bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic and Biochemical Effects of the AT
1
Receptor Antagonist Irbesartan in Hypertension
Authors: van den Meiracker Anton H. , Admiraal Peter J.J. , Janssen Joop A. , Kroodsma Jan-Maarten , de Ronde Wijnand A.M. , Boomsma Frans , Sissmann Joëlle , Blankestijn P.J. , Mulder Paul G.M. , Man in ‘t Veld Arie J. , Schalekamp Maarten A.D.H.
Published: June 2012

Abstract
We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT
1
) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT
1
receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (
r
=.68,
P
<.01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT
1
receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT
1
receptor blockade, did not fall. Compared with baseline values, plasma norepinephrine increased moderately with the 100-mg but not with 25- or 1-mg dose. Serum uric acid and its 24-hour urinary excretion did not change. In conclusion, in essential hypertension, once-daily irbesartan effectively lowers blood pressure. This effect is maintained for 24 hours with a 100-mg dose. Unlike the AT
1
receptor antagonist losartan, irbesartan exerts no uricosuric effect, suggesting that this is an effect unrelated to AT
1
receptor blockade.
Gender Differences and the Electrocardiogram in Left Ventricular Hypertrophy
Authors: Okin Peter M. , Roman Mary J. , Devereux Richard B. , Kligfield Paul
Published: June 2012

Abstract
We examined the relations of gender differences in electrocardiographic (ECG) voltages and QRS duration to differences in cardiac dimensions and body size between men and women and gender differences in test performance of ECG criteria for the detection of echocardiographic left ventricular hypertrophy in 389 subjects (112 women and 277 men). ECG voltage-duration products were calculated as the product of QRS duration and voltages. Among subjects with normal left ventricular mass and also among subjects with left ventricular hypertrophy, men had longer QRS duration, higher Cornell voltage, higher 12-lead sum of QRS voltage, and higher Cornell and 12-lead voltage-duration products than did women. Significant gender differences in QRS duration, Cornell voltage, the 12-lead sum of voltage and their voltage-duration products remained after adjusting for the greater left ventricular mass, height, and weight in men than women. Comparison of areas under receiver operating characteristic curves using gender-specific criteria demonstrated higher performance of QRS duration, Cornell voltage, the 12-lead sum of QRS voltage, and the respective voltage-duration products for the identification of left ventricular hypertrophy in men than women. Thus, gender differences in body size and left ventricular mass do not completely account for gender differences in QRS duration and voltage measurements, and ECG criteria for left ventricular hypertrophy have lower accuracy in women even when gender differences in partition value selection are taken into account. These findings indicate a need for new, more accurate, and gender-specific ECG criteria for the detection of hypertrophy and suggest that factors other than left ventricular dimensions and body size may play a role in the observed differences in QRS voltages and durations between men and women.
Enhanced Slow Pressor Effect of Angiotensin II in Two-Kidney, One Clip Rats
Authors: Melaragno Matthew G. , Fink Gregory D.
Published: June 2012

Abstract
Phase II of two-kidney, one clip (2K1C) Goldblatt hypertension in the rat is characterized by elevated blood pressure and near-normal plasma concentrations of angiotensin II (Ang II) but is reversed by inhibition of the renin-angiotensin system. We hypothesized that this angiotensin dependence is due to enhanced responsiveness to the slow pressor effect of Ang II caused by renal artery stenosis. To test this idea, we submitted rats to either renal artery clipping or sham operation. These groups were immediately subdivided; some animals received enalapril in their drinking water (508 μmol/L), and the rest drank distilled water only. After 10 to 14 days, catheters were inserted into the aorta and vena cava, and the rats were housed in metabolism cages. After 3 control days of measurement of mean arterial pressure and other variables, the enalapril-treated groups received an intravenous infusion of Ang II at a dose of 3.8 pmol/min (4 ng/min) for 14 days. Rats not drinking enalapril received only saline vehicle (2 mmol Na
+
per day). After 3 days of Ang II infusion, the enalapril-treated 2K1C rats had attained a significantly higher level of mean arterial pressure than the enalapril-treated sham rats. At the end of the Ang II infusion, mean arterial pressure in enalapril-treated 2K1C rats was 151±6 mm Hg versus 107±7 mm Hg in enalapril-treated sham rats. Mean arterial pressure in the enalapril-treated sham rats after Ang II infusion was not significantly different from that of untreated sham rats (109±2 mm Hg). No significant differences in urinary sodium excretion or water balance were noted between the 2K1C and sham rats. These results support the hypothesis that 2K1C rats exhibit enhanced responsiveness to the slow pressor effect of Ang II.
Testosterone Regulation of Renal α
2B
-Adrenergic Receptor mRNA Levels
Authors: Gong Guodong , Johnson Mark L. , Pettinger William A.
Published: June 2012

Abstract
Androgens regulate blood pressure and renal α
2
-adrenergic receptors in a parallel fashion in the spontaneously hypertensive rat (SHR). The present studies investigated whether this regulation of renal α
2B
-adrenergic receptors occurs at the mRNA level. Male and female SHR were gonadectomized at 4 weeks of age. The gonadectomized rats were implanted with or without testosterone propionate. Sham- gonadectomized rats served as controls. Total kidney RNA was purified, and α
2B
-adrenergic receptor mRNA was quantified with a reverse transcriptase–polymerase chain reaction (RT-PCR) assay. The assay uses a mimic RNA added at known concentrations to the sample RNA. The mimic was constructed from the target sequence in the α
2B
-adrenergic receptor mRNA plus a 20-bp insertion of a random nucleotide sequence. The amount of α
2B
-adrenergic receptor mRNA present in each sample was obtained by determining the equivalence point between the amount of RT-PCR product formed in the target band versus the mimic band, which were resolved by gel electrophoresis. Intact males had more than two times as much α
2B
-adrenergic receptor mRNA as intact females. Castration of males reduced the male-female difference by more than 60%. Ovariectomy slightly increased the α
2B
-adrenergic receptor mRNA level compared with that of intact females. Treatment with testosterone elevated α
2B
-adrenergic receptor mRNA levels of gonadectomized males and females to the level of intact males. The α
2B
-adrenergic receptor mRNA levels correlated remarkably well with renal α
2
-adrenergic receptor density. We conclude that testosterone regulates renal α
2B
-adrenergic receptor gene expression at the mRNA level in the SHR.
Pressure Enhances Endothelin-1 Release From Cultured Human Endothelial Cells
Authors: Hishikawa Keiich , Nakaki Toshio , Marumo Takeshi , Suzuki Hiromichi , Kato Ryuichi , Saruta Takao
Published: June 2012

Abstract
The effect of pure pressure without shear stress or stretch on the release of endothelin-1 was investigated. Elevation of pressure significantly enhanced endothelin-1 release from cultured human umbilical vein endothelial cells. A calcium channel blocker, nifedipine, and a putative stretch-activated channel blocker, gadolinium, did not affect the pressure-induced endothelin-1 increase. On the other hand, a phospholipase C inhibitor, 2-nitro-4-carboxyphenyl-
N
,
N
-diphenylcarbamate, and protein kinase C inhibitors, 1-5-(isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine, significantly inhibited the pressure-induced endothelin-1 increase. Moreover, pure pressure reduced basal nitric oxide release, while pretreatment with a nitric oxide synthase inhibitor,
N
G
-monomethyl-
l
-arginine, had no effect on the pressure-induced endothelin-1 increase. In conclusion, our results show for the first time that pressure enhances endothelin-1 release partially through activation of phospholipase C and protein kinase C in human endothelial cells.
Angiotensinogen Gene and Blood Pressure in the Japanese Population
Authors: Iwai Naoharu , Shimoike Hitoshi , Ohmichi Nobuyuki , Kinoshita Masahiko
Published: June 2012

Abstract
A molecular variant of the angiotensinogen gene with threonine instead of methionine at position 235 (ie, with M235T polymorphism) has been shown to be associated with essential hypertension in Caucasian populations. The purpose of the present study was to assess whether the M235T polymorphism was associated with essential hypertension in the Japanese population. The study population consisted of 347 subjects selected in our outpatient clinic. The clinical data included in the analyses were sex, age, body mass index, cholesterol level, genotype of the angiotensinogen gene, genotype of the angiotensin-converting enzyme gene, and systolic and diastolic blood pressure. Multiple regression analysis revealed that only body mass index was a predictor of both diastolic and systolic blood pressure in these 347 subjects, but the genotype of the angiotensinogen gene was identified as a predictor of both diastolic and systolic blood pressure in a subpopulation less than 50 years of age. However, in a subpopulation more than 50 years of age, body mass index was the only predictor of both systolic and diastolic blood pressure. Of the 347 subjects, 189 had a technically excellent echocardiogram at the initial observation period. Multiple regression analysis revealed that sex, body mass index, diastolic blood pressure, and genotype of the angiotensin-converting enzyme gene were predictors of left ventricular mass. Although subjects with the TT angiotensinogen genotype had significantly greater left ventricular mass than those with either the TM or the MM genotype, the effects of the genotype of the angiotensinogen gene on left ventricular mass were mainly due to effects on blood pressure.
Decreased Dihydropyridine Receptor Number in Hypertensive Rat Vascular Muscle Cells
Authors: Hermsmeyer Kent , White Anita C. , Triggle David J.
Published: June 2012

Abstract
To further investigate the altered function of Ca
2+
channels in vascular muscle cells in hypertension, a novel fluorescently labeled dihydropyridine was used with ultrahigh-sensitivity photometry to study dihydropyridine binding sites on the surface membrane of living vascular muscle cells from stroke-prone spontaneously hypertensive rats and their normotensive controls. Fluorescent nitrobenzoxadiazol-6-dihydropyridine in concentrations of 1 to 100 nmol/L bound specifically to vascular muscle cells’ Ca
2+
channels, and was displaced by the unlabeled dihydropyridine analogue or nisoldipine (10 μmol/L). Stroke-prone spontaneously hypertensive rat vascular muscle cells showed significantly decreased binding of nitrobenzoxadiazol-6-dihydropyridine compared with normotensive National Institutes of Health rats. Decreased binding of dihydropyridine by vascular muscle cells from stroke-prone spontaneously hypertensive rats (cells that in other studies show increased Ca
2+
channel function) indicates a change in channel regulation that is possibly due to a deficiency in the inactivation mechanism, consistent with our earlier electrophysiological studies reporting deficiencies in Ca
2+
-dependent inactivation in genetic hypertension. These data demonstrate decreased numbers of localized sites of dihydropyridine binding on the sarcolemma of living vascular muscle cells, and support the hypothesis that Ca
2+
channel alterations may significantly contribute to the molecular etiology of genetic hypertension.
Shear Stress–Induced Dilation Is Attenuated in Skeletal Muscle Arterioles of Hypertensive Rats
Authors: Koller Akos , Huang An
Published: June 2012

Abstract
Hypertension is thought to alter many of the functions of the vascular endothelium. The present study examines whether shear stress–induced endothelium-dependent skeletal muscle arteriolar dilation is compromised in genetically hypertensive rats. Changes in the diameter of isolated, perfused arterioles (approximately 60 μm) from gracilis muscles of 12-week-old normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR) were investigated. At a constant perfusion pressure (80 mm Hg), the active diameter of NWR and SHR arterioles was 57.1±2.0 and 50.9±3.5 μm, respectively (mean±SEM), while the passive diameter (in Ca
2+
-free solution) was 113.2±3.1 and 100.6±2.9 μm, respectively. Increases in wall shear stress (from 0 to 100 dyne/cm
2
) elicited by increases in perfusate flow (from 0 to 25 μL/min) resulted in marked increases in the diameter of NWR arterioles, but such increases produced substantially smaller dilations in SHR arterioles (43.0 versus 18.9 μm). The prostaglandin synthesis inhibitor indomethacin (10
−5
mol/L) significantly attenuated the shear stress–induced dilations in both strains of rats. In contrast, the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine (10
−4
mol/L) significantly shifted the shear stress–diameter curve to the right in vessels from NWR (by 50 dyne/cm
2
) but not in those from SHR. Thus, in gracilis muscle arterioles of SHR, the reduced dilation to increases in shear stress seems to be due to the lack of nitric oxide synthesis and/or release in response to shear stress. The absence of this mechanism could result in elevated shear stress and power dissipation in the peripheral circulation and may promote further pathological changes in the endothelium in hypertension.
Cyclosporin A Inhibits Nitric Oxide Synthase Induction in Vascular Smooth Muscle Cells
Authors: Marumo Takeshi , Nakaki Toshio , Hishikawa Keiichi , Suzuki Hiromichi , Kato Ryuichi , Saruta Takao
Published: June 2012

Abstract
The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1α (100 U/mL) and tumor necrosis factor−α (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC
50
of 4×10
−7
mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1α and tumor necrosis factor–α was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 μg/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor–α and bacterial lipopolysaccharide or that of interleukin-1α and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10
−6
mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
Deoxycorticosterone Acetate Plus Salt Induces Overexpression of Vascular Endothelin-1 and Severe Vascular Hypertrophy in Spontaneously Hypertensive Rats
Authors: Schiffrin Ernesto L. , Larivière Richard , Li Jin S. , Sventek Pavol , Touyz Rhian M.
Published: June 2012

Abstract
Endothelin-1 gene expression is enhanced in the aorta and mesenteric arteries, and possibly other vessels, of deoxycorticosterone acetate (DOCA)–salt hypertensive rats. In contrast, endothelin-1 gene expression is normal or reduced in spontaneously hypertensive rats (SHR). Severe vascular hypertrophy is present in DOCA-salt hypertensive rats but not in SHR. In this study we investigated whether treatment of SHR with DOCA and salt would result in enhanced endothelin-1 expression and at the same time in severe vascular hypertrophy. Increased abundance of endothelin-1 mRNA was found in the aorta and the mesenteric arterial bed of SHR treated simultaneously with DOCA and salt but not when rats were treated with either separately. The wet weight of the aorta and of the mesenteric arterial bed, media thickness, media cross-sectional area, and media-to-lumen ratio of mesenteric small arteries of DOCA- salt–treated SHR were exaggerated beyond what could be explained by the elevation of blood pressure, relative to SHR treated with salt or with DOCA, which did not overexpress vascular endothelin-1. In conclusion, SHR may exhibit enhanced expression of the endothelin-1 gene in blood vessels when treated with DOCA and salt, and associated with this there is severe vascular hypertrophy. These data support the hypothesis of a role of endothelin-1 in vascular hypertrophy.
Lead Increases Aldosterone Production by Rat Adrenal Cells
Authors: Goodfriend Theodore L. , Ball Dennis L. , Elliott Mary E. , Shackleton Cedric
Published: June 2012

Abstract
Exposure to lead has been postulated to contribute to elevated blood pressure in humans and has been shown to raise blood pressure in animals. The mechanism of action of lead on blood pressure is unknown. We fed lead to rats in their drinking water and then examined the production of aldosterone by their adrenal cells in vitro. We also measured excretion of aldosterone and corticosterone by intact rats stimulated with corticotropin, with and without lead treatment. At a dose (273 ppm) that raised blood levels to 30 to 40 μg/dL, comparable to blood levels in exposed humans, lead induced increased aldosterone secretion in vitro and in vivo. The effect of lead was most evident when cells or animals were stimulated with aldosterone secretagogues. Experiments in vitro indicate that exposure to lead in vivo increases activity of one or more steps in the late pathway of aldosterone biosynthesis. The results suggest that the hypertensive effect of lead involves relative hyperaldosteronism and may be most evident when secretion of this hormone is stimulated.
Mechanisms of Adrenomedullin-Induced Vasodilation in the Rat Kidney
Authors: Hirata Yasunobu , Hayakawa Hiroshi , Suzuki Yasuko , Suzuki Etsu , Ikenouchi Hiroshi , Kohmoto Osami , Kimura Kenjiro , Kitamura Kazuo , Eto Tanenao , Kangawa Kenji , Matsuo Hisayuki , Omata Masao
Published: June 2012

Abstract
To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: −29±2% [SEM];
P
<.01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%;
P
<.05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%;
P
<.05). Adrenomedullin decreased renal vascular resistance (10
−7
mol/L adrenomedullin: −41±2%;
P
<.001) and increased release of nitric oxide (+5.1±0.7 fmol/min per gram kidney weight;
P
<.001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor
N
G
-monomethyl-
l
-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate–salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10
−7
mol/L adrenomedullin: +0.8±0.2 fmol/min per gram kidney weight;
P
<.01 versus control) and renal vasodilation (−28±6%;
P
<.05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%;
P
<.05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate–salt hypertension, probably due to endothelial damage.
Effect of Angiotensin II Blockade on the Fibroproliferative Response to Phenylephrine in the Rat Heart
Authors: Farivar R. Saeid , Crawford Dennis C. , Chobanian Aram V. , Brecher Peter
Published: June 2012

Abstract
In this study we infused phenylephrine into adult Wistar rats and used losartan to test for a possible role of angiotensin II in the phenylephrine-induced fibrosis. Phenylephrine, given by Alzet minipumps at a rate of 25 mg · kg
−1
· d
−1
, produced a rapid and striking fibrotic response that was obvious after 1 day and progressed throughout a 3-day infusion period. Northern and Western blot analyses showed large increases in cardiac fibronectin expression and atrial natriuretic peptide mRNA, corresponding to fibroblast proliferation and myocyte hypertrophy, respectively. Cardiac fibrosis, fibronectin mRNA, and atrial natriuretic peptide mRNA were blocked by prazosin (7 mg · kg
−1
· d
−1
). Administration of losartan (10 mg · kg
−1
· d
−1
) resulted in a threefold decrease in interstitial and perivascular fibroblast proliferation, as measured by proliferating cell nuclear antigen immunoreactivity (
P
<.05), a marked reduction of fibronectin mRNA in the heart, and a moderate reduction of cardiac atrial natriuretic peptide mRNA. The data suggest that effects mediated by α
1
-adrenergic and angiotensin type 1 receptors may promote cardiac fibrosis.
Differential Regulation of Angiotensin II Receptor Subtypes in Rat Kidney by Low Dietary Sodium
Authors: Du Yong , Yao Aqing , Guo Dengfu , Inagami Tadashi , Wang Donna H.
Published: June 2012

Abstract
This study was designed to determine whether expression of renal messenger RNA (mRNA) encoding the two known angiotensin II type 1 (AT
1
) receptor subtypes (AT
1A
and AT
1B
) can be regulated by dietary sodium. Seven-week-old male Wistar rats were fed a low-sodium diet (0.07%, n=9) or a normal-sodium diet (0.5%, n=9 [control]) for 14 days. A rat AT
1
complementary DNA (cDNA) probe, which hybridizes to mRNA encoding both the AT
1A
and AT
1B
receptor subtypes, and cDNA probes, which are selective for AT
1A
or AT
1B
mRNA, were used in Northern blot or in situ hybridization analysis. By use of Northern blot analysis, renal mRNA levels for the AT
1
and AT
1A
receptors in rats fed a low-sodium diet were found to be increased twofold (
P
<.05) compared with control. Because renal AT
1B
mRNA content was not detected by Northern blot analysis, quantitative image analysis of in situ hybridization with a digoxigenin-labeled cRNA probe made from AT
1B
cDNA was used. In situ hybridization analysis indicated that AT
1B
mRNA was expressed in the proximal and collecting tubules of the kidney in rats fed a normal-sodium diet. The low-sodium diet significantly decreased the percent positive staining area of AT
1B
mRNA in the renal cortex (5.51±0.77% versus 2.73±0.35%,
P
<.05) and medulla (4.76±0.70% versus 2.01±0.43%,
P
<.05) compared with the control diet. These results indicate that the increase in AT
1
mRNA levels in the kidney induced by low sodium intake is the result of a selective increase in AT
1A
mRNA and suggest that AT
1A
is the predominant receptor subtype of AT
1
in the kidney. The data also suggest that dietary sodium differentially modulates the expression of genes encoding AT
1
receptor subtypes, because there is an inverse relationship between the expression of the AT
1A
and AT
1B
subtypes in response to a low-sodium diet. The functional implications are discussed.
Endothelin Antagonists Improve Renal Function in Spontaneously Hypertensive Rats
Authors: Kato Tatsuya , Kassab Salah , Wilkins Fred C. , Kirchner Kent A. , Keiser Joan , Granger Joey P.
Published: June 2012

Abstract
Hypertension in the spontaneously hypertensive rat (SHR) is associated with reduced renal excretory function, low renal plasma flow, reduced glomerular filtration rate, and reduced renal interstitial hydrostatic pressure. The mechanisms responsible for these abnormalities in renal function are unknown. The purpose of this study was to determine the role of intrarenal endothelin in altering renal hemodynamic and excretory function in the SHR. Both PD 145065 (an endothelin A and B receptor antagonist) and FR 139317 (a selective endothelin A receptor antagonist) or saline was infused into the renal interstitium of 14- to 16-week-old SHR (n=7) and age-matched Wistar-Kyoto rats (WKY) (n=7). Renal perfusion pressure in some SHR was reduced to that of the WKY by a servocontrol system. At a renal perfusion pressure of 124±4 mm Hg, infusion of PD 145065 (0.03 mg · kg
−1
· min
−1
) and FR 139317 (0.02 mg · kg
−1
· min
−1
) significantly increased glomerular filtration rate (Δ22%), renal plasma flow (Δ37%), and renal interstitial hydrostatic pressure (from 3.2±0.5 to 5.4±0.6 mm Hg) in the SHR. These changes were associated with significant increases in urine flow, absolute sodium excretion, and fractional excretion of sodium. Similar improvements in renal plasma flow, renal interstitial hydrostatic pressure, and renal excretory function were obtained in the SHR whose renal perfusion pressure was not reduced (n=7). Renal interstitial infusion of endothelin receptor antagonists had no effect on renal hemodynamic or excretory function in the WKY. These data demonstrate that endothelin receptor blockade within the kidney improves renal hemodynamic and excretory function in the SHR. These results suggest that intrarenal endothelin may mediate, in part, the abnormal renal function in the SHR.
Effects of Bromocriptine on Cardiovascular Regulation in Healthy Humans
Authors: Schobel Hans P. , Schmieder Roland E. , Hartmann Silke , Schächinger Hartmut , Luft Friedrich C.
Published: June 2012

Abstract
Bromocriptine, a dopamine agonist with central nervous system actions, may reduce sympathetic nervous system activity. We tested this hypothesis by measuring arterial blood pressure, central venous pressure, heart rate, muscle sympathetic nerve activity, and forearm blood flow before and after unloading the arterial baroreceptors with sodium nitroprusside (0.5 to 1.5 mcg/kg per minute IV), before and after unloading the cardiopulmonary baroreceptors with incremental lower body negative pressure (0 to −15 mm Hg), and before and after immersion of the hand in ice-cold water for 2 minutes (cold pressor test). After obtaining basal responses to provocative maneuvers, we gave 20 healthy subjects either 5 mg oral bromocriptine (n=10) or placebo (n=10) in a randomized, double-blind fashion. Bromocriptine did not affect resting mean arterial pressure, heart rate, or forearm blood flow. Bromocriptine decreased resting central venous pressure by 1.2 mm Hg (
P
<.05) and tended to increase total integrated muscle sympathetic nerve activity (from 151±44 to 212±82 U/min,
P
=NS). The reflex increases in muscle sympathetic nerve activity to nitroprusside infusion and lower body negative pressure were unchanged by bromocriptine; however, vascular responsiveness to both maneuvers was impaired after bromocriptine administration compared with control. Without bromocriptine, the reflex increase in muscle sympathetic nerve activity after nitroprusside-induced hypotension maintained forearm blood flow at a constant level, whereas with bromocriptine the forearm blood flow increased from 1.9±0.3 to 2.8±0.6 mL/min per 100 mL (
P
<.05). Similarly, the forearm blood flow response to lower body negative pressure at −15 mm Hg was decreased with bromocriptine (+0.0±0.4 mL/min per 100 mL) compared with control values (−0.4±0.3 mL/min per 100 mL,
P
<.05). Responses to the cold pressor test were not altered by bromocriptine. We conclude that bromocriptine inhibits catecholamine release in peripheral nerves. However, we were unable to substantiate a central effect of bromocriptine on either sympathetic outflow or baroreflex sensitivity.
Inhibition of Endothelin Production by Adrenomedullin in Vascular Smooth Muscle Cells
Authors: Kohno Masakazu , Kano Hiroaki , Horio Takeshi , Yokokawa Koji , Yasunari Kenichi , Takeda Tadanao
Published: June 2012

Abstract
Adrenomedullin recently has been found to potently stimulate cAMP formation in cultured rat vascular smooth muscle cells (VSMCs). In the present study, we examined the effect of adrenomedullin on the production of a vasoconstrictive and growth-promoting peptide, endothelin-1, after stimulation with a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF), in cultured rat VSMCs. Thrombin and PDGF stimulated endothelin-1 production in a dose-dependent manner. Rat adrenomedullin significantly inhibited thrombin- and PDGF-stimulated endothelin-1 production in a dose-dependent manner between 10
−7
and 10
−9
mol/L. Inhibition by rat adrenomedullin of thrombin- and PDGF-stimulated endothelin-1 production was paralleled by an increase in the cellular level of cAMP. Human adrenomedullin also inhibited thrombin- and PDGF-stimulated endothelin-1 production and increased cAMP levels. The addition of 8-bromo-cAMP, a cAMP analogue, reduced thrombin- and PDGF-induced endothelin-1 production. Furthermore, forskolin, a potent activator of adenylate cyclase, reduced thrombin- and PDGF-induced endothelin-1 production. In contrast, basal production of endothelin-1 was not altered by rat or human adrenomedullin. These results indicate that adrenomedullin inhibits not basal but thrombin- and PDGF-induced ET-1 production in cultured VSMCs probably through a cAMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may modulate vascular tone as a paracrine regulator partially through the inhibition of VSMC endothelin-1 production in some pathophysiological states.
Hypertensive Retinopathy in Afro-Caribbeans and Europeans
Authors: Sharp P. S. , Chaturvedi N. , Wormald R. , McKeigue P. M. , Marmot M. G. , Young S. McHardy
Published: June 2012

Abstract
The prevalence of hypertension is particularly high in people of black African descent throughout the world, and the consequences of hypertension, such as hypertensive heart and renal disease and stroke, are also more common. But there is little consensus on whether hypertensive retinopathy follows a similar pattern. We determined the prevalence of hypertensive retinopathy and its relationships with resting and ambulatory blood pressure in a population study of Afro-Caribbeans and Europeans aged 40 to 64 years in London, UK. Retinal photographs of 651 participants were graded for hypertensive retinopathy. Age- and sex-standardized prevalence of retinopathy was 11% (95% confidence interval, 8% to 14%) in Europeans and 21% (95% confidence interval, 16% to 26%) in Afro-Caribbeans (
P
<.001), respectively. This ethnic difference in prevalence was greatest in normotensive women (8% in Europeans versus 20% in Afro-Caribbeans,
P
<.001). Resting systolic pressure was 8 mm Hg higher in normotensive Afro-Caribbean compared with European women, but this could not fully account for the ethnic difference in the prevalence of retinopathy. Examination of the different relationships of age and resting and ambulatory blood pressures with hypertensive retinopathy showed that these relationships were strongest in European women and weakest in Afro-Caribbean women. We conclude that hypertensive retinopathy is more common in Afro-Caribbeans, particularly women, and that ethnic differences in resting blood pressure cannot fully account for this. The relatively weak relationship between resting and ambulatory blood pressures and retinopathy in Afro-Caribbeans suggests that factors other than blood pressure determine the high rates of hypertensive retinopathy in this group.
Salt-Induced Increases in Systolic Blood Pressure Affect Renal Hemodynamics and Proteinuria
Authors: Weir Matthew R. , Dengel Donald R. , Behrens M. Theresa , Goldberg Andrew P.
Published: June 2012

Abstract
Nine white and 13 black hypertensive patients with normal serum creatinine were randomized to receive either 2 weeks of a low-salt (40 mEq Na
+
/d) or high-salt (200 mEq Na
+
/d) diet followed by 2 weeks of the other diet separated by a 1-week washout on their regular diet. The entire study was conducted in an outpatient setting with intensive dietary instruction and monitoring of blood pressure and 24-hour collections of urine for analysis. Urine electrolyte measurement showed that the patients were able to achieve only a modestly reduced (100±14 mEq Na
+
/24 h [mean±SEM]) low-salt diet as outpatients, while the higher-salt diet (236±22 mEq Na
+
/24 h) was more easily achieved. Eleven patients (8 black, 3 white) were classified as modestly salt sensitive on the basis of an increase or decrease in mean arterial pressure of ≥3 mm Hg going from lower- to high- or high- to lower-salt diets, respectively. In the salt-sensitive patients, the increase in dietary salt intake increased glomerular filtration rate by 29% (71.2±6.6 to 85.8±7.3 mL · min
−1
· 1.73 m
2
,
P
=.05), with no significant change in renal plasma flow (412.7±36.4 to 399.6±27.8 mL · min
−1
· 1.73 m
2
). There were no changes in these parameters in the salt-resistant patients. Increased dietary salt intake in the salt-sensitive patients was associated with a 15% increase in glomerular filtration fraction (0.18±0.02 to 0.22±0.01,
P
=.09), whereas in the salt-resistant group, glomerular filtration fraction did not change (0.16±0.01 to 0.17±0.02,
P
=.47). Greater dietary salt intake also resulted in an increase in 24-hour urine protein excretion in the salt-sensitive population (74.0±8.3 to 139.0±31.3 mg/24 h), while there was no significant change in the salt-resistant population (115.5±16.6 to 86.4±14.3 mg/24 h,
P
=.03 versus salt sensitive). The salt-induced increase in proteinuria was related to the increase in systolic blood pressure on the high-salt diet (
r
=.54,
P
=.04). These studies demonstrate that in the presence of modest salt sensitivity (mean arterial pressure increase ≥3 mm Hg), an increase in systolic blood pressure is predictive of potentially adverse renal hemodynamic responses to higher dietary salt in essential hypertensive patients. Consequently, modest salt restriction may reduce the risk for acute changes in renal hemodynamics in salt-sensitive patients, which may be important for long-term protection and prevention of deterioration of renal function.
Left Ventricular Fibrosis in Renovascular Hypertensive Rats
Authors: Nicoletti Antonino , Heudes Didier , Hinglais Nicole , Appay Marie-Dominique , Philippe Monique , Sassy-Prigent Caroline , Bariety Jean , Michel Jean-Baptiste
Published: June 2012

Abstract
Myocardial fibrosis resulting from arterial hypertension alters myocardial structure and function. Myocardial fibrosis is characterized by a pathological accumulation of types I and III collagens. We used an aldosterone antagonist (spironolactone) and an angiotensin II antagonist (losartan) to elucidate the respective role of these hormones and hypertension in the development of myocardial fibrosis in the Goldblatt model of two-kidney, one clip hypertension in the rat. Fibrosis was assessed by computer-assisted morphometry in the interstitial space, around coronary arteries, in microscar areas, and on left ventricular sections stained with Sirius red and by biochemical techniques. Morphometry was performed with both standard light and polarization microscopy; this latter method was used to quantify yellow-red and green collagen fibers. Concurrently, type I and type III collagen mRNAs were evaluated by a semiquantitative polymerase chain reaction method. The collagen content of the untreated two-kidney, one clip hypertensive rats increased mainly around the coronary arteries; the number and surface area of microscars also increased in chronic hypertension. Losartan treatment decreased systolic pressure and yellow-red collagen fiber content in all areas, whereas spironolactone treatment decreased green collagen fiber content without decreasing systolic pressure. mRNA levels for types I and III collagens showed profiles similar to those of yellow-red and green collagen fiber contents, respectively, suggesting that yellow-red collagen fibers are mainly type I collagen fibers and green collagen fibers are mainly type III collagen fibers. These results suggest that angiotensin II, possibly together with hypertension, and aldosterone, independently of hypertension, have a major influence on myocardial fibrosis, inducing type I and type III collagen deposits, respectively, mainly around coronary arteries.
Calcium Supplementation Attenuates an Enhanced Platelet Function in Salt-Loaded Mildly Hypertensive Patients
Authors: Saito Komei , Sano Hiroshi , Kawahara Jun , Yokoyama Mitsuhiro
Published: June 2012

Abstract
We designed this study to evaluate the effect of low versus high calcium intake on platelet function in salt-loaded patients with mild hypertension. After a 7-day period of dietary salt restriction, 19 patients were placed on a high salt (300 mmol/d), low calcium (6.25 mmol/d) diet for 7 days; 10 of these patients were given 54 mmol/d of supplementary calcium, and 9 patients were given placebo. At the end of the low and high salt regimens, we evaluated changes in blood pressure, platelet aggregation, and the platelet release reaction measured as plasma β-thromboglobulin and platelet factor 4 levels. With high salt intake, significant increases in mean blood pressure (
P
<.02), red blood cell sodium (
P
<.01), and platelet aggregation induced by 3 μmol/L ADP (
P
<.01) and by 3.0 mg/L epinephrine (
P
<.05) were observed in the placebo-treated patients but not in the calcium-supplemented ones. Compared with the placebo-treated patients, calcium-supplemented patients had a smaller weight gain (
P
<.05) but excreted more sodium and calcium (
P
<.01) at the end of the high salt regimen. Calcium supplementation resulted in decreases in β-thromboglobulin (
P
<.05), platelet factor 4 (
P
<.01), and plasma and urinary excretions of norepinephrine (
P
<.02) during the high salt, low calcium regimen. The decrease in plasma norepinephrine correlated positively with the decreases in β-thromboglobulin (
r
=.72,
P
<.02) and platelet factor 4 (
r
=.85,
P
<.01). These results indicate that calcium supplementation prevents salt-induced high blood pressure and platelet hyperaggregability, with a suppression of the platelet release reaction. The beneficial effects of oral calcium for reducing thrombotic cardiovascular risk during high salt intake may partly be attributed to an attenuation of intracellular sodium retention and a decrease in sympathetic nervous activity.
Glucose Metabolism in Abdominally Obese Hypertensive and Normotensive Subjects
Authors: O’Shaughnessy Irene M. , Myers Thomas J. , Stepniakowski Konrad , Nazzaro Pietro , Kelly Thomas M. , Hoffmann Raymond G. , Egan Brent M. , Kissebah Ahmed H.
Published: June 2012

Abstract
To determine whether the combination of obesity and hypertension results in additive defects in oxidative and nonoxidative glucose metabolism and the association of these changes with altered hemodynamic actions of insulin, we studied 11 abdominally obese hypertensive, 6 abdominally obese normotensive, and 7 lean normotensive nondiabetic subjects. Endogenous glucose production and glucose metabolized were calculated from a euglycemic clamp at 72 and 287 pmol insulin/m
2
per minute. Glucose metabolized divided by insulin was lower at 72 pmol/m
2
per minute in both obese groups than in lean normotensive subjects, at 148±14, 144±33, and 373±69 (μmol/m
2
per minute)/(pmol/L), respectively (
P
<.01). Similar results were obtained during the higher insulin dose. Nonoxidative and oxidative glucose disposals by indirect calorimetry were lower in both abdominally obese groups (
P
<.05). Hepatic glucose production was completely suppressed in lean subjects at the lower insulin dose and in all three groups at the higher insulin dose. Hemodynamic responses during the clamp were not significantly different among the three groups. Abdominal obesity is associated with defects in insulin-regulated oxidative and nonoxidative glucose disposal as well as in insulin suppression of hepatic glucose production. Mild hypertension does not exacerbate these defects. Whereas the global impairment in glucose metabolism suggests the presence of an early defect or defects, including reduced tissue perfusion, systemic and regional hemodynamic responses to insulin were not altered. These findings do not support a direct role for insulin resistance in the pathogenesis of the hypertension associated with abdominal obesity.
Transforming Growth Factor-β1 Expression and Phenotypic Modulation in the Kidney of Hypertensive Rats
Authors: Hamaguchi Akinori , Kim Shokei , Ohta Kensuke , Yagi Keiko , Yukimura Tokihito , Miura Katsuyuki , Fukuda Taneo , Iwao Hiroshi
Published: June 2012

Abstract
We have previously reported that renal mRNA levels for transforming growth factor-β1, fibronectin, and collagens were increased in 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) with severe nephrosclerosis. To elucidate the mechanism of hypertension-induced nephrosclerosis, we examined gene expression and localization of transforming growth factor-β1 and cellular phenotype in the kidney of 25-week-old SHRSP with moderate renal damage. Renal mRNA was measured by Northern blot analysis. The localization of transforming growth factor-β1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-β1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-β1 in SHRSP was mainly localized in glomerular cells. Furthermore, α-smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. α-Smooth muscle actin staining was also observed in interstitial cells, and vimentin, another phenotypic marker, was expressed in atrophic tubular cells of SHRSP, despite no staining of these proteins in WKY. Furthermore, all these phenotypic changes in SHRSP were associated with increased cell proliferation, as shown by the increased number of proliferating cell nuclear antigen–positive cells. Treatment of SHRSP with cilazapril and nifedipine (from the age of 13 to 25 weeks) prevented the increase in transforming growth factor-β1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation. These results indicated that sustained hypertension causes the increased glomerular transforming growth factor-β1 expression and cellular phenotypic modulation, which may play an important role in the progression of glomerulosclerosis and tubulointerstitial fibrosis in hypertension.
Effects of SC-56525, a Potent, Orally Active Renin Inhibitor, in Salt-Depleted and Renal Hypertensive Dogs
Authors: McMahon Ellen G. , Yang Po-Chang , Babler Maribeth A. , Bittner Stephen E. , Suleymanov Osman D. , Cain-Janicki Kimberly J. , Bedell Louis J. , Hanson Gunnar J. , Cook Chyung S.
Published: June 2012

Abstract
SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1±16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.
Renal Vasodilation With
l
-Arginine
Authors: Deng Xiaolin , Welch William J. , Wilcox Christopher S.
Published: June 2012

Abstract
Infusion of
l
-arginine, the substrate for nitric oxide synthase, causes renal vasodilation. Since dietary salt restriction blunts the renal vasoconstrictor response to inhibition of nitric oxide synthase, we investigated the hypothesis that dietary salt intake determines the renal vascular response to
l
-arginine. Bolus intravenous doses of
l
-arginine given to anesthetized Sprague-Dawley rats caused dose-dependent increases in renal blood flow and decreases in renal vascular resistance, whereas
d
-arginine was not effective. The response to
l
-arginine was prevented by pretreatment with
N
G
-nitro-
l
-arginine methyl ester. Compared with rats adapted to a high salt diet, those adapted to a low salt diet were more sensitive to the reductions in blood pressure and renal vascular resistance (threshold dose of
l
-arginine for renal vascular resistance: low salt, 2.9±0.9 μmol · kg
−1
versus high salt, 20.0±6.2;
P
<.025), but the maximal changes in renal vascular resistance were similar (low salt, −43±5% versus high salt, −34±5%;
P
=NS). Bolus doses of
l
-glycine also caused dose-dependent renal vasodilation, but the renal vasodilator responses were not affected by salt intake. Preinfusion of
l
-arginine augmented the renal vasoconstrictor response to
N
G
-nitro-
l
-arginine methyl ester in low salt but not high salt rats; after
l
-arginine dietary salt no longer significantly affected the renal vasoconstrictor response to
N
G
-nitro-
l
-arginine methyl ester. In conclusion, renal vasodilation is more sensitive to
l
-arginine during salt restriction. This effect is specific for
l
-arginine. A decreased availability of
l
-arginine during low salt intake may limit renal nitric oxide generation and thereby reduce the renal vasoconstrictor response to inhibition of nitric oxide synthase.