bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypertension, aging, and myocardial synthesis of heat-shock protein 72.
Authors: Bongrazio M , Comini L , Gaia G , Bachetti T , Ferrari R
Published: June 2012

We determined the temperature-induced synthesis of the 72-kD heat-shock protein (hsp72) in hearts of normotensive and spontaneously hypertensive rats (SHR) subjected to whole-body hyperthermia (42.0 +/- 0.5 degrees C for 15 minutes). The animals were studied at three different ages: young (2 months), adult (6 months), and old (18 months). The hsp72 was determined by Western blot analysis using a monoclonal antibody. The results were calculated densitometrically as a percentage of a commercial standard. Young SHR responded to hyperthermic stress with increased synthesis of hsp72 compared with age-matched normotensive rats (298.8 +/- 70.0% versus 88.3 +/- 25.5%). This trend was maintained in adult rats (118.1 +/- 31.0% versus 54.8 +/- 21.3%) but not in old rats (65.3 +/- 29.4% versus 43.6 +/- 15.1%). Aging caused a reduction of hsp72 expression in response to hyperthermic stress in both SHR (4.6-fold) and normotensive rats (twofold). These data show that hearts of young and adult SHR respond to heat shock with enhanced synthesis of hsp72. This abnormal response, attenuated by aging, is independent of the presence and degree of hypertension or hypertrophy and is potentially linked to the genetic determination of the disease.
Metoclopramide stimulates kaliuresis during felodipine without affecting its natriuresis.
Authors: van Hamersvelt H W , Wetzels J F , Koene R A , Huysmans F T
Published: June 2012

Calcium entry blockers such as felodipine induce natriuresis without a parallel rise of potassium excretion. Previous studies with exogenous aldosterone and felodipine have suggested that the absence of kaliuresis might be explained by a felodipine-induced inhibition of aldosterone release. The natriuresis with calcium entry blockers could not be attributed to a similar mechanism but might be due to the stimulation of intrarenal natriuretic systems such as the dopaminergic system. We studied whether the aselective dopamine antagonist metoclopramide prevents the natriuresis with low and therapeutic felodipine doses and whether metoclopramide-induced aldosterone release promotes kaliuresis with felodipine. Twelve healthy male volunteers participated in a randomized, placebo-controlled, crossover study comparing felodipine infusion during metoclopramide with felodipine alone. Metoclopramide had no significant influence on the pronounced and dose-dependent increases of renal plasma flow and urinary sodium excretion with felodipine. Metoclopramide increased plasma aldosterone concentration from 0.17 +/- 0.03 to 0.60 +/- 0.14 nmol/L, and subsequent felodipine infusion clearly increased urinary potassium excretion by 23 +/- 6 and 35 +/- 8 mumol/min (low and therapeutic doses, respectively). In contrast, potassium excretion remained stable with felodipine alone (+5 +/- 4 and +7 +/- 5 mumol/min, respectively). In conclusion, the natriuretic action of calcium entry blockers cannot be blocked by the aselective dopamine antagonist metoclopramide. This natriuresis is accompanied by kaliuresis only in the presence of elevated endogenous aldosterone concentrations. The ability of calcium entry blockers to prevent a rise of plasma aldosterone thus seems essential for the prevention of urinary potassium losses.
Effects of insulin on vascular responses to mental stress and norepinephrine in human forearm.
Authors: Jern S
Published: June 2012

Essential hypertension is frequently associated with insulin resistance and hyperinsulinemia. In vitro, insulin has vasodilator actions, but its possible hemodynamic effect on muscular vascular beds in humans is a matter of controversy. We investigated the effects of local hyperinsulinemia on the vascular responses to norepinephrine and physiological vasodilation during mental stress in the perfused-forearm model. Nine glucose-tolerant, normotensive, nonobese men (aged 22 to 36 years) participated. Forearm perfusion studies (venous occlusion plethysmography) were performed during randomized, double-blind intrabrachial artery infusions of insulin (to raise plasma insulin 100 microU/mL) or placebo for 2 hours. A mental stress test and stepwise intra-arterial infusion of norepinephrine (6 to 1200 ng/min) were performed during each infusion. Insulin infusion increased venous plasma insulin to 98.4 microU/mL and increased net glucose uptake threefold. Insulin had a gradual vasodilator effect (P < .05 by ANOVA), and after 90 minutes blood flow was 36 percent units higher relative to the control arm than during placebo (P = .005). During mental stress, forearm blood flow increased by 81% (t test, P = .006) and 92% (P = .01) in the study arm during insulin and placebo infusions, respectively (insulin versus placebo, P = NS). An increased forearm blood flow was maintained throughout the mental stress test during insulin infusion (ANOVA, P = .03). Forearm glucose uptake increased during stress, reflecting forearm hyperperfusion since fractional glucose extraction was unaffected by stress. The increased blood flow was maintained throughout the five norepinephrine dose steps (ANOVA, P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)
Additive effects of obesity, hypertension, and type 2 diabetes on insulin resistance.
Authors: Maheux P , Jeppesen J , Sheu W H , Hollenbeck C B , Clinkingbeard C , Greenfield M S , Chen Y D , Reaven G M
Published: June 2012

Resistance to insulin-mediated glucose disposal has been previously shown to be increased in association with obesity, high blood pressure, and non-insulin-dependent diabetes mellitus. We initiated the present study to quantify the separate effects of hypertension and non-insulin-dependent diabetes mellitus on insulin resistance in both nonobese and obese subjects. To accomplish this, 88 subjects were divided into the following five experimental groups: normal blood pressure, nonobese (n = 17); normal blood pressure, obese (n = 18); high blood pressure, nonobese (n = 18); high blood pressure, obese (n = 19); and high blood pressure, obese, non-insulin-dependent diabetes mellitus (n = 16). Plasma glucose and insulin concentrations were measured before and after a 75-g oral glucose load. Resistance to insulin-mediated glucose disposal was estimated by determining the steady-state plasma insulin and glucose concentrations during the last 30 minutes of a continuous infusion of somatostatin (5 micrograms/min), exogenous insulin (25 mU/m2 per minute), and glucose (240 mg/m2 per minute). Since the steady-state plasma insulin concentrations are similar in all subjects, the higher the steady-state plasma glucose, the more insulin resistant the individual. Nonobese subjects with normal blood pressure had the lowest plasma glucose and insulin responses and steady-state plasma glucose concentrations, and their values were significantly different from the other four groups. Obese or nonobese subjects with high blood pressure had significantly higher plasma glucose responses and steady-state plasma glucose concentrations than did their respective weight-matched control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal effects of nifedipine and captopril in patients with essential hypertension and reduced renal reserve.
Authors: Buzio C , Regolisti G , Perazzoli F , Mutti A , Bergamaschi E , Borghetti A
Published: June 2012

In this study we investigated the short-term effects of calcium channel blockers and angiotensin-converting enzyme inhibitors on renal hemodynamics and the urinary excretion of proteins with different relative mass in subjects with mild to moderate essential hypertension and apparently normal glomerular filtration rate but reduced renal functional reserve. Sixteen subjects underwent the following four treatments: (1) low-protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg body wt), (3) high-protein meal plus oral nifedipine (20 mg), and (4) high-protein meal plus oral captopril (50 mg). Two urine samples were obtained after meals. Blood samples were drawn at the midpoint of each 120-minute urine collection period. Urine and serum were tested for total protein, immunoglobulin G, albumin, alpha 1-microglobulin, retinol binding protein, and beta 2-microglobulin. Glomerular filtration rate and renal plasma flow were assessed by iothalamate and p-aminohippuric clearance, respectively. Compared with the high-protein meal alone, nifedipine elicited a clear-cut increase in the urinary excretion of total protein (+60%, P < .01), immunoglobulin G (+58%, P < .01), albumin (+25%, P < .05), retinol binding protein (+47%, P < .05), and beta 2-microglobulin (+52%, P < .05); captopril decreased the urinary excretion rate of immunoglobulin G (-26%, P < .05), albumin (-22%, P < .05), and beta 2-microglobulin (-34%, P < .05). The ratio between the clearances of immunoglobulin G and albumin was higher after nifedipine (+21%, P < .01) and unchanged after captopril (-9%, P = NS) compared with the high-protein meal alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of antihypertensive agents on baroreceptor function in early hypertensive rats.
Authors: Ichikawa M , Suzuki H , Kumagai K , Ryuzaki M , Kumagai H , Jimbo M , Nishizawa M , Saruta T
Published: June 2012

To investigate the effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor function at the early phase of hypertension, we administered the agents to spontaneously hypertensive rats and Wistar-Kyoto rats from 8 to 10 weeks of age and examined the aortic nerve activity function. In untreated spontaneously hypertensive rats, the relation between the arterial pressure and aortic nerve activity was shifted to the right, that is, to a higher pressure level (threshold pressure, 90 +/- 3 versus 76 +/- 1 mm Hg, P < .05), and the maximum gain which was obtained by logistic function analysis was depressed (1.55 +/- 0.08% versus 2.18 +/- 0.13% maximum/mm Hg, P < .01) as compared with untreated Wistar-Kyoto rats. An equivalent decrease in arterial pressure with each of the four agents (-20 +/- 1 mm Hg, P < .01) produced a leftward shift of the arterial pressure-aortic nerve activity relation to a similar extent (threshold pressure, 77 +/- 1 mm Hg, P < .05) in spontaneously hypertensive rats. In addition, treatment with the four agents equally augmented the maximum gain in spontaneously hypertensive rats (2.13 +/- 0.09% maximum/mm Hg, P < .05). The antihypertensive agents affected neither the blood pressure nor the aortic nerve activity in Wistar-Kyoto rats. These findings suggest that antihypertensive treatment with the four classes of agents equally enhances the arterial baroreceptor function through blood pressure reduction but not through specific depressor mechanisms at the early stage of hypertension.
Myofilament Calcium Sensitivity of Normotensive and Hypertensive Resistance Arteries
Authors: Bian Ka , Bukoski Richard D.
Published: June 2012

Abstract
We measured intracellular Ca
2+
and isometric force simultaneously in endothelium-denuded mesenteric resistance arteries of 12- to 15-week-old male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and Wistar rats. Basal Ca
2+
did not differ among vessels of these strains (SHR, 86.6±4.5 nmol/L; WKY, 78.5±4.7 nmol/L; Wistar, 83.1±3.9 nmol/L). Myofilament Ca
2+
sensitivity was determined by measuring the intracellular Ca
2+
and force responses to cumulative addition of extracellular Ca
2+
(0.025 to 2.5 mmol/L) in the presence of 100 mmol/L K
+
or 10 μmol/L norepinephrine after depletion of releasable intracellular Ca
2+
stores. With 100 mmol/L K
+
, no between-strain differences in active stress, intracellular Ca
2+
, or myofilament Ca
2+
sensitivity were observed. With 10 μmol/L norepinephrine, the active stress response of SHR vessels to 0.025 and 0.05 mmol/L Ca
2+
was increased compared with both normotensive strains. The intracellular Ca
2+
response was not different in vessels of SHR and WKY rats but was depressed in Wistar vessels. Myofilament Ca
2+
sensitivity of SHR was elevated compared with both WKY and Wistar rats (
P
<.05) (ED
25
for SHR, 74.4±5.1 nmol/L; WKY, 89.8±5.5 nmol/L; Wistar, 86.9±3.4 nmol/L). No strain differences in intracellular Ca
2+
or active stress responses of SHR and WKY vessels were detected during cumulative addition of norepinephrine with constant extracellular Ca
2+
(1.5 mmol/L). These results indicate that no hypertension-associated defect in vascular Ca
2+
handling exists in mesenteric arteries of the SHR. Moreover, although resistance arteries of SHR exhibit enhanced myofilament Ca
2+
sensitivity compared with two normotensive strains after depletion of intracellular Ca
2+
and activation with 10 μmol/L norepinephrine, this difference is not observed under the more physiological manipulation of cumulative addition of norepinephrine in the presence of constant Ca
2+
. We conclude that enhanced myofilament Ca
2+
sensitivity is unlikely to contribute to the hypertension of SHR.
Rapid Effects of Aldosterone on Sodium Transport in Vascular Smooth Muscle Cells
Authors: Christ Michael , Douwes Kathrin , Eisen Christoph , Bechtner Günther , Theisen Karl , Wehling Martin
Published: June 2012

Abstract
Increasing evidence has accumulated for rapid nongenomic steroid actions in various cell systems and, more recently, for rapid aldosterone effects on the Na
+
-H
+
antiport in human mononuclear leukocytes. The aim of the present study was to demonstrate a rapid, nongenomic aldosterone action in rat vascular smooth muscle cells as a key effector cell in cardiovascular regulation. Basal
22
Na
+
influx in quiescent vascular smooth muscle cells was 22.1±1.9 nmol/mg protein per minute (mean±SEM, n=9). Aldosterone (1 nmol/L) stimulated influx to 28.6±1.5 nmol/mg protein per minute after 4 minutes (n=9,
P
<.05), with a half-maximal effect between 0.1 and 0.5 nmol/L; the effects were inhibited by ethylisopropylamiloride, the specific inhibitor of the Na
+
-H
+
exchanger, demonstrating the involvement of this transport system in rapid effects of aldosterone. Hydrocortisone (1 μmol/L) was ineffective, and fludrocortisone and deoxycorticosterone increased influx with half-maximal effects at approximately 0.5 nmol/L. Canrenone, a classic antagonist of aldosterone action, did not inhibit stimulation by aldosterone at a 1000-fold excess concentration. Aldosterone significantly stimulated intracellular inositol 1,4,5-trisphosphate levels (
P
<.05) after 30 seconds; the inhibitors of phospholipase C, neomycin and U-73122, inhibited aldosterone-stimulated Na
+
influx and increase of intracellular inositol 1,4,5-trisphosphate. The rapid stimulation of sodium transport in vascular smooth muscle cells and the pharmacological characteristics of this effect are clearly incompatible with the classic, genomic pathway of steroid action and represent further evidence for nongenomic effects of aldosterone.
Monocyte Infiltration and c-
fms
Expression in Hearts of Spontaneously Hypertensive Rats
Authors: Haller Hermann , Behrend Martin , Park Joon Keun , Schaberg Tom , Luft Friedrich C. , Distler Armin
Published: June 2012

Abstract
To elucidate mechanisms of myocardial hypertrophy in spontaneously hypertensive rats (SHR), we examined by Northern blotting the expression of the proto-oncogenes c-
myc
, c-
fos
, c-
sis
, and c-
fms
in the hearts of 4- and 14-week-old SHR and normotensive Wistar-Kyoto (WKY) rats. No difference in c-
myc
or c-
fos
expression could be found between SHR and WKY rats. In SHR, c-
sis
gave a weak and c-
fms
a very strong signal at 14 weeks, whereas no signal for these oncogenes was found in either WKY rats or Sprague-Dawley controls. Since c-
fms
codes for the receptor of monocyte colony-stimulating factor, we next used in situ hybridization to localize the presence of c-
fms
in hearts of SHR at 14 weeks. We found strong signals for c-
fms
around small blood vessels and between cardiac myocytes in 14-week-old SHR but none in WKY rats. Immunohistochemical staining corroborated the presence of clusters of monocyte infiltration at these same perivascular sites in significantly greater numbers in SHR than in WKY rats. We conclude that c-
fms
expression and macrophage infiltration are increased in the perivascular space of hypertrophied hearts from SHR. We suggest that mononuclear cell recruitment and induction of c-
fms
may play a role in the development of hypertension-associated myocardial hypertrophy.
Evaluation of the SA Locus in Human Hypertension
Authors: Nabika Toru , Bonnardeaux Alain , James Michael , Julier Cecile , Jeunemaitre Xavier , Corvol Pierre , Lathrop Mark , Soubrier Florent
Published: June 2012

Abstract
The SA gene is expressed at 10-fold greater levels in the kidney of the spontaneously hypertensive rat compared with the normotensive Wistar-Kyoto rat. The gene is linked to blood pressure levels in a number of crosses involving the spontaneously hypertensive rat and other strains of genetically hypertensive rats. To assess its role in human hypertension, a human SA cDNA was cloned from a liver library. The cDNA was 1513 bp in length and exhibited a high identity with the published rat SA cDNA sequence in the coding region. A microsatellite marker was developed from a yeast artificial chromosome clone containing SA and mapped by linkage to human chromosome 16p13.11-12.3. Polymerase chain reaction amplification of human genomic DNA revealed two introns located in the SA gene, one of which contains a frequent polymorphism due to a single nucleotide substitution (cytosine to thymidine at residue 79 of the intron). Association and linkage studies in a large sample of hypertensive patients, normotensive control subjects, and multiplex sibships with these markers and other microsatellites in close proximity to SA revealed no evidence favoring involvement of the gene in the disease in humans. The methodology used in this study can be applied to the evaluation of other novel candidate genes obtained from investigations of experimental models of hereditary hypertension.
Evidence of Coexisting Changes in 11β-Hydroxysteroid Dehydrogenase and 5β-Reductase Activity in Subjects With Untreated Essential Hypertension
Authors: Soro Aldo , Ingram Mary C. , Tonolo Giancarlo , Glorioso Nicola , Fraser Robert
Published: June 2012

Abstract
We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11β-hydroxysteroid dehydrogenase and 5β-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.
Resetting Blood Pressure in Spontaneously Hypertensive Rats
Authors: O’Sullivan Joseph B. , Harrap Stephen B.
Published: June 2012

Abstract
Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B
2
receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Ramipril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140–treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development.
Nitric Oxide Synthesis Inhibition Blocks Reversal of Two-Kidney, One Clip Renovascular Hypertension After Unclipping
Authors: Beierwaltes William H. , Potter D’Anna L. , Carretero Oscar A. , Sigmon David H.
Published: June 2012

Abstract
It is well established that two-kidney, one clip renovascular hypertension can be rapidly reversed by unclipping. We hypothesized that rapid renal reperfusion and the subsequent fall in blood pressure are mediated in part by nitric oxide, the endothelium-derived relaxing factor. We tested whether the hypotensive response to unclipping could be blocked by nitric oxide synthesis inhibition using a bolus of 10 mg/kg body wt
N
ω
-nitro-
l
-arginine methyl ester. Rats were made hypertensive by placing a silver clip on the left renal artery. After 4 weeks, they were anesthetized and either not treated (controls) or had nitric oxide synthesis blockade. After 10 minutes, the clip was removed and blood pressure monitored over 60 minutes. Initial pressure in controls was 157±8 mm Hg, and heart rate was 310±21 beats per minute. Unclipping resulted in pressure falling to 125±6 mm Hg within 45 minutes (
P
<.005). Heart rate was unchanged (312±9 beats per minute). In contrast, nitric oxide synthesis inhibition increased blood pressure from 149±6 to 174±9 mm Hg (
P
<.001). Unclipping did not change blood pressure, which was 167±8 mm Hg after 60 minutes (
P
<.005 versus controls), and heart rate remained unchanged (282±13 versus 276±16 beats per minute). We determined the blood flow to the clipped kidneys using radioactive microspheres. Unclipping untreated hypertensive rats resulted in a 10-fold increase in renal blood flow (
P
<.001), concomitant with a decrease in blood pressure. In rats with nitric oxide synthesis inhibition, unclipping resulted in an increase in renal blood flow that was only a third of that seen in untreated rats, with no change in blood pressure. Our results show that nitric oxide synthesis inhibition eliminates the acute reversal of renovascular hypertension caused by unclipping. This suggests that endothelium-derived nitric oxide may be an important component in the reversal of two-kidney, one clip renovascular hypertension, either by facilitating renal reperfusion or by mediating the systemic response secondary to renal reperfusion.
Blood Pressure Response to the Valsalva Maneuver in Pheochromocytoma and Pseudopheochromocytoma
Authors: Hamada Mareomi , Shigematsu Yuji , Mukai Mikio , Kazatani Yukio , Kokubu Tatsuo , Hiwada Kunio
Published: June 2012

Abstract
To elucidate whether a difference in blood pressure reactivity exists between patients with pheochromocytoma (n=8) and pseudopheochromocytoma (n=22), we evaluated blood pressure changes during a Valsalva maneuver and baroreceptor reflex sensitivity. We also examined the effects of propranolol and prazosin on blood pressure reactivity during a Valsalva maneuver in patients with pseudopheochromocytoma. Pseudopheochromocytoma was defined as a paroxysmal rise in blood pressure accompanying pheochromocytoma-like symptoms and normal catecholamine values. The difference in systolic blood pressure between phase IV of the Valsalva maneuver and baseline (ΔSBP) was markedly smaller in the pheochromocytoma patients (8.4±18.4 mm Hg) than in the essential hypertension patients (n=30, 30.9±19.4 mm Hg) and normotensive control subjects (n=10, 31.3±11.4 mm Hg), whereas ΔSBP in the pseudopheochromocytoma patients (77.8±11.2 mm Hg) was markedly greater than in the other three groups. ΔSBP was markedly suppressed by the administration of both propranolol and prazosin. Baroreceptor reflex sensitivity index was lower in the pheochromocytoma group than in the other three groups. In conclusion, blood pressure reactivity responses to a Valsalva maneuver are disparate between pheochromocytoma and pseudopheochromocytoma. The high blood pressure reactivity to a Valsalva maneuver in pseudopheochromocytoma is due to hyperactivity in both β- and α
1
-adrenergic receptor functions, and the low blood pressure reactivity to a Valsalva maneuver in pheochromocytoma seems to be mainly due to the desensitization of both adrenergic systems associated with chronic catecholamine excess. In addition, the impaired baroreceptor function in pheochromocytoma is partially responsible for it.
Effect of EXP 3174 on Blood Pressure of Normoreninemic Renal Hypertensive Rats
Authors: Basso Nidia , Kurnjek María L. , Ruiz Patricia , Cannata Miguel A.
Published: June 2012

Abstract
This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163±12 to 110±9 mm Hg,
P
<.05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112±6 to 96±6 mm Hg,
P
<.05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156±9 to 132±5 mm Hg,
P
<.05) than in sham (104±3 to 94±4 mm Hg,
P
<.05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8±8.3 versus 95.7±10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42±1.58 versus 6.74±2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4±3.0 versus 26.0±2.4 ng Ang I/mL,
P
<.05) and in the artery wall of hypertensive conscious rats (103.1±10.3 versus 75.2±7.8 ng Ang I/g,
P
<.05). In summary, the central renin-angiotensin system does not seem to participate in the maintenance of high blood pressure in hypertensive animals. The enzymatic system present in the vascular wall appears to be activated in hypertensive rats. The hypotensive effect of EXP 3174 suggests that Ang II could be one of the factors involved in the maintenance of two-kidney, two clip hypertension.
Effects of Different Training Intensities on the Cardiopulmonary Baroreflex Control of Forearm Vascular Resistance in Hypertensive Subjects
Authors: Kouamé N’guessan , Nadeau André , Lacourcière Yves , Cléroux Jean
Published: June 2012

Abstract
We recently reported that ambulatory blood pressure decreased during the awake period after training at low intensity but not after training at moderate intensity in subjects with mild to moderate hypertension. The reasons for the failure of moderate-intensity training to reduce blood pressure are not clear. In the present article, we report the effects of different training intensities on cardiopulmonary baroreflex control of forearm vascular resistance, left ventricular function, vascular reactivity, and resistive vessel structure. After moderate-intensity training, the cardiopulmonary baroreflex control of forearm vascular resistance was significantly attenuated, left ventricular performance was enhanced, and vascular reactivity and resistive vessel wall thickness in the calf were reduced compared with values after the control sedentary period. No significant changes in these indexes were found after low-intensity training compared with sedentary values. These results indicate that attenuation of the cardiopulmonary baroreflex control of skeletal muscle vascular resistance after training at moderate intensity may contribute to the lack of antihypertensive effects, as seen from unchanged ambulatory blood pressure levels during the awake period, after training at this intensity. A decreased vascular smooth muscle response to sympathetic nervous stimulation appears to be partly involved in the alteration in the baroreflex control of forearm vascular resistance after moderate-intensity training. Although these findings should be confirmed in a greater number of subjects, the present results point to a key mechanism that might explain why moderate endurance exercise training fails to lower arterial blood pressure in hypertensive subjects.
Decreased Glomerular Basement Membrane Heparan Sulfate Proteoglycan in Essential Hypertension
Authors: Heintz Bernhard , Stöcker Georg , Mrowka Christian , Rentz Uwe , Melzer Heinrich , Stickeler Elmar , Sieberth Heinz-Günther , Greiling Helmut , Haubeck Hans-Dieter
Published: June 2012

Abstract
Heparan sulfate proteoglycans are major components of the glomerular basement membrane and play a key role in the molecular organization and function of the basement membrane. Moreover, their presence is essential for maintenance of the selective permeability of the glomerular basement membrane. Recently, we isolated and characterized a novel small basement membrane–associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show that this heparan sulfate proteoglycan is distinct from the large basement membrane–associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we have shown that the novel heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli. Turnover or, in the course of kidney diseases, degradation of heparan sulfate proteoglycan from glomerular basement membranes may lead to urinary excretion of heparan sulfate proteoglycan, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be directly detected by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine. The excretion of this small heparan sulfate proteoglycan was compared after physical exercise in normotensive and hypertensive subjects. Normotensive subjects and treated, essential hypertensive patients underwent a standardized workload on a bicycle ergometer. Biochemical characterization of the urinary proteins and heparan sulfate proteoglycan was performed before and 15 and 45 minutes after exercise. In both groups, physical exercise induced a significant increase in the excretion of urinary α1 microglobulin and albumin. However, a 10-fold increase in the urinary excretion rate of heparan sulfate proteoglycan was seen in normotensive subjects under exercise. In hypertensive patients, the relative increase in heparan sulfate proteoglycan excretion was significantly diminished (
P
<.05). These data, supported by immunohistochemistry, indicate changes in the glomerular basement membrane of the kidney in hypertension. Therefore, determination of urinary excretion of this novel small heparan sulfate proteoglycan after exercise may be a sensitive marker for the detection of basement membrane alterations in hypertension.
Regulation of Endothelial Constitutive Nitric Oxide Synthase by Protein Kinase C
Authors: Ohara Yuichi , Sayegh Hassan S. , Yamin Jay J. , Harrison David G.
Published: June 2012

Abstract
Protein kinase C (PKC) plays a key role in a variety of signal transduction processes. The promoter region of the endothelial constitutive nitric oxide synthase (ecNOS) gene contains a transcriptional factor AP-1 binding element. In the present study, we sought to determine the effect of PKC inhibition on the expression of ecNOS in cultured bovine aortic endothelial cells (BAEC). The PKC inhibitor staurosporine (10 to 100 nmol/L) increased the expression of ecNOS mRNA, assessed by Northern analysis, in a dose-dependent manner. A newly developed, more specific PKC inhibitor, chelerythrine (1 to 3 μmol/L), also increased the level of ecNOS mRNA. Incubation of BAEC with phorbol 12-myristate 13-acetate (100 nmol/L) for 24 hours, which downregulates PKC, increased ecNOS mRNA expression. The protein content of ecNOS, assessed by Western analysis, was also increased in staurosporine-treated or chelerythrine-treated BAEC. The release of nitrogen oxides from staurosporine-treated or chelerythrine-treated cells both under basal conditions and in response to calcium ionophore A23187 was significantly increased (
P
<.05). In conclusion, the present study suggests that regulation of ecNOS is mediated by PKC. The increased release of nitric oxide induced by PKC inhibition may play a protective role against atherogenic process.
Locally Generated Angiotensin II in the Adrenal Gland Regulates Basal, Corticotropin-, and Potassium-Stimulated Aldosterone Secretion
Authors: Gupta Prem , Franco-Saenz Roberto , Mulrow Patrick J.
Published: June 2012

Abstract
The zona glomerulosa cells of the adrenal gland have an intrinsic renin-angiotensin system that appears to modulate the aldosterone response to potassium and corticotropin. The actions of circulating angiotensin II (Ang II) are mediated by the activation of the Ang II type 1 (AT
1
) receptor on the adrenal cortex. In this study we examined the effects of the AT
1
receptor antagonist DuP 753 and other antagonists on aldosterone secretion in cultured bovine zona glomerulosa cells. Zona glomerulosa cells were cultured in PFMR-4 medium containing 10% fetal calf serum for 72 hours, and the medium was replaced with serum-free medium for the next 24-hour experimental period. DuP 753 (10 μmol/L) inhibited basal aldosterone secretion (from 88.6±7.1 to 54.8±9.6 pg/10
6
cells per hour; 38% inhibition). EXP 3174, an active metabolite of DuP 753, also inhibited aldosterone dose dependently (from 88.6±7.1 to 55.9±8.4 at 1 μmol/L and 88.6±7.1 to 21.7±3.3 at 100 μmol/L; 37% and 75% inhibition, respectively). Another and more potent AT
1
receptor antagonist, L158,809, showed significant inhibition at 100 nmol/L, and at 10 μmol/L it inhibited basal aldosterone secretion (from 144.7±18.2 to 83.4±17.1 pg/10
6
cells per hour; 42% inhibition). DuP 753 inhibited Ang II (100 nmol/L)–stimulated aldosterone production in a dose-dependent fashion, with a 30% reduction at 100 nmol/L and complete inhibition at 100 μmol/L. DuP 753 also inhibited potassium (12 nmol/L) and corticotropin (1 nmol/L) stimulation of aldosterone in a dose-dependent fashion. There was no evidence of cell toxicity as judged by gross and microscopic appearance of the cell culture, trypan blue exclusion, and the ability of cells to synthesize the protein renin. Furthermore, the AT
2
receptor antagonist PD 123319 did not inhibit basal, Ang II–, corticotropin-, or potassium-stimulated aldosterone. In conclusion, the AT
1
receptor antagonists inhibit basal, corticotropin-, and potassium-stimulated aldosterone. These data suggest that the adrenal renin-angiotensin system plays an important role in the regulation of aldosterone secretion.
Low-Density Lipoprotein Induces Vascular Adhesion Molecule Expression on Human Endothelial Cells
Authors: Haller Hermann , Schaper Doris , Ziegler Wolfgang , Philipp Sebastian , Kuhlmann Martin , Distler Armin , Luft Friedrich C.
Published: June 2012

Abstract
We tested the hypothesis that low-density lipoprotein (LDL) and its acetylated form influence surface expression of vascular adhesion molecules on human endothelial cells. Vascular adhesion molecule surface expression was assessed with flow cytometry on cultured endothelial cells with a modified enzyme-linked immunosorbent assay. LDL acetylation was determined by chromatography. Monocyte adhesion to endothelial cells was assessed with U937 cells by direct counting. Tumor necrosis factor-α (10 ng/mL), a positive control, induced a time-dependent expression of vascular adhesion molecules (
P
<.05), which peaked at 5 hours. Incubation of endothelial cells with LDL (1.3 to 26.0 mmol/L) led to an increase in expression at 2 and 5 hours (
P
<.05). Prolonged (24-hour) exposure to LDL resulted in a second peak. The effect of acetylated LDL on expression was not different from that of native LDL. Incubation with the protein kinase C inhibitor staurosporine (5×10
−8
mol/L) blocked the effects of both native and acetylated LDL completely (
P
<.05). The calcium channel blocker nitrendipine (10
−7
mol/L) did not influence the expression of vascular adhesion molecule at 2 and 5 hours but did reduce the effect of LDL on expression at 24 hours. LDL (2.6 mmol/L) also induced a significant increase in the surface expression of intercellular adhesion molecule-1 but did not affect the expression of endothelial adhesion molecules. LDL (2.6 mmol/L) induced a significant increase in monocyte binding. We conclude that LDL can induce the expression of vascular adhesion molecules on endothelial cells. This effect is mediated by protein kinase C and partially inhibited by calcium channel blockade. Our results suggest that LDL may increase the recruitment of monocytes through a protein kinase C–mediated increase in adhesion molecule surface expression.
Analysis of Renal Sympathetic Nerve Responses to Stress
Authors: DiBona Gerald F. , Jones Susan Y.
Published: June 2012

Abstract
We studied sympathetic nerve activity responses to acute environmental stress (air jet stress) in conscious Wistar-Kyoto, spontaneously hypertensive, and borderline hypertensive rats. The borderline hypertensive rats were fed either 1% (normotensive) or 8% (hypertensive) NaCl. Renal sympathetic nerve activity responses were analyzed with three methods: mean integrated voltage over time, power spectrum analysis, and sympathetic peak detection analysis. Measurements of mean integrated voltage over time showed that air jet stress increased renal sympathetic nerve activity in spontaneously hypertensive rats and in borderline hypertensive rats on 8% NaCl but not in the other groups. In the NaCl responders, power spectrum analysis of renal sympathetic nerve activity indicated that the increase in relative power was at the heart rate frequency, indicating that it was related to renal sympathetic nerve discharge coupled to the cardiac cycle. Sympathetic peak detection analysis of renal sympathetic nerve activity indicated that there was an increase in frequency of sympathetic peaks of greater height and shorter duration because of sinoaortic baroreceptor deactivation (increased peak frequency) and the recruitment of more active fibers (greater peak height) firing with greater synchronization (shorter peak duration). Additional methods of analysis of renal sympathetic nerve activity provide information in addition to that derived from measurement of mean integrated voltage over time.
Modeling Hemodynamic Profiles by Telemetry in the Rat
Authors: Bonizzoni Erminio , Milani Silvano , Ongini Ennio , Casati Carlo , Monopoli Angela
Published: June 2012

Abstract
The newly developed radiotelemetry system offers a number of advantages for the measurement of blood pressure and heart rate in laboratory animals. However, no available statistical methods permit valid use of the many data gathered with this continuous recording of hemodynamic parameters. This study describes elaboration and testing of mathematical functions as applied to the measurement of the effects of drugs on blood pressure and heart rate in spontaneously hypertensive rats. We used parametric functions analogous to those for pharmacokinetic studies. Curve fitting is in fact the only approach that provides reasonable estimates of hemodynamic kinetic constants. Nonlinear functions were assessed by analyzing telemetric hemodynamic effects induced by three adenosine receptor agonists with different selectivity for the A
1
or A
2a
receptor. After acute administration in conscious rats, the A
1
agonist 2-chloro-
N
6
-cyclopentyladenosine induced dose-related hypotension (eg, 0.03 mg/kg; peak, −70 mm Hg; time to peak, 0.34 hour) and bradycardia (eg, 0.03 mg/kg; peak, −186 beats per minute [bpm]; time to peak, 0.38 hour). The A
2a
agonist 2-hexynyl-5′-
N
-ethylcarboxamidoadenosine induced dose-related hypotension (eg, 0.003 mg/kg; peak, −36 mm Hg; time to peak, 0.32 hour) with reflex tachycardia (eg, 0.003 mg/kg; peak, 152 bpm; time to peak, 0.35 hour). The nonselective adenosine agonist 5′-
N
-ethylcarboxamidoadenosine (0.1 mg/kg) induced hypotension (peak, −75 mm Hg; time to peak, 2.2 hours) and bradycardia followed by tachycardia (first peak, −131 bpm; time to peak, 1.26 hours; second peak, 123 bpm; time to peak, 13.9 hours). With this model, other parameters, such as persistence (eg, half-life) or amount (eg, area under the curve) of the effects, can also be evaluated. Finally, the telemetry system permits precise characterization of the hemodynamic profile of different classes of cardiovascular drugs.
Effectiveness of Enalapril Versus Nifedipine to Antagonize Blood Pressure and the Renal Response to Endothelin in Humans
Authors: Kaasjager Karin A. H. , Koomans Hein A. , Rabelink Ton J.
Published: June 2012

Abstract
Endothelin-1 infusion into humans to obtain pathophysiological plasma levels causes mild hypertension, strong renal vasoconstriction, and sodium retention. We studied whether oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD) could attenuate these effects of endothelin-1 (2.5 ng/kg per minute for 90 minutes) in six healthy volunteers. Endothelin infusion alone increased plasma endothelin from 3.0±0.3 to 8.8±1.0 pmol/L (
P
<.05). Blood pressure rose by approximately 6 mm Hg (
P
<.05). Renal function changes were relatively large: Renal blood flow decreased from 941±76 to 729±118 mL/min (
P
<.05) and glomerular filtration rate from 105±9 to 92±10 mL/min (
P
<.05); renal vascular resistance increased from 101±7 to 152±20 mm Hg · min/L (
P
<.05); and sodium excretion decreased from 158±54 to 86±27 μmol/min (
P
<.05). Enalapril treatment reduced blood pressure from 94±2 to 87±3 mm Hg (
P
<.05) and prevented the hypertensive response to endothelin. By contrast, despite renal predilatation, endothelin reduced renal blood flow strongly (from 1063±127 to 763±100 mL/min,
P
<.05), although maximal renal vascular resistance was numerically lower (124±11 mm Hg · min/L) than during endothelin alone (
P
<.05). Glomerular filtration rate fell from 118±11 to 108±11 mL/min (
P
<.05). Enalapril did not alter the antinatriuretic effect of endothelin. Nifedipine did not affect blood pressure but prevented the increase caused by endothelin. The endothelin-induced fall in renal blood flow (from 1084±100 to 888±65 mL/min,
P
<.05) was less than during endothelin infusion alone (
P
<.05), and maximal renal vascular resistance (111±7 mm Hg · min/L) was lower than in both other experiments (
P
<.05), whereas glomerular filtration rate was maintained. Nifedipine increased basal sodium excretion (
P
<.05), which compensated for the decrease observed during superimposed endothelin infusion. In conclusion, both enalapril and nifedipine can counteract the hypertensive effect of endothelin, but nifedipine is more effective in antagonizing the renal effects of endothelin.
Natriuretic Response to Neutral Endopeptidase Inhibition Is Blunted by Enalapril in Healthy Men
Authors: Motwani Joseph G. , Lang Chim C. , Cramb Gordon , Struthers Allan D.
Published: June 2012

Abstract
We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II–dependent effects on the renal tubule or on systemic blood pressure.
Spectral Analysis of Blood Pressure Variability in Heart Transplant Patients
Authors: Hughson Richard L. , Maillet Alain , Dureau Georges , Yamamoto Yoshiharu , Gharib Claude
Published: June 2012

Abstract
The cardiac transplant patient provides a unique model for the study of blood pressure variability in the absence of heart rate variability. We examined the harmonic and fractal components of blood pressure variability in 14 heart transplant patients (12 men, 2 women; 21 to 62 years of age) and in age- and sex-matched control subjects during seated rest, supine rest, and supine rest with fixed-pace breathing (12 respirations per minute). Heart rate was faster in transplant patients than in control subjects, with much less heart rate variability (
P
<.0001). Spectral analysis of blood pressure variability revealed no difference in total power for either systolic or diastolic pressure, but transplant patients had less low-frequency (0 to 0.15 Hz) harmonic spectral power in both systolic (
P
<.01) and diastolic (
P
<.03) pressure and more high-frequency power (0.15 to 0.5 Hz) in diastolic pressure than control subjects. The ratio of high-frequency power in diastolic relative to systolic pressure was consistently higher (
P
<.0001) in the transplant patients (0.29 to 0.51) than in control subjects (0.11 to 0.13). The slope of the fractal component of systolic pressure was approximately 1.8 in both transplant patients and control subjects. This was greater than the slope for heart rate variability (approximately 1.1 in control subjects). These data provide clear evidence of independence of the fractal component of heart rate and blood pressure variabilities in both transplant patients and control subjects. The heart rate component of the arterial baroreflex minimized high-frequency diastolic pressure changes while contributing to low-frequency variations in both systolic and diastolic pressures.