bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrial Natriuretic Peptide Blunts Arterial Baroreflex in Spontaneously Hypertensive Rats
Authors: Zhu Su-Tao , Chen Yu-Fai , Wyss J. Michael , Nakao Kazuwa , Imura Hiroo , Oparil Suzanne , Calhoun David A.
Published: June 2012

Abstract
We and other laboratories have reported that arterial baroreflex–mediated control of heart rate is blunted in spontaneously hypertensive rats (SHR) compared with normotensive controls. Recently, we reported that atrial natriuretic peptide (ANP) microinjected into the caudal nucleus tractus solitarii of SHR further blunts this defect. The present study tested the hypothesis that ANP modulates arterial baroreflex–mediated control of sympathetic nervous system activity. Nine-week-old, male SHR (n=29) and normotensive Wistar-Kyoto control rats (n=24) were instrumented for microinjection into the caudal nucleus tractus solitarii and for direct measurement of arterial blood pressure, heart rate, and lumbar sympathetic nervous system activity. After urethane- and α-chloralose–induced anesthesia, arterial baroreflex–mediated control of heart rate and lumbar sympathetic nerve activity was assessed during phenylephrine- (5 to 40 μg·kg
−1
·min
−1
) induced increases and sodium nitroprusside– (15 to 300 μg·kg
−1
·min
−1
) induced decreases in mean blood pressure before and after microinjection of ANP (50 ng) or monoclonal antibody to ANP (0.55 μg) into the caudal nucleus tractus solitarii. ANP reduced and the antibody enhanced the sensitivity of baroreflex-mediated control of both heart rate and lumbar sympathetic nerve activity in SHR but not in Wistar-Kyoto controls (
P
<.05). Arterial baroreflex sensitivity was unchanged with control microinjections of vehicle or mouse IgG in SHR. These data suggest that endogenous ANP in the caudal nucleus tractus solitarii may contribute to the development and/or maintenance of hypertension in SHR by blunting baroreflex-mediated control of sympathetic nervous system activity.
Preglomerular Sudanophilia in L-NAME Hypertensive Rats
Authors: Bouriquet Nathalie , Dupont Madeleine , Herizi Abderraouf , Mimran Albert , Casellas Daniel
Published: June 2012

Abstract
To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME) (20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21±2% and 42±3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black–positive lipid droplets. At 25 days, vessel wall thickness increased by 72±6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26±2% and 36±3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME–treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for α-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.
Importance of Tyrosine Phosphorylation in Angiotensin II Type 1 Receptor Signaling
Authors: Schieffer Bernhard , Paxton William G. , Marrero Mario B. , Bernstein Kenneth E.
Published: June 2012

Abstract
Angiotensin II is the major effector peptide of the renin-angiotensin system. In addition to its vasoconstrictor activity, angiotensin II stimulates smooth muscle cell growth in arterial hypertension and in models of vascular injury. The angiotensin II type 1 receptor is a seven-transmembrane receptor and is responsible for virtually all the physiological actions of angiotensin II. This class of receptor signals in part through its association with heterotrimeric G proteins. A newly developed concept for guanine nucleotide protein–coupled receptors is the activation of intracellular second-messenger proteins via tyrosine phosphorylation. For instance, angiotensin II stimulates the rapid tyrosine phosphorylation and activation of phospholipase C-γ1. Also, angiotensin II stimulates the tyrosine phosphorylation of Janus kinases. In this review, we discuss early signaling events induced by angiotensin II with an emphasis on tyrosine phosphorylation. Understanding the importance of tyrosine phosphorylation in the signaling pathways of the angiotensin II type 1 receptor may lead to new treatment modalities for cardiovascular disease.
Human Renin-Dependent Hypertension in Rats Transgenic for Human Angiotensinogen
Authors: Bohlender Jürgen , Ménard Joël , Wagner Jürgen , Luft Friedrich C. , Ganten Detlev
Published: June 2012

Abstract
To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed assays to measure both the human and rat renin-angiotensin systems in these rats. We used human and mouse renin, transgenic human angiotensinogen, and the human renin inhibitor Ro 42-5892 to determine human- and rat-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human plasma mixed in known amounts and with plasma from rats transgenic for human renin. We then tested the human angiotensinogen–transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osmotic minipumps. High human angiotensinogen transgene expression was found in the liver, brain, kidney, gastrointestinal tract, and aorta, whereas rat angiotensinogen gene expression was detected in the liver and brain. During human renin infusion, blood pressure increased to >200/150 mm Hg. Before infusion, human angiotensinogen was 100-fold greater than rat angiotensinogen (141±73 versus 1.2±0.16 μg angiotensin I/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increased to very high levels (449±262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable levels. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. However, even at these levels, human angiotensinogen was not rate limiting and angiotensin II was not a significant stimulus for angiotensinogen production. We conclude that these transgenic rats represent a novel model of human renin-dependent hypertension.
SA
Gene Expression in the Proximal Tubule of Normotensive and Hypertensive Rats
Authors: Yang Tianxin , Hassan Sohail A. , Singh Inderjit , Smart Ann , Brosius Frank C. , Holzman Lawrence B. , Schnermann Jurgen B. , Briggs Josie P.
Published: June 2012

Abstract
Previous studies have shown that the
SA
gene is expressed at higher levels in the kidney of genetically hypertensive rats than in control strains and that in hybrid crosses of genetically hypertensive rats and normotensive controls, markers in or close to the
SA
gene cosegregate with blood pressure. The present studies examine the localization of the
SA
gene product in the kidney by semiquantitative reverse transcription–polymerase chain reaction (RT-PCR). cDNA was prepared from microdissected nephron segments from Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHRs), and Wistar-Kyoto (WKY) rats, and RT-PCR was performed using specific primers. In all three strains,
SA
gene mRNA was found to be abundantly expressed in proximal tubules.
SA
PCR product was occasionally detected at approximately 100-fold lower abundance in glomeruli, while no signal was obtained from the collecting duct, thick ascending limb of the loop of Henle, or arcuate artery. Within the proximal tubule of normotensive rats, distribution of
SA
mRNA was found to be strain dependent: in SD rats it was expressed at high levels in the proximal convoluted tubule, whereas in WKY rats it was restricted to the proximal straight tubule. In SHRs,
SA
PCR product was detected along the entire proximal tubule. Induction of hypertension by renal artery clamping (two-kidney, one-clamp Goldblatt model) did not alter the pattern of expression observed in the SD rat. These results indicate that an extension of
SA
gene expression to the full length of the proximal tubule accompanies spontaneous hypertension and that in nonhypertensive animals the pattern of gene product expression is more restricted but shows substantial strain variability.
Salt-Sensitive Hypertension in (
m
REN-2)27 Transgenic Rats
Authors: Callahan Michael F. , Li Ping , Ferrario Carlos M. , Ganten Detlev , Morris Mariana
Published: June 2012

Abstract
The (
m
REN-2)27 transgenic model of hypertension was developed to investigate the effect of genetic over activity of angiotensin II systems as a contributing factor in the development of arterial hypertension. In this model, transgene-positive rats demonstrate elevated renin-angiotensin system activity not only in the circulatory system but also in adrenal gland, reproductive organs, and brain. Since evidence indicates that angiotensin peptides and osmotic stimuli interact synergistically to produce exaggerated behavioral, endocrine, and cardiovascular effects, we examined the effect of salt consumption on arterial pressure, plasma vasopressin, and body fluid balance in male (
m
REN-2)27 transgene-positive and -negative rats. Four days of drinking 2% NaCl increased mean arterial pressure from 165±10 to 199±7 mm Hg in transgene-positive rats. In contrast, transgene-negative rats showed no change in arterial pressure (126±5 to 128±3 mm Hg). Plasma vasopressin levels were significantly elevated only in transgene-positive rats, whereas pituitary levels of vasopressin were significantly lower in transgene-positive rats compared with transgene-negative controls (18±3 and 118±14 ng, respectively). Although transgene-positive rats consumed significantly more 2% NaCl than did transgene-negative rats, during this period 24-hour sodium balance did not differ between the groups. Since fluid and electrolyte balance is similar between the two groups of rats, the data suggest that transgene-positive rats may be more sensitive to the effects of increased NaCl intake in terms of both endocrine and cardiovascular responses.
Renal Sympathetic Neural Mechanisms as Intermediate Phenotype in Spontaneously Hypertensive Rats
Authors: DiBona Gerald F. , Jones Susan Y. , Sawin Linda L.
Published: June 2012

Abstract
The borderline hypertensive rat, the F
1
of a cross between a hypertensive spontaneously hypertensive rat (SHR) and a normotensive Wistar-Kyoto (WKY) rat, is a NaCl-sensitive model of genetic hypertension. In addition to hypertension, borderline hypertensive rats fed 8% NaCl develop characteristic alterations in the regulation of efferent renal sympathetic nerve activity and the neural control of renal function that are similar to those observed in the SHR parent. Like the normotensive WKY rat parent, borderline hypertensive rats fed 1% NaCl remain normotensive and do not exhibit these alterations in renal sympathetic neural mechanisms. These renal sympathetic neural mechanisms constitute a complex quantitative trait that may represent an intermediate phenotype. They have a plausible pathogenetic role in hypertension and are different between SHR and WKY rats. This study evaluated two aspects of this complex quantitative trait, enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz, as a candidate intermediate phenotype. As neither of these aspects was observed in two-kidney, one clip Goldblatt-hypertensive rats, this suggests that the trait is not secondary to hypertension from an acquired cause. In a backcross population (F
1
×WKY) fed 8% NaCl for 12 weeks, both enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz cosegregated with the hypertension. These results support renal sympathetic neural mechanisms as an intermediate phenotype in SHR.
Acute Na
+
,K
+
-ATPase Inhibition With Bufalin Impairs Pressure Natriuresis in the Rat
Authors: Patel Ami R. , Kurashina Toshiaki , Granger Joey P. , Kirchner Kent A.
Published: June 2012

Abstract
Although it has been reported that Na
+
,K
+
-ATPase inhibition with bufalin induces acute and chronic hypertension in the rat, the mechanisms mediating this response are unclear. To examine the role of the kidney in this process, glomerular filtration rate, renal blood flow, and pressure natriuresis were determined in rats treated with bufalin or vehicle during changes in renal perfusion pressure. Mean arterial pressure increased from 123±4 to 149±3 mm Hg (
P
<.05) after 40 minutes of intravenous bufalin and remained at this level. In control rats, glomerular filtration rate was well autoregulated. In bufalin-treated rats, glomerular filtration rate fell with decreasing renal perfusion pressure. Glomerular filtration rate autoregulatory index was greater in bufalin-treated than control rats (
P
<.05). Renal blood flow showed a similar pattern. Urine flow and sodium excretion were less in bufalin-treated than control rats at equivalent renal perfusion pressures. The slope of the line describing the relation between urine flow and renal perfusion pressure was greater (
P
<.05) in control than bufalin-treated rats. Similarly, the slope of the line relating sodium excretion to renal perfusion pressure was greater (
P
<.05) in control than bufalin-treated rats. Thus, acute increases in blood pressure during Na
+
,K
+
-ATPase inhibition are associated with impaired renal autoregulation and pressure natriuresis. This effect may be important in chronic hypertension associated with Na
+
,K
+
-ATPase inhibition in the rat.
Sexual Dimorphism of Cardiovascular Responses to Early Blockade of Bradykinin Receptors
Authors: Madeddu Paolo , Parpaglia Paolo Pinna , Anania Vittorio , Glorioso Nicola , Chao Caroline , Wang Cindy , Chao Julie
Published: June 2012

Abstract
To assess whether the cardiovascular effects induced by early blockade of bradykinin B
2
-receptors with Hoe 140 (
d
-Arg[Hyp
3
,Thi
5
,
d
-Tic
7
,Oic
8
]-bradykinin) are influenced by sex, Wistar rats of both sexes received the antagonist (300 nmol/d per kilogram body wt) or vehicle from 2 days to 7 weeks of age by subcutaneous injection and then by intraperitoneal infusion. Compared with control rats, Hoe 140–treated female rats showed higher systolic blood pressure levels at 7 and 9 weeks of age (125±2 versus 111±2 mm Hg and 132±3 versus 116±2 mm Hg, respectively,
P
<.05), whereas in male rats a difference was found at 7 weeks (122±4 versus 108±4 mm Hg,
P
<.05) but not at 9 weeks. At this stage, the mean blood pressure of Hoe 140–treated rats was higher than that of control animals, and this difference was more pronounced at 12 weeks in female rats (121±2 versus 100±3 mm Hg in control animals,
P
<.01) compared with males (116±3 versus 104±2 mm Hg in control rats,
P
<.05). After the first week of life, body weight gain was greater in Hoe 140–treated female rats than in control rats, whereas a group-difference was detected in male rats only after weaning. In Hoe 140–treated female rats, heart weight was already increased at 9 weeks (330±6 versus 305±5 mg/100 g body wt in control rats,
P
<.05), whereas it was necessary to prolong Hoe 140 administration in male rats to develop heart hypertrophy (300±4 versus 275±4 mg/100 g body wt in control rats at 12 weeks,
P
<.05). Tissue kallikrein mRNA levels were higher in the kidney of adult female rats, whereas no sex difference was detected in the heart. The finding of a sexual dimorphism in the cardiovascular response to early blockade of bradykinin receptor suggests that endogenous kinins play a role in the regulation of cardiovascular function in both sexes, but they may be functionally more important in the female rat.
Opposing Actions of Angiotensin II on Microvascular Growth and Arterial Blood Pressure
Authors: Munzenmaier Diane H. , Greene Andrew S.
Published: June 2012

Abstract
We performed studies to further elucidate the mechanisms of angiotensin II (Ang II)–induced angiogenesis of the microvasculature. Rats were placed on a high salt diet (4% NaCl), and Ang II was infused at a subpressor rate (5 ng/kg per minute) for 3 days. Blood pressure was measured daily for 2 control and 3 infusion days. Microvessel density in the cremaster muscle was measured at the end of the infusion. Vessel density in rats that received subpressor Ang II infusion increased by 12.6% compared with rats that received vehicle infusion. When the angiotensin type 2 (AT
2
) receptor antagonist PD 123319 was coinfused with Ang II, blood pressure was elevated and vessel density increased above that observed with Ang II infusion alone (23% increase). When the AT
1
receptor antagonist losartan was coinfused with Ang II, blood pressure was lower than control and vessel density was reduced compared with the Ang II group but was still greater than control (7.8% increase). In this study, Ang II stimulated angiogenesis in the rat cremaster muscle; this effect was enhanced by AT
2
antagonism and inhibited by AT
1
antagonism. Ang II infusion at a subpressor dose resulted in a pressor response with AT
2
antagonism and a depressor response with AT
1
antagonism. This suggests that in the microvasculature, the AT
1
receptor mediates angiogenesis and vasoconstriction, and the AT
2
receptor mediates an inhibition of angiogenesis and vasodilation.
Effects of Endothelin Receptor Inhibition on Cerebral Arterioles in Hypertensive Rats
Authors: Chillon Jean-Marc , Heistad Donald D. , Baumbach Gary L.
Published: June 2012

Abstract
The purpose of this study was to examine the effects of endothelin receptor inhibition on cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP). Structure and mechanics of cerebral arterioles were examined in untreated Wistar-Kyoto rats (WKY) and SHRSP that were either untreated or treated for 3 months with bosentan, an inhibitor of endothelin receptors (100 mg/kg per day). We measured pressure, external diameter, and cross-sectional area of the vessel wall (histologically) in maximally dilated (EDTA) arterioles on the cerebrum. Bosentan reduced but did not normalize arteriolar mean pressure (103±3 and 81±5 mm Hg in untreated and treated SHRSP versus 51±4 mm Hg in WKY,
P
<.05; mean±SEM) and pulse pressure (40±2 and 33±2 mm Hg in untreated and treated SHRSP versus 25±3 mm Hg in WKY,
P
<.05) in SHRSP. Cross-sectional area of the vessel wall (CSA) was increased in untreated SHRSP (1627±173 μm
2
), and CSA in treated SHRSP (1287±78 μm
2
) was similar to that in WKY (1299±65 μm
2
). Bosentan had no effect on reductions in external diameter (remodeling) of cerebral arterioles (104±7 and 96±4 μm in untreated and treated SHRSP compared with 126±7 μm in WKY,
P
<.05). Stress-strain curves indicate that bosentan had no significant effect on distensibility of arterioles on the cerebrum in SHRSP. The results suggest that endothelin-1 may contribute to the development of hypertrophy, but not remodeling or changes in distensibility, of cerebral arterioles in SHRSP.
Vascular Endothelial Growth Factor Suppresses C-Type Natriuretic Peptide Secretion
Authors: Doi Kentaro , Itoh Hiroshi , Komatsu Yasato , Igaki Toshio , Chun Tae-Hwa , Takaya Kazuhiko , Yamashita Jun , Inoue Mayumi , Yoshimasa Takaaki , Nakao Kazuwa
Published: June 2012

Abstract
Angiogenesis plays a pivotal role not only in wound healing and tumor progression but also in diabetic angiopathy, arteriosclerosis, and collateral formation of obstructive vascular diseases. Vascular endothelial growth factor (VEGF) is now thought to be an endothelium-specific and potent angiogenic factor. We previously demonstrated that C-type natriuretic peptide (CNP), originally isolated from porcine brain, is produced by endothelial cells and proposed that CNP can exert control over vascular tone and growth as a local vascular regulator. In the present study, we examined the effect of VEGF on CNP secretion from endothelial cells using the specific radioimmunoassay for CNP we developed. VEGF (1 to 100 ng/mL) dose-dependently suppressed CNP secretion from cultured bovine endothelial cells, and 100 ng/mL VEGF suppressed endothelial CNP secretion to 28% of control levels (31.7±5.5 versus 8.9±0.8 fmol/mL, vehicle versus VEGF). VEGF also suppressed CNP mRNA expression in endothelial cells 9 hours after administration. In contrast, basic fibroblast growth factor (20 ng/mL), an endothelium-nonspecific angiogenic factor, significantly stimulated CNP secretion by 290%. These results indicate that VEGF can regulate vascular tone and growth in the process of angiogenesis through suppression of endothelial secretion of CNP, which is an endothelium-derived vasorelaxing and growth-inhibitory peptide.
Nitric Oxide Induces Upregulation of Fas and Apoptosis in Vascular Smooth Muscle
Authors: Fukuo Keisuke , Hata Shigeki , Suhara Toshimitsu , Nakahashi Takeshi , Shinto Yoshitaka , Tsujimoto Yoshihide , Morimoto Shigeto , Ogihara Toshio
Published: June 2012

Abstract
Interleukin-1 induced a time-dependent release of high levels of nitric oxide from rat vascular smooth muscle cells up to 96 hours. A time-dependent release of lactate dehydrogenase was also induced by Interleukin-1 from 72 to 96 hours after its stimulation. In situ nick end-labeling assay revealed that incubation for 48 hours with interleukin-1 induced a positive staining of fragmented nuclei. However,
N
G
-monomethyl-
l-
arginine, an inhibitor of nitric oxide synthase, inhibited both lactate dehydrogenase release and DNA fragmentation induced by interleukin-1. Furthermore, sodium nitroprusside, a nitric oxide donor, also induced lactate dehydrogenase release and DNA fragmentation. Fluorescent staining of DNA revealed patches of irregularly dispersed, brightly staining, and condensed chromatin in rat vascular smooth muscle cells treated with sodium nitroprusside. Flow cytometric analysis with monoclonal antibody against human Fas revealed that expression of Fas was upregulated by sodium nitroprusside in human vascular smooth muscle cells. Methylene blue, an inhibitor of soluble guanylate cyclase, did not affect sodium nitroprusside–induced upregulation of Fas. Furthermore, 8-bromo-guanosine 3′:5′-cyclic monophosphate, an analogue of cGMP, did not upregulate Fas expression. These findings indicate that nitric oxide released from vascular smooth muscle cells may induce apoptosis in vascular smooth muscle cells themselves and also induces upregulation of Fas via a cGMP-independent mechanism. Thus, nitric oxide could trigger the remodeling of atherosclerotic plaques.
Evidence for Cell-Specific Regulation of Transcription of the Rat α
2A
-Adrenergic Receptor Gene
Authors: Handy Diane E. , Gavras Haralambos
Published: June 2012

Abstract
We investigated the transcriptional activity of the −131 to −92 region of the rat α
2A
-adrenergic receptor gene. In HT29 cells, this region has a positive effect on transcription, whereas in RINm5F cells, this region has a negative effect on transcription. The −131 to −92 region has a GC box (GGGGCGG) surrounded by overlapping GGAGG repeats. To analyze nuclear factor binding to this region, we made a series of sequence substitutions in the GGAGG repeats, the GC box, or both regions. Gel mobility shift assays indicated that most of the nuclear factor complexes formed between the wild-type −131/−92 sequence and either HT29 or RINm5F extracts were specific for Sp1 or related proteins that recognize a GC box. Mutation of either the GGAGG repeats or the GC box did not eliminate the binding of Sp1 or related nuclear factors, suggesting that both the GGAGG repeats and the GC box could bind Sp1-related factors. Mutation of both these sites eliminated the binding of Sp1-related factors. In the absence of Sp1 binding sites, this region had a negative effect on transcription in HT29 and a positive effect on transcription in RINm5F cells. These data support the notion that Sp1 and/or a related factor may control both positive and negative gene expression and suggest that the −131/−92 region may be involved in regulating tissue-specific levels of α
2A
-adrenergic receptor gene expression.
Angiotensin Mediates Forearm Glucose Uptake by Hemodynamic Rather Than Direct Effects
Authors: Jamerson Kenneth A. , Nesbitt Shawna D. , Amerena John V. , Grant Eric , Julius Stevo
Published: June 2012

Abstract
Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (
P
<.05) and 59% increase in the arteriovenous glucose gradients (
P
<.05) to maintain a steady glucose utilization (a decrease of 4%,
P
=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.
Regulation of Angiotensin II Receptor Subtypes by Dexamethasone in Rat Mesangial Cells
Authors: Chansel Dominique , Llorens-Cortes Catherine , Vandermeersch Sophie , Pham Paul , Ardaillou Raymond
Published: June 2012

Abstract
The objective of this study was to examine the role of dexamethasone on the expression of angiotensin II (Ang II) receptors in cultured rat mesangial cells. Dexamethasone caused concentration- and time-dependent decreases in
125
I–[Sar
1
,Ala
8
]Ang II binding that were prevented by glucocorticoid receptor inhibition with mifepristone. A lag time of 24 hours and a dexamethasone concentration of at least 10 nmol/L were necessary for this effect to occur. Dexamethasone-induced reduction of
125
I–[Sar
1
,Ala
8
]Ang II binding resulted from decreased Ang II type 1 (AT
1
) receptor density. No change in the apparent dissociation constant was observed. Dexamethasone also markedly inhibited Ang II–dependent inositol phosphate accumulation. Both reverse transcription–polymerase chain reaction and Northern blot analysis using specific short probes from the 3′ noncoding region of the cDNA demonstrated the presence of AT
1A
and AT
1B
receptor mRNAs in rat mesangial cells, with a slight predominance of AT
1B
. Therefore, we studied the effect of dexamethasone on the expression of these two subtypes in rat mesangial cells. Dexamethasone produced a time-dependent decrease of AT
1B
receptor mRNA that was apparent after 6 hours of incubation, whereas AT
1A
receptor mRNA did not change. Mifepristone also suppressed the dexamethasone-induced decrease in AT
1B
receptor mRNA. In conclusion, glucocorticoids diminish Ang II receptor density at the mesangial cell surface through a mechanism that implies successive interaction with the glucocorticoid receptor and specific reduction in AT
1B
receptor mRNA expression. This differential regulation of both AT
1
receptor subtypes might allow glucocorticoids to exert adjusted effects in their various target tissues.
Evidence for a Physiological Role of Angiotensin-(1-7) in the Control of Hydroelectrolyte Balance
Authors: Santos Robson A.S. , Simões e Silva Ana C. , Magaldi Antônio J. , Khosla Mahesh C. , Cesar Katia R. , Passaglio Katia T. , Baracho Nilo C.V.
Published: June 2012

Abstract
In this study we evaluated the possibility that angiotensin-(1-7) [Ang-(1-7)] acts as an endogenous osmoregulatory peptide by determining the effect of acute administration of its selective antagonist [
d
-Ala
7
]Ang-(1-7) (A-779) on renal function parameters in rats. In addition, we investigated the physiological mechanisms involved in the antidiuretic effect of Ang-(1-7). The antidiuretic effect of Ang-(1-7) (40 pmol/0.05 mL per 100 g BW) in water-loaded rats was completely blocked by A-779 (vehicle-treated, 3.34±0.43 mL/h; Ang-(1-7), 1.48±0.23; A-779, 2.72±0.35; Ang-(1-7) plus A-779, 3.26±0.49). In contrast, the antidiuretic effect of Ang-(1-7) was not significantly changed by a vasopressin V
2
receptor antagonist in a dose that completely blocked the antidiuresis produced by an equipotent dose of vasopressin. In addition, Ang-(1-7) administration did not significantly change vasopressin plasma levels in water-loaded rats. The antidiuretic effect of Ang-(1-7) in water-loaded rats was associated with a reduction of creatinine clearance (0.68±0.04 versus 1.38±0.32 mL/min in vehicle-treated rats,
P
<.05) and an increase in urine osmolality (266.8±32.7 versus 182.8±14 mOsm/kg in vehicle-treated rats,
P
<.05). An effect of Ang-(1-7) in tubular water transport was demonstrated in vitro by a fourfold increase in the hydraulic conductivity of inner medullary collecting ducts in the presence of 1 nmol/L Ang-(1-7). Subcutaneous administration of A-779 (2.3 to 9.2 nmol/100 g) produced a significant increase in urine volume (4.6 nmol/100 g, 0.45±0.12 mL/h; vehicle-treated rats, 0.16±0.03 mL/h;
P
<.05) comparable to that of acute administration of a vasopressin V
2
receptor antagonist. The diuretic effect of A-779 was associated with an increase in creatinine clearance and decrease in urine osmolality. In contrast, no significant effects on urine volume were observed after systemic administration of angiotensin subtype 1 or 2 receptor antagonists (DuP 753 and CGP 42112A, respectively). These findings suggest that endogenous Ang-(1-7), acting on specific receptors, participates in the control of hydroelectrolyte balance by influencing especially water excretion.
l
-Arginine Restores Dilator Responses of the Basilar Artery to Acetylcholine During Chronic Hypertension
Authors: Kitazono Takanari , Faraci Frank M. , Heistad Donald D.
Published: June 2012

Abstract
The objective of this study was to test the hypothesis that administration of
l
-arginine, a substrate for nitric oxide synthase, restores acetylcholine-induced dilatation of the basilar artery in chronically hypertensive rats. Basilar artery diameter was measured through a cranial window in anesthetized stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) aged 6 to 7 months (adult) and 12 months (older adult). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (adult, 239±30 μm; older adult, 198±13 μm) (mean±SE) than in WKY (adult, 261±10 μm; older adult, 259±7 μm) (
P
<.05 versus SHRSP). Topical application of acetylcholine (10
−5
mol/L) produced dilatation of the basilar artery in WKY, which was impaired in both adult and older SHRSP (
P
<.05). Topical
l
-arginine (10
−3
mol/L for 30 minutes) did not affect responses to acetylcholine in adult SHRSP but enhanced vasodilatation in response to acetylcholine (10
−5
mol/L) in older SHRSP without affecting responses to sodium nitroprusside. In contrast,
d
-arginine did not affect acetylcholine-induced vasodilatation in older SHRSP. These results suggest that impaired dilatation of the basilar artery in response to acetylcholine in older SHRSP is restored toward normal by
l
-arginine, a substrate for nitric oxide synthase.
Preweanling Administration of Terazosin Decreases Blood Pressure of Hypertensive Rats in Adulthood
Authors: McCarty Richard , Lee Jana H.
Published: June 2012

Abstract
To examine the contribution of the sympathetic nervous system to the development of hypertension, we injected spontaneously hypertensive rat (SHR) pups and normotensive Wistar-Kyoto rat (WKY) pups twice daily with saline (1.0 mL/kg SC) or terazosin (0.5 mg/kg SC), an α
1
-adrenoceptor antagonist, from postnatal day 1 through 21. We determined the effectiveness and duration of action of this terazosin dose in pilot studies with adult SHR and WKY. Body weights of WKY pups were greater than body weights of SHR pups from postnatal day 1 through 21. In addition, body weights of terazosin-treated pups of both strains were comparable to body weights of saline-injected littermate controls. Indirectly measured systolic pressures of terazosin-treated SHR were reduced significantly at 60 and 90 days of age but not at 30 days of age compared with saline-injected littermate controls. Terazosin did not affect systolic pressures of WKY, measured at 30, 60, and 90 days of age. At 100 days of age, in chronically catheterized rats, mean arterial pressures of terazosin-treated SHR were reduced significantly compared with those of saline-injected littermate controls. In contrast, terazosin did not affect mean arterial pressures of WKY at 100 days of age. Finally, preweanling treatment with terazosin did not alter patterns of open field behavior of adult SHR or WKY. SHR were significantly more active and reared more frequently compared with WKY. These findings indicate that the time between birth and weaning at 21 days of age is critical for the full expression of the hypertensive phenotype in SHR. Chronic blockade of α
1
-adrenoceptors during the preweanling period in SHR may reduce vascular hypertrophy, leading to long-term reductions in arterial pressure.
Sodium-Lithium Countertransport and Blood Pressure Change Over Time
Authors: Cirillo Massimo , Laurenzi Martino , Panarelli Walter , Trevisan Maurizio , Dyer Alan R. , Stamler Rose , Stamler Jeremiah
Published: June 2012

Abstract
Sodium-lithium countertransport activity in red blood cells relates to blood pressure (BP) and the prevalence of hypertension. This study investigated in adults the relation of sodium-lithium (Na-Li) countertransport to BP change from baseline to 6-year follow-up. In the Gubbio Population Study, 4210 men and women were 18 to 74 years old at baseline (1983-1986), and 3766 had a valid baseline Na-Li countertransport measurement; of these, 2729 were reexamined at 6 years of follow-up (1989-1992) and made up the study cohort. At baseline, data collection included age, height, weight, BP, pulse rate, drug treatment, alcohol intake, ratio of sodium to potassium in spot urine, plasma cholesterol, and Na-Li countertransport in red blood cells. At 6-year follow-up, data for age, BP, and drug treatment were collected as at baseline. From baseline, average BP declined for people on antihypertensive medication at follow-up and for those with baseline BP greater than or equal to 140/90 mm Hg (systolic/diastolic) and did not change or increased for the remaining participants. In quartile and correlation analyses controlled for sex, baseline BP, and antihypertensive treatment, BP change related significantly and directly to baseline Na-Li countertransport. In multiple linear regression analyses done for the entire cohort with control for other confounders, the regression coefficient of baseline Na-Li countertransport to BP change over time was positive and borderline significant. The Na-Li countertransport coefficient was positive and significant when analyses were done with the use of a categorical value of baseline Na-Li countertransport (quartile 4 and quartiles 1 through 3 combined). In both models, the Na-Li countertransport coefficient was the strongest for people with baseline BP greater than or equal to 120/80 mm Hg or for people with baseline age of 45 years or older. In conclusion, Na-Li countertransport significantly relates to BP change over time in adults.
Comparison of Nifedipine Alone and With Diltiazem or Verapamil in Hypertension
Authors: Saseen Joseph J. , Carter Barry L. , Brown Thomas E.R. , Elliott William J. , Black Henry R.
Published: June 2012

Receptor binding studies suggest that combinations of calcium channel blockers may result in either enhanced or diminished pharmacological effects, but clinical data in hypertension are incomplete. In this study, we compared blood pressure reductions using nifedipine alone, nifedipine plus diltiazem, and nifedipine plus verapamil and determined whether combinations alter nifedipine pharmacokinetics. After determination of baseline blood pressures, 16 subjects with essential hypertension (12 men, 4 women; mean age, 48 years) received 30 mg/d open-label, sustained release nifedipine for 2 weeks. If still hypertensive (n=16), they were randomized (double-blind) to receive either additional sustained release diltiazem or sustained release verapamil, both 180 mg/d, for 2 weeks and were then crossed-over for the final 2 weeks of the study. All medications were once-daily, extended-release formulations. Blood pressures and nifedipine plasma concentrations were measured during the final day of each treatment. Overall, each combination lowered mean systolic and diastolic pressures more than nifedipine alone. Mean supine diastolic pressures were significantly lower at 8 hours (77.6 versus 84.6 mm Hg,
P
=.001) and 12 hours (81.5 versus 87.1 mm Hg,
P
=.04) with nifedipine plus diltiazem than nifedipine plus verapamil. Mean nifedipine concentrations were inversely correlated with mean blood pressures. Mean nifedipine area under the curve values were greater with diltiazem than verapamil (1430 versus 1134 ng·h/mL,
P
=.026), with each greater than nifedipine alone (957 ng·h/mL). Nifedipine plus diltiazem had a greater antihypertensive effect than nifedipine plus verapamil. Diltiazem caused greater increases in nifedipine plasma concentrations than did verapamil. These data suggest that combined calcium channel blockers result in additive antihypertensive effects, perhaps because of a pharmacokinetic interaction.
Residual Pressor Effects of Chronic Alcohol in Detoxified Alcoholics
Authors: York James L. , Hirsch Judith Ann
Published: June 2012

Although research in population studies has indicated that recent alcohol intake is positively correlated with blood pressure, there is a need to study the relationship of blood pressure to measures of lifetime alcohol intake in alcoholics. To this end, we assessed systolic and diastolic pressures and lifetime alcohol intake through structured interviews with 253 normotensive recovering alcoholics. Blood pressures were first corrected with multiple linear regression for the influence of confounding or modifying variables and then were regressed against alcohol consumption measures. Systolic pressure was significantly correlated (positively) with only a few measures of recent alcohol intake, and the correlations were not high (
r
2
=.05 to .11,
P
<.05). Diastolic pressure was found to be highly and positively correlated with the duration of the drinking career, but more so in blacks than in whites. The total lifetime dose of alcohol was found to be positively correlated with diastolic but not systolic pressure, but only in black male alcoholics. The steeper slope of the regression of blood pressure versus lifetime total alcohol or duration of the drinking career in black alcoholics suggests greater cardiovascular susceptibility to alcohol toxicity as lifetime doses increase and as the drinking career lengthens.
Prognostic Value of Invasive Hemodynamic Measurements at Rest and During Exercise in Hypertensive Men
Authors: Fagard Robert H. , Pardaens Karel , Staessen Jan A. , Thijs Lutgarde
Published: June 2012

In 1994, we ascertained the outcome of 143 hypertensive men in whom invasive hemodynamic measurements were performed at rest and during graded bicycle exercise during the period 1972-1982 to assess (1) which of the hemodynamic components of blood pressure is associated with the incidence of cardiovascular events and total mortality, and (2) whether the hemodynamic response to dynamic exercise adds prognostic precision to the data at rest. During 2186 patient years of follow-up, 38 patients suffered at least one fatal or nonfatal cardiovascular event and 17 patients died. Cox regression analysis showed that systolic pressure and systemic vascular resistance measured at rest, during submaximal exercise (50 W), and at peak effort were significant (
P
<.01) predictors of the age-adjusted incidence of cardiovascular events and total mortality. However, exercise blood pressure did not significantly predict the incidence of cardiovascular events over and above pressure at rest; by contrast, exercise systemic vascular resistance added prognostic precision to vascular resistance at rest (
P
<.01). As for total mortality, systolic pressure and systemic vascular resistance at peak exercise carried prognostic information that was independent of the results at rest (
P
<.05); this was not the case for measurements during submaximal exercise. We conclude that the prognostic importance of blood pressure is related to systemic vascular resistance. The prognostic precision of exercise pressure, on top of pressure at rest, is limited. Exercise systemic vascular resistance, however, provides prognostic information beyond that available from measurements at rest, particularly for the incidence of cardiovascular events.
Effect of Long-term Treatment With Propionyl-
l
-Carnitine on Smooth Muscle Cell Polyploidy in Spontaneously Hypertensive Rats
Authors: Mauriello Alessandro , Sangiorgi Giuseppe , Orlandi Augusto , Schiaroli Stefania , Perfumo Sabina , Spagnoli Luigi Giusto
Published: June 2012

Experimental studies suggest that DNA content is increased in the smooth muscle cells of the arteries of hypertensive animals. It is unclear whether an increase in DNA content occurring in the smooth muscle cells of hypertensive rats represents a pressure-dependent effect. To evaluate the antihypertensive effect of long-term treatment with propionyl-
l
-carnitine and the possible morphological changes in thoracic smooth muscle cells correlated with this effect, we studied 4-month-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) randomly divided into five groups. One group of SHR was treated with propionyl-
l
-carnitine for 12 months; the other four groups of SHR and WKY received no treatment and were controls. We used static and flow cytometry to evaluate the polyploid cell content in thoracic aorta smooth muscle cells. Systolic pressure in untreated SHR progressively increased during the experiment. Treatment did not significantly influence pressure values in SHR. In WKY, blood pressure was significantly lower than that in treated and untreated age-matched SHR (2
P
<.02). The number of polyploid smooth muscle cells was significantly lower in the propionyl-
l
-carnitine–treated SHR than in the untreated rats (2
P
<.04) and similar to values for WKY. The reduction of polyploid cells in treated SHR was paralleled by a significant decrease of the aortic total DNA content, whereas no modifications occurred in smooth muscle cell mass. Long-term treatment with propionyl-
l
-carnitine may interfere with cellular mechanisms regulating the secondary responses involved in DNA synthesis.
Noninvasive Assessment of Baroreflex Control in Borderline Hypertension
Authors: Watkins Lana L. , Grossman Paul , Sherwood Andrew
Published: June 2012

In this study, we examined the sensitivity of two recently developed noninvasive baroreflex measurement techniques to assess baroreflex control in hypertension. We assessed baroreflex sensitivity noninvasively from covariations of systolic pressure and RR interval using spectral analysis and sequence detection. The noninvasive estimates of baroreflex control were compared with estimates derived from phenylephrine-induced increases in systolic pressure and RR interval in normotensive subjects (n=27) and borderline hypertensive subjects (n=15). Baroreflex sensitivity was significantly reduced in the borderline hypertensive group relative to the normotensive group when assessed with the use of either the noninvasive or invasive methods to index baroreflex control. In addition, estimates obtained from the noninvasive methods were significantly correlated with baroreflex sensitivity assessed with the phenylephrine method (spectral:
r
=.48,
P
<.001; sequence:
r
=.50,
P
<.001). These findings suggest that spectral analysis and the sequence method provide viable alternatives to the pharmacological approach for estimation of baroreflex sensitivity in hypertension.