotype of essential hypertension in 153 white patients with essential hypertension and 18 normotensive white control subjects. Analyses were controlled for dietary sodium and gender to adjust for potential confounding effects of these variables on cortisol excretion. Urinary cortisol excretion measured on both high- and low-salt diets was significantly related to hypertension by repeated measures ANCOVA (
P
=.02). Additional determinants of urinary free cortisol included dietary sodium intake and gender; cortisol excretion was significantly higher in men (
P
=.0006) and during a high-sodium diet (
P
=.0001). Maximum likelihood analysis showed urinary cortisol to have a bimodal distribution on both 200-mmol (
P
<.01) and 10-mmol (
P
<.002) sodium diets in hypertensive subjects. On the low-salt diet, the mean urinary cortisol in normotensive subjects (108.7±44.7 nmol/d) was similar to the mean of hypertensive subjects in the low mode (127.2±43.0 nmol/d). The high mode comprised 31.2% of the hypertensive population and had a mean urinary cortisol of 224.3±93.8 nmol/d. Subjects with the highest urinary free cortisol showed the least sensitivity of blood pressure to dietary sodium loading (
P
<.05). These data suggest that there is an association between salt-resistant hypertension and high urine cortisol levels. This association may have a genetic basis.
Prostaglandin E
2
–Induced Aldosterone Release Is Mediated by an EP
2
Receptor
Authors: Csukas Stephen , Hanke Craig J. , Rewolinski David , Campbell William B.
Published: June 2012

Abstract
—Prostaglandin E
2
(PGE
2
) is an endogenous hormone of adrenal zona glomerulosa cells and is released in response to stimulation by agonists such as angiotensin II (Ang II). It stimulates the release of aldosterone from cultured bovine adrenal zona glomerulosa cells. These studies were designed to determine whether this steroidogenic effect of PGE
2
was mediated by an EP
1
, EP
2
, or EP
3
receptor. Prostaglandin E
2
and 11-deoxy PGE
1
, an EP
2
-selective agonist, stimulated aldosterone release in a concentration-related manner with an ED
50
of 300 nmol/L for PGE
2
and 2 μmol/L for 11-deoxy PGE
1
. The maximal effect of PGE
2
was less than that of angiotensin II. 17-Phenyl trinor PGE
2
, an EP
1
-selective agonist, required concentrations of 100 μmol/L to stimulate aldosterone release and sulprostone, an EP
3
/EP
1
-selective agonist, failed to alter aldosterone release. The EP
1
-selective antagonist SC19220 failed to alter basal or PGE
2
-stimulated aldosterone release over a range of concentrations. PGE
2
and 11-deoxy PGE
1
also stimulated an increase in both intracellular and extracellular cAMP. This increase was time- and concentration-related. The ED
50
for PGE
2
was 9.8 μmol/L. 17-Phenyl trinor PGE
2
and sulprostone were without effect. Using fura-2 loaded cells, PGE
2
(2 μmol/L), dibutyryl cAMP (2 mmol/L), and Ang II (2 μmol/L) increased intracellular calcium over basal concentrations by 5.5-fold, 3-fold, and 6.2-fold, respectively. Like PGE
2
, dibutyryl cAMP also stimulated aldosterone release. PGE
2
- and dibutyryl cAMP–induced aldosterone release were blocked by the calcium channel inhibitor diltiazem. These studies indicate that PGE
2
is a potent stimulus for aldosterone release and that the effect is mediated by EP
2
receptors. Both cAMP and calcium appear to mediate the steroidogenic effect of PGE
2
and calcium seems to be distal to cAMP.
Alterations of Nitric Oxide Synthase Expression With Aging and Hypertension in Rats
Authors: Chou Tz-Chong , Yen Mao-Hsiung , Li Chi-Yuan , Ding Yu-An
Published: June 2012

Abstract
—The activity and protein expression of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) were investigated during the development of hypertension in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were studied at three different ages: 4, 14 to 17, and 63 weeks of age. After treatment with saline or lipopolysaccharide (LPS, 10 mg/kg IV) for 3 hours, the aortas were removed for measurement of NOS activity and protein expression assay by [
3
H]-
l
-citrulline formation method and Western blot analysis, respectively. Plasma levels of nitrite/nitrate (NO
2
−
/NO
3
−
) and tumor necrosis factor-α (TNF-α) were also determined. At 14 to 17 weeks and 63 weeks, the basal activity and protein expression of eNOS in the aortas were significantly lower in SHR than in WKY. In addition, the aged WKY exhibited lower eNOS activity than that of adult WKY, but this change was not seen in SHR. By comparison, the basal activity and protein expression of iNOS were only observed in SHR of the 14-to-17-week group and in the 63-week group; SHR still exhibited higher activities, and these differences were further exaggerated by treatment with LPS. The basal and LPS-induced NO
2
−
/NO
3
−
and TNF-α levels in the plasma were also higher in the SHR except the 4-week group. After treatment with quinapril, the basal and LPS-induced expressions of iNOS in SHR were significantly attenuated. Our results demonstrated that alterations of activity and protein expression of eNOS and iNOS occurred in SHR. In addition, aging may reduce the activity of eNOS in WKY but not in SHR. The decline of eNOS activity and/or expression may contribute to the development of hypertension, whereas the increase of iNOS expression may be a consequence of the pathological state of vessels associated with hypertension in SHR. However, the augmented expression of iNOS in SHR was attenuated by antihypertensive therapy, suggesting that the abnormal expression of iNOS is associated with hypertension.
Efficacy and Tolerability of Losartan in Hypertensive Patients With Renal Impairment
Authors: Toto Robert , Shultz Pamela , Raij Leopoldo , Mitchell Helen , Shaw Wayne , Ramjit Denise , Toh Jenny , Shahinfar Shahnaz
Published: June 2012

Abstract
—We evaluated the blood pressure–lowering activity, tolerability, and safety of losartan in 112 hypertensive (sitting diastolic blood pressure, 90 to 115 mm Hg) patients with chronic renal insufficiency including mild renal insufficiency (30 to 60 mL/min per 1.73 m
2
; n=51), moderate to severe renal insufficiency (10 to 29 mL/min per 1.73 m
2
; n=33), or hemodialysis (n=28). After a 3-week placebo period, once-daily losatan was administered for 12 weeks. The daily dose of 50 mg was increased to 100 mg after 4 weeks in patients whose sitting diastolic blood pressure remained ≥90 mm Hg or was reduced by <5 mm Hg. A second, non–angiotensin-converting enzyme inhibitor, antihypertensive drug was added after 8 weeks as needed. Twenty-four–hour creatinine clearance was determined and renal clearance studies of inulin and para-aminohippurate were done in a subset of 11 patients. Trough sitting blood pressures were reduced at the end of the first week in all groups. At weeks 4, 8, and 12, the reductions in systolic blood pressure/diastolic blood pressure averaged −11.9/−8.7, −10.8/−9.4, and −14.7/−12.1 mm Hg in patients with mild renal insufficiency; −7.7/−6.3, −13.1/−11.8, and −14.1/−10.6 mm Hg, in moderate to severe renal insufficiency; −17.0/−12.7, −19.1/−14.4, and −22.7/−18.0 mm Hg in hemodialysis. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were stable. Losartan was withdrawn in only 6 patients because of a clinical or laboratory adverse experience. Hyperkalemia (>6 mEq/L) requiring discontinuation of losartan occurred in only one (group 2) patient. We conclude that once-daily losartan, given as monotherapy at doses of 50 or 100 mg or in combination with other antihypertensive drugs, was effective in reducing blood pressure in hypertensive patients with chronic renal disease and that losartan regimens were well tolerated in all groups, including those on hemodialysis.
Vasodepressor Actions of Angiotensin-(1–7) Unmasked During Combined Treatment With Lisinopril and Losartan
Authors: Iyer Shridhar N. , Chappell Mark C. , Averill David B. , Diz Debra I. , Ferrario Carlos M.
Published: June 2012

Abstract
—Blockade of angiotensin II (Ang II) function during 8 days of oral therapy with lisinopril (20 mg/kg) and losartan (10 mg/kg) normalized the arterial pressure (112±3/70±3 mm Hg) and raised the plasma concentrations of the vasodilator peptide angiotensin-(1–7) [Ang-(1–7)] of 21 male spontaneously hypertensive rats (SHR). Treated animals were then given a 15-minute infusion of either mouse immunoglobulin G
1
or a specific monoclonal Ang-(1–7) antibody while their blood pressure and heart rate were recorded continuously in the awake state. The concentrations of Ang II and Ang-(1–7) in arterial blood were determined by radioimmunoassay. Infusion of the Ang-(1–7) antibody caused significant elevations in mean arterial pressure that were sustained for the duration of the infusion and were accompanied by transient bradycardia. Although the hemodynamic effects produced by infusion of the Ang-(1–7) antibody had no effect on plasma levels of Ang II, they caused a twofold rise in the plasma concentrations of Ang-(1–7). A pressor response of similar magnitude and characteristics was obtained in a separate group of SHR treated with the combination of lisinopril and losartan for 8 days during an infusion of [Sar
1
-Thr
8
]Ang II. The pressor response induced by the administration of this competitive, non–subtype-selective Ang II receptor blocker was not modified by pretreatment of the rats with an angiotensin type-2 (AT
2
) receptor blocker (PD123319). Plasma concentrations of Ang II and Ang-(1–7) were not changed by the administration of [Sar
1
-Thr
8
]Ang II either in the absence or in the presence of PD123319 pretreatment. These results are the first to indicate an important contribution of Ang-(1–7) in mediating the vasodilator effects caused by combined inhibition of angiotensin-converting enzyme and AT
1
receptors. The comparable results obtained by administration of [Sar
1
-Thr
8
]Ang II suggest that the vasodepressor effects of Ang-(1–7) during the combined treatment is modulated by a non-AT
1
/AT
2
angiotensin subtype receptor.
White Coat Effect and Reactivity to Stress
Authors: Lantelme Pierre , Milon Hugues , Gharib Claude , Gayet Christian , Fortrat Jacques-Olivier
Published: June 2012

Abstract
—The aim of this study was to elucidate further the precise nature of the so-called “white coat” (WC) effect. We enrolled 88 hypertensive (46 men, 42 women) and 18 normotensive (4 men, 14 women) subjects in whom beat-to-beat blood pressure (BP) and heart rate (HR) were measured with a Finapres device at rest (R period) and during conventional BP measurement (WC period). The WC effect was defined as WC period minus R period values of Finapres systolic BP. Using the same method, we also measured the BP and HR variations induced by mental stress (MS period) and by assuming the standing position (S period). Variability was estimated in the frequency domain for BP (BPV) and HR (HRV) and gave indices of the autonomic nervous system. Pulse wave velocity was taken as an index of arterial distensibility. In hypertensive subjects, the WC effect was significantly and positively correlated with the BP response to stress (0.51,
P
<.0001) and standing (0.63,
P
<.0001). An increased BPV was observed in the low-frequency band (0 to 0.150 Hz) during WC, MS, and S periods. In normotensive subjects, the WC effect was very slight and not correlated with the responses to stress and standing. In this group, the WC period was not accompanied with an increased BPV, unlike the stress and standing periods. HRV was similar in normotensives and in hypertensives: decreased, unchanged, and increased during MS, S, and WC periods, respectively. The PWV was significantly increased in the hypertensives relative to the normotensives, even in the quartile of those with the lowest BP (on average similar to that of the normotensives). This work shows that the WC effect is associated with an enhanced BP response to standing and mental stress; these three situations are characterized by an increased BPV in the low frequencies, suggesting a similar modification of the sympathovagal balance. The WC effect may entail an increased risk because it is associated with impaired arterial distensibility.
Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat
Authors: Thorin Eric , Cernacek Peter , Dupuis Jocelyn
Published: June 2012

Abstract
—Chronic elevation of plasma endothelin-1 (ET-1) levels has been reported in several pathological conditions. To investigate the consequences of increased circulating ET-1 on vascular responsiveness, Sprague-Dawley rats (n=16) were chronically instrumented with a minipump delivering ET-1 at a constant dose for 7 days. Plasma ET-1 levels were more than doubled in treated (0.98±0.09 pmol/L;
P
<.05) versus untreated sham-operated rats (0.43±0.04 pmol/L), whereas systolic arterial blood pressure increased (139±5 versus 128±4 mm Hg in untreated rats;
P
<.05). After rats were killed, segments of middle cerebral (MCA) and mesenteric (MES) arteries were mounted on an isometric myograph. ET-induced contraction was shifted to the right in ET-1–treated animals and not modified by BQ123 (an ET
A
receptor antagonist); bosentan (ET
A/B
receptor antagonist) prevented ET-1–induced contraction in both groups. After inhibition of nitric oxide synthase with
N
ω
-nitro-
l
-arginine (L-NNA), both phenylephrine and oxymetazoline (an α
2
-adrenoceptor agonist) induced MCA contraction. The sensitivity to phenylephrine was decreased in ET-1–treated compared with control rats (
P
<.05). Sensitivity to phenylephrine-induced contraction was decreased by BQ123 in control rats only. In contrast, L-NNA revealed greater oxymetazoline-induced contractions in treated compared with control MCA rings (
P
<.05); this potentiation was blunted by bosentan but unaffected by BQ123. Removal of the endothelium revealed a direct constrictor effect of oxymetazoline that was insensitive to L-NNA alone or combined with bosentan; however, oxymetazoline induced significantly lower constriction in treated rat MCA segments. Responses to oxymetazoline were also blunted in treated compared with untreated denuded MES arteries. In conclusion, chronic elevated plasmatic ET-1 decreases smooth muscle cell sensitivity to contractile agonists both in MCA and MES rings. In cerebral vessels, endothelial α
2
-adrenoceptor–dependent stimulation induced greater contractile responses in treated rats which were sensitive to bosentan, suggesting that oxymetazoline stimulates ET-1 release from the endothelium. This may represent a compensatory mechanism for the loss of smooth muscle sensitivity.
Three Candidate Genes and Angiotensin-Converting Enzyme Inhibitor–Related Cough
Authors: Zee Robert Y. L. , Rao Valluri S. , Paster Robert Z. , Sweet Charles S. , Lindpaintner Klaus
Published: June 2012

Abstract
—Unexplained, persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE, chymase, and B2-bradykinin receptor have been implicated. To investigate this question, we determined genotypes for common polymorphisms for these three genes in subjects with a history of ACE inhibitor–related cough. Specificity of the adverse effect was confirmed by a blinded, double-crossover design protocol in which subjects were rechallenged with either lisinopril or placebo. In 99 case subjects and 70 control subjects (who failed to develop cough on rechallenge with ACE inhibitor) thus selected, frequencies for the
ACE D
and
I
alleles were 0.56 and 0.44 (cases) and 0.56 and 0.44 (controls), respectively; frequencies for chymase
A
and
B
alleles (absence/presence of
Bst
XI site) were 0.56 and 0.44 (cases) and 0.46 and 0.54 (controls), respectively; frequencies for B2-bradykinin receptor
+
and − alleles (presence/absence of a 21 to 29 nonanucleotide sequence) were 0.52 and 0.48 (cases) and 0.53 and 0.47 (controls), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for association between genotype at either gene examined and cough (adjusted for gender and age). Our data indicate that common genetic variants of ACE, chymase, and B2-bradykinin receptor do not explain the occurrence of ACE inhibitor–related cough.
Relation of Left Ventricular Midwall Function to Cardiovascular Risk Factors and Arterial Structure and Function
Authors: Devereux Richard B. , de Simone Giovanni , Pickering Thomas G. , Schwartz Joseph E. , Roman Mary J.
Published: June 2012

Abstract
—Left ventricular (LV) midwall shortening (MWS) is subnormal in relation to LV circumferential end-systolic stress (ESS) (ESS-corrected MWS) in many hypertensive patients with normal LV chamber function and predicts subsequent morbidity and mortality. However, little is known of the relations of LV midwall function to demographic and metabolic variables or to arterial geometry. Asymptomatic, unmedicated normotensive (n=366) or hypertensive (n=282) adults were assessed with echocardiography and carotid ultrasound. In normal adults, lower LV MWS and ESS-corrected MWS, an index of LV contractility, were related independently to high total peripheral resistance, high heart rate, and male gender (all
P
<.00001), lower serum HDL cholesterol (
P
=.001) and diastolic pressure (
P
=.003), and for ESS-corrected MWS only, arterial relative wall thickness (RWT,
P
=.03). Among hypertensive patients, lower values for both midwall function indices were associated independently with higher peripheral resistance (
P
<.00001), heart rate (
P
<.00005), body mass index (
P
<.01), and arterial RWT (
P
=.04), as well as male gender (
P
<.0002). In the entire population, lower LV MWS was independently related to higher peripheral resistance, heart rate (both
P
<.00001), body mass index (
P
=.0006) and arterial RWT (
P
=.009); male gender (
P
<.00001); and lower age (
P
=.004), diastolic pressure (
P
=.042), and systolic carotid artery expansion (
P
=.032). Lower ESS-corrected MWS in the entire population was independently associated with higher peripheral resistance and heart rate (both
P
<.00001), body mass index (
P
=.0006), arterial RWT (
P
=.004); male gender; and lower diastolic pressure (both
P
<.00001), age (
P
<.00005), arterial expansion in systole (
P
=.006), and serum HDL cholesterol levels (
P
=.04). Among a subset (n=60), ESS-corrected MWS was positively related to apolipoprotein A1 (
P
=.004) and negatively to hemoglobin A1c (
P
<.01). Thus, higher LV midwall function is associated with female gender and more favorable profiles of hemodynamics, metabolic pattern, and arterial structure and function.
Adenosine Inhibits Collagen and Protein Synthesis in Cardiac Fibroblasts
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Jackson Edwin K.
Published: June 2012

Abstract
—The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [
3
H]proline and [
3
H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [
3
H]proline and [
3
H]leucine incorporation. These effects were blocked by KF17837 (selective A
2
antagonist) and 1,3-dipropyl-8-(
p
-sulfophenyl)xanthine (A
1
/A
2
receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A
1
antagonist), thus excluding the participation of A
1
receptors. The lack of effect of
CGS21680
(selective A
2A
agonist) excluded involvement of A
2A
receptors, thus suggesting a major role for A
2B
receptors. Comparisons of the inhibitory potencies of
N
6
-cyclopentyladenosine (selective A
1
agonist), 5′-
N
-ethylcarboxamidoadenosine (A
1
/A
2
agonist), and 5′-
N
-methylcarboxamidoadenosine (A
1
/A
2
agonist) were consistent with that of an A
2B
receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A
2B
receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.
Characterization of a Urinary Bufodienolide Na
+
,K
+
-ATPase Inhibitor in Patients After Acute Myocardial Infarction
Authors: Bagrov Alexei Y. , Fedorova Olga V. , Dmitrieva Renata I. , Howald William N. , Hunter Ann P. , Kuznetsova Elena A. , Shpen Vladimir M.
Published: June 2012

Abstract
—Recent evidence suggests the existence of several endogenous Na
+
,K
+
-ATPase inhibitors in mammals. Previously, we have shown that the amphibian Na
+
,K
+
-ATPase inhibitor marinobufagenin (3,5-dihydroxy-14,15-epoxy bufodienolide) acts as a vasoconstrictor in isolated rat and human arteries. Mammalian plasma was shown to contain marinobufagenin-like immunoreactive material, which is responsive to saline volume expansion. The present study describes purification of a bufodienolide, which is similar to marinobufagenin, from the urine of patients after acute myocardial infarction with the use of thin-layer chromatography and reverse-phase high-performance liquid chromatography (HPLC). The purified substance cross-reacted with marinobufagenin antibody, demonstrated maximal UV absorbance at 300 nm characteristic of bufodienolides, and eluted from HPLC columns with the same retention time as marinobufagenin. Mass spectrometry of purified material revealed the presence of a substance indistinguishable from amphibian marinobufagenin and having molecular mass of 400 D. The present studies show that one of the human digitalis-like factors may have a bufodienolide structure and is likely to represent marinobufagenin or its isomer, and they suggest a role for this substance in the pathogenesis of myocardial ischemia.
Localization and Production of Angiotensin II in the Isolated Perfused Rat Heart
Authors: de Lannoy Larissa M. , Danser A.H. Jan , Bouhuizen Angelique M.B. , Saxena Pramod R. , Schalekamp Maarten A.D.H.
Published: June 2012

Abstract
—We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the localization and production of angiotensin II (Ang II) in the heart. During combined renin (0.7 to 1.5 pmol Ang I/mL per minute) and angiotensinogen (6 to 12 pmol/mL) perfusion (4 to 8 mL/min) for 60 minutes (n=3), the steady-state levels of Ang II in interstitial transudate in two consecutive 10-minute periods were 4.3±1.5 and 3.6±1.5 fmol/mL compared with 1.1±0.4 and 1.1±0.6 fmol/mL in coronary effluent (mean±half range). During perfusion with Ang II (n=5), steady-state Ang II in interstitial transudate was 32±19% of arterial Ang II compared with 65±16% in coronary effluent (mean±SD,
P
<.02). During perfusion with Ang I (n=5), Ang II in interstitial transudate was 5.1±0.6% of arterial Ang I compared with 2.2±0.3% in coronary effluent (
P
<.05). The tissue concentration of Ang II in the combined renin/angiotensinogen perfusions (per gram) was as high as the concentration in interstitial transudate (per milliliter). Addition of losartan (10
−6
mol/L) to the renin/angiotensinogen perfusion (n=3) had no significant effect on the tissue level of Ang II, whereas losartan in the perfusions with Ang I (n=5) or Ang II (n=5) decreased tissue Ang II to undetectably low levels. The results indicate that the heart is capable of producing Ang II and that this can lead to higher levels in tissue than in blood plasma. Cardiac Ang II does not appear to be restricted to the extracellular fluid. This is in part due to AT
1
-receptor–mediated cellular uptake of extracellular Ang II, but our results also raise the possibility of intracellular Ang II production.