bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of AT
2
Receptors by Endogenous Angiotensin II Is Involved in Flow-Induced Dilation in Rat Resistance Arteries
Authors: Matrougui Khalid , Loufrani Laurent , Heymes Christophe , Lévy Bernard I. , Henrion Daniel
Published: June 2012

Abstract
—Pressure-induced tone (myogenic, MT) and flow (shear stress)–induced dilation (FD) are potent modulators of resistance artery tone. We tested the hypothesis that locally produced angiotensin II interacts with MT and FD. Rat mesenteric resistance arteries were perfused in situ. Arterial diameter was measured by intravital microscopy after a bifurcation on 2 distal arterial branches equivalent in size (150 μm, n=7 per group). One was ligated distally and thus submitted to pressure only (MT, no FD). The second branch was submitted to flow and pressure (MT and FD). The difference in diameter between the 2 vessels was considered to be FD. Flow-diameter-pressure relationship was established in the absence and then in the presence of 1 of the following agents. In the nonligated segment (MT+FD), angiotensin II type 1 (AT
1
) receptor blockade (losartan) had no significant effect, whereas angiotensin II type 2 (AT
2
) receptor blockade (PD123319) or saralasin (AT
1
+AT
2
blocker) decreased the diameter significantly, by 9±1 and 10±0.8 μm, respectively. Angiotensin II in the presence of losartan increased the diameter by 18±0.6 μm (inhibited by PD123319). PD123319 or saralasin had no effect after NO synthesis blockade or after endothelial disruption. In the arterial segment ligated distally (MT only), AT
1
or AT
2
receptor blockade had no significant effect. AT
2
-dependent dilation represented 20% to 39% of FD (shear stress from 22 to 37 dyn/cm
2
), and AT
2
-receptor mRNA was found in mesenteric resistance arteries. Thus, resistance arterial tone was modulated in situ by locally produced angiotensin II, which might participate in flow-induced dilation through endothelial AT
2
receptor activation of NO release.
Commissural NTS Lesions and Cardiovascular Responses in Aortic Baroreceptor–Denervated Rats
Authors: Sato Monica Akemi , Menani José Vanderlei , Lopes Oswaldo Ubríaco , Colombari Eduardo
Published: June 2012

Abstract
—Both acute (1 day) lesions of the commissural nucleus of the solitary tract (commNTS) and aortic baroreceptor denervation increase pressor responses to bilateral common carotid occlusion (BCO) during a 60-second period in conscious rats. In this study, we investigated the following: (1) the effects of commNTS lesions on basal mean arterial pressure (MAP) and heart rate (HR) of aortic denervated (ADNx) rats; (2) the effects of acute commNTS lesions on pressor responses to BCO in ADNx rats; and (3) the effects of chronic (10 days) commNTS lesions on the pressor response to BCO. ADNx increased basal MAP and HR in sham-lesioned rats. Acute commNTS lesions abolished the MAP and HR increases observed in ADNx rats. Acute commNTS lesions increased the pressor responses to BCO in rats with intact-baroreceptor innervation but produced no additional change in the pressor response to BCO in ADNx rats. Chronic commNTS lesions did not change the pressor responses to BCO in rats with intact-baroreceptor innervation. The data show that acute commNTS lesions abolish the MAP increase produced by aortic baroreceptor denervation. They also suggest that acute commNTS lesions enhance the pressor response to BCO by partial withdrawal of aortic baroreceptor inputs into the NTS. Chronically, reorganization in the remaining aortic baroreceptor or in the baroreflex function as a whole might produce normalization of the cardiovascular responses to BCO.
Rostral Ventrolateral Medulla
Authors: Bergamaschi Cássia T. , Campos Ruy R. , Lopes Oswaldo U.
Published: June 2012

Abstract
—The major aim of the present study was to evaluate the role of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats subjected to long-term treatment with
N
G
-nitro-
l
-arginine methyl ester (L-NAME) (70 mg/kg orally for 1 week). We inhibited or stimulated RVLM neurons with the use of drugs such as glycine,
l
-glutamate, or kynurenic acid in urethane-anesthetized rats (1.2 to 1.4 g/kg IV). Bilateral microinjection of glycine (50 nmol, 100 nL) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 158±4 to 71±4 mm Hg (
P
<0.05), which was similar to the decrease produced by intravenous administration of hexamethonium. In normotensive rats, glycine microinjection reduced MAP from 106±4 to 60±3 mm Hg (
P
<0.05). Glutamate microinjection into the RVLM produced a significant increase in MAP in both hypertensive rats (from 157±3 to 201±6 mm Hg) and normotensive rats (from 105±5 to 148±9 mm Hg). No change in MAP was observed in response to kynurenic acid microinjection into the RVLM in either group. These results suggest that hypertension in response to long-term L-NAME treatment is dependent on an increase in central sympathetic drive, mediated by RVLM neurons. However, glutamatergic synapses within RVLM are probably not involved in this response.
Cardiopulmonary Reflex Impairment in Experimental Diabetes in Rats
Authors: Oliveira Vera Lucia Longo , Moreira Edson Dias , Farah Vera de Moura Azevedo , Consolim-Colombo Fernanda , Krieger Eduardo Moacyr , Irigoyen Maria Claudia
Published: June 2012

Abstract
—The aim of the present study was to evaluate the sensitivity of the cardiopulmonary receptors in experimental diabetes induced by streptozotocin by the use of 2 different methods: (1) administration of increasing doses of serotonin to analyze peak changes of arterial pressure and heart rate for each given dose in conscious intact normal and diabetic rats; (2) expanding blood volume with the use of dextran (6%) to produce similar increases in left ventricular end-diastolic pressure to quantify the arterial pressure, heart rate, and renal sympathetic nerve activity in sinoaortic, denervated, anesthetized normal and diabetic rats. Blood samples were collected to measure blood glucose. Diabetic rats showed hyperglycemia (22±0.7 versus 7±0.2 mmol/L), reduced body weight (226±12 versus 260±4 g) and heart rate (294±14 versus 350±10 bpm), and similar arterial pressure (104±4 versus 113±4 mm Hg) when compared with control rats. Serotonin induced significant bradycardia and hypotension, which were similar and proportional to the dose injected in both groups. Mean arterial pressure and heart rate decreases in response to volume overload were significantly lower in diabetic than in control rats. The reflex reduction of the renal sympathetic nerve activity as expressed by percentage changes in nerve activity in response to increasing left end-diastolic pressure was abolished in diabetic animals (1.9±0.8% versus −14±4%/mm Hg in controls). These results showed an impairment of cardiopulmonary reflex control of circulation in diabetes during acute volume expansion. The normal responses to serotonin administration indicated that the cardiopulmonary reflex is still preserved in diabetic rats.
Effects of Aging on Serum Ionized and Cytosolic Free Calcium
Authors: Barbagallo Mario , Dominguez Ligia J. , Licata Giuseppe , Resnick Lawrence M.
Published: June 2012

Abstract
—Elevated cytosolic free calcium (Ca
i
) and reciprocally reduced, extracellular ionized calcium (Ca-ion) levels are observed in both hypertension and non–insulin-dependent diabetes mellitus (NIDDM). Because the changes of vascular function and insulin sensitivity in these conditions resemble the changes associated with “normal” aging, we wondered to what extent similar alterations in calcium metabolism occur with aging per se in the absence of overt hypertension or diabetes. We therefore measured platelet Ca
i
levels by spectrofluorometry and serum Ca-ion levels in normotensive, nondiabetic, healthy, normal, elderly (>65 years old) subjects, mean age ±SEM, 72.2±1.5 years old (n=11); in healthy, normal, young (<65 years old) adults, 46.1±2.3 years old (n=12); in 10 young adult hypertensives, 48.6±1.9 years old; and in 10 normotensive NIDDM subjects, 49.2±1.6 years old. Platelet Ca
i
levels were higher (104.5±4.9 versus 80.2±1.8 nmol/L,
P
<0.01) and Ca-ion levels lower (1.212±0.010 versus 1.236±0.011 mmol/L,
P
<0.05) in normal elderly compared with young control subjects, but normal elderly Ca
i
and Ca-ion levels were indistinguishable from those in hypertensive (Ca
i
107.5±3.6 nmol/L, Ca-ion 1.210±0.009 mmol/L) and NIDDM (Ca
i
110.7±4.7 nmol/L, Ca-ion 1.204±0.014 mmol/L) subjects. In normal subjects, significant correlations were found between platelet Ca
i
levels and age (
r
=0.655,
P
<0.01) and between Ca
i
levels and systolic blood pressure (
r
=0.733,
P
<0.001). We conclude that aging is associated with alterations of Ca
i
and Ca-ion levels resembling those changes present at any age in hypertension and type 2 diabetes. We hypothesize that these alterations of calcium metabolism underlie the predisposition to the alterations of blood pressure and insulin sensitivity characteristic of “normal” aging. The data also suggest that studies of the aging process should be limited to subjects with normal blood pressure and glucose tolerance.
Role of Angiotensin and Oxidative Stress in Essential Hypertension
Authors: Romero J. Carlos , Reckelhoff Jane F.
Published: June 2012

Abstract
—In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng · kg
−1
· min
−1
, which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F
2α
(F
2
-isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F
2
-isoprostanes. F
2
-isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F
2
-isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.
Angiotensin II Stimulates Gene Expression of Cardiac Insulin-Like Growth Factor I and Its Receptor Through Effects on Blood Pressure and Food Intake
Authors: Brink Marijke , Chrast Jacqueline , Price S. Russ , Mitch William E. , Delafontaine Patrick
Published: June 2012

Abstract
—Angiotensin II (Ang II) is known to act as a growth factor and may be involved in cardiac remodeling. We have shown that insulin-like growth factor-I (IGF-I) is an autocrine mediator of growth responses to Ang II in vascular smooth muscle cells in vitro, and we hypothesized that IGF-I also serves as an important modulator of cardiovascular growth in vivo. To study the effect of Ang II on cardiac IGF-I, we infused rats for 3, 7, or 14 days with Ang II through osmotic minipumps. After 7 days, left ventricular mass normalized for body weight was increased by 20% (
P
<0.01) in Ang II rats compared with pair-fed control rats that were given a restricted amount of food identical to that eaten by the anorexic, Ang II–infused rats. Ang II increased left ventricular IGF-I mRNA levels by 1.5- to 1.8-fold compared with ad libitum–fed or pair-fed control rats (
P
<0.05). Cardiac IGF-I protein was increased correspondingly and was localized on the cardiomyocytes. Treatment with hydralazine abolished the induction of IGF-I mRNA, which indicates that Ang II induces cardiac IGF-I mRNA expression through a pressor-mediated mechanism. IGF-I receptor (IGF-IR) mRNA was induced 2.1-fold in Ang II rats compared with ad libitum–fed rats (
P
<0.01). However, this increase was also observed in pair-fed controls and is thus due to the anorexigenic effect of Ang II. We have recently shown that circulating IGF-I levels are reduced in response to Ang II infusion. Elevation of IGF-I levels by coinfusion of IGF-I and Ang II significantly increased left ventricular index by 16% compared with rats infused with Ang II alone (
P
<0.05). In conclusion, autocrine upregulation of cardiac IGF-I and IGF-IR mRNA by Ang II occurs through hemodynamic and nonhemodynamic mechanisms, respectively, and may modulate cardiac structural changes that occur in hypertension.
11β-Hydroxysteroid Dehydrogenase and Corticosteroid Action in Lyon Hypertensive Rats
Authors: Lloyd-MacGilp Susan A. , Nelson Susan M. , Florin Marine , Lo Ming , McKinnell Joanna , Sassard Jean , Kenyon Christopher J.
Published: June 2012

Abstract
—Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains differ in several respects. Abnormal activity of 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2), which interconvert corticosterone and inactive 11-dehydrocorticosterone, might contribute to the LH phenotype by regulating corticosteroid hormone access to receptors. 11β-HSD2 (expressed in kidney but not liver) prevents endogenous glucocorticoids from binding to mineralocorticoid receptors. 11β-HSD1 (expressed in liver and kidney) favors active glucocorticoid formation from 11-dehydrocorticosterone. 11β-HSD properties in LH and LL have been compared by several approaches: (1) 11βHSD activities have been measured in vitro as corticosterone dehydrogenation and in vivo as interconversion of injected cortisol and cortisone; (2) the effects of cortisol and cortisone on urine electrolytes and volume have been measured; and (3) 11β-HSD mRNA expression has been measured by in situ hybridization. 11β-HSD2 enzyme activities in LH and LL rats were similar and urinary cortisone:cortisol ratios were not different after cortisol injection. Cortisol caused a natriuresis and kaliuresis in both strains, with a slightly reduced response in LH rats. Renal 11β-HSD2 mRNA expression was slightly lower in LH rats. 11β-HSD1 was less active in LH than LL rats: enzyme activities were lower in tissue extracts; urinary cortisone:cortisol was lower in LL rats after cortisone injections; cortisone increased urine volume in LL but not LH rats; and mRNA levels tended to be lower in LH tissues. We conclude that 11β-HSD1 is impaired in LH rats. The LH phenotype of heavier adrenals, raised corticosterone, and reduced thymus weight is similar to that described for 11β-HSD1 knockout mice.
Influence of Age on Contractile Response to Insulin-Like Growth Factor 1 in Ventricular Myocytes From Spontaneously Hypertensive Rats
Authors: Ren Jun , Jefferson LeQuishia , Sowers James R. , Brown Ricardo A.
Published: June 2012

Abstract
—Evidence suggests a pathophysiological role of insulin-like growth factor 1 (IGF-1) in hypertension. Cardiac function is altered with advanced age, similar to hypertension. Accordingly, the effects of IGF-1 on cardiac myocyte shortening and intracellular Ca
2+
were evaluated in hypertension at different ages. Ventricular myocytes were isolated from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), aged 12 and 36 weeks. Mechanical and intracellular Ca
2+
properties were examined by edge-detection and fluorescence microscopy. At 12 weeks, IGF-1 (1 to 500 ng/mL) increased peak twitch amplitude (PTA) and FFI changes (ΔFFI) in a dose-dependent manner in WKY myocytes, with maximal increases of 27.5% and 35.2%, respectively. However, IGF-1 failed to exert any action on PTA and ΔFFI in the age-matched SHR myocytes. Interestingly, at 36 weeks, IGF-1 failed to exert any response in WKY myocytes but depressed both PTA and ΔFFI in a dose-dependent manner in SHR myocytes, with maximal inhibitions of 40.5% and 16.1%, respectively. Myocytes from SHR or 36-week WKY were less sensitive to norepinephrine (1 μmol/L) and KCl (30 mmol/L). Pretreatment with nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 100 μmol/L) did not alter the IGF-1–induced response in 12-week WKY myocytes but unmasked a positive action in 12-week SHR and 36-week WKY myocytes. L-NAME also significantly attenuated IGF-1–induced depression in 36-week SHR myocytes. In addition, the Ca
2+
channel opener Bay K8644 (1 μmol/L) abolished IGF-1–induced cardiac depression in 36-week SHR myocytes. Collectively, these results suggest that the IGF-1–induced cardiac contractile response was reduced with advanced age as well as with hypertension. Alterations in nitric oxide and intracellular Ca
2+
modulation may underlie, in part, the resistance to IGF-1 in hypertension and advanced age.
Effects of Superoxide on Signaling Pathways in Smooth Muscle Cells From Rats
Authors: Wu Lingyun , de Champlain Jacques
Published: June 2012

Abstract
—The effects of hypoxanthine and xanthine oxidase–induced superoxide anion were evaluated on various signal transduction pathways in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Superoxide increased inositol 1,4,5-tris-phosphate (IP
3
) formation in a concentration- and time-dependent manner in both strains but more markedly in SMCs from SHR. Various antioxidants significantly decreased the superoxide-induced IP
3
formation in both strains. In addition, tyrosine kinase inhibitors, genistein and tyrphostin A25, inhibited the superoxide-induced IP
3
formation more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced by
S
-nitroso-
N
-acetylpenicillamine. In addition, the superoxide-induced increase in IP
3
formation was significantly inhibited by guanylyl cyclase stimulator
S
-nitroso-
N
-acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase inhibitor, 1
H
-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) and KT5823 (a cGMP-dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the superoxide-enhanced IP
3
formation was not accompanied by simultaneous changes in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the superoxide-induced IP
3
formation. Our results thus demonstrate a stimulatory effect of superoxide on IP
3
formation, mediated by the tyrosine kinase–coupled phospholipase C
γ
activity, and an inhibitory effect of superoxide on cGMP formation in vascular SMCs. The increased reactivity of the phospholipase C pathway and the decreased cross inhibition of the IP
3
pathway by cGMP in the presence of superoxide may underlie the altered functions of vascular SMCs in SHR.
Genes and Hypertension
Authors: Dominiczak Anna F. , Negrin Domingo C. , Clark James S. , Brosnan M. Julia , McBride Martin W. , Alexander M. Yvonne
Published: June 2012

Abstract
—Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a “speed” congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2×10
6
base pairs of DNA and ≈50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.
Role of Ca
2+
-Independent Phospholipase A
2
in the Regulation of Inducible Nitric Oxide Synthase in Cardiac Myocytes
Authors: Isenović Esma , LaPointe Margot C.
Published: June 2012

Abstract
—We have previously shown that the regulation by interleukin-1β (IL-1β) of inducible nitric oxide synthase (iNOS) involves phospholipase A
2
(PLA
2
) metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS-082 is used to inhibit secretory PLA
2
and methyl arachidonyl fluorophosphonate is used to inhibit cytosolic PLA
2
, our data suggest that a secretory PLA
2
metabolite was involved in the regulation by IL-1β of iNOS. In addition, a third PLA
2
isoform, which is Ca
2+
independent (iPLA
2
), has also been detected in cardiac myocytes and shown to be regulated by cytokines. We tested whether iPLA
2
metabolites are involved in the regulation by IL-1β of iNOS with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of iPLA
2
. For this, we measured IL-1β–stimulated nitrite (NOx) production with use of the Griess reagent, prostaglandin E
2
(PGE
2
) production with use of an enzyme immunoassay, and arachidonic acid release in the presence and absence of BEL. We also detected iNOS and iPLA
2
proteins by Western blotting. Treatment with IL-1β (5 ng/mL) for 24 hours stimulated NOx production by 8-fold and iNOS protein levels by at least 10-fold. In addition, arachidonic acid release was increased by 1.6-fold and PGE
2
production was increased by 300-fold. When neonatal ventricular myocytes were treated with 10 μmol/L BEL, both IL-1β–stimulated PGE
2
production and arachidonic acid release were inhibited. BEL inhibited IL-1β–stimulated NOx production and iNOS protein by 88% and 93%, respectively. Lysophosphatidic acid, but not arachidonic acid or lysophosphatidylcholine, stimulated iNOS expression. Our results indicate that an iPLA
2
metabolite, perhaps lysophosphatidic acid, may be involved in the IL-1β–signaling pathway, regulating the synthesis of iNOS.
Angiotensin II Enhances Integrin and α-Actinin Expression in Adult Rat Cardiac Fibroblasts
Authors: Kawano Hiroaki , Cody Robert J. , Graf Kristof , Goetze Stephan , Kawano Yasuko , Schnee Janet , Law Ronald E. , Hsueh Willa A.
Published: June 2012

Abstract
—Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as α-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 μmol/L), a specific Ang II type 1 (AT
1
) receptor antagonist, or PD 123319 (10 μmol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II–induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT
1
receptor blocker, losartan, or with hydralazine to investigate integrin and α-actinin expression in treated and untreated SHR. Ang II enhanced α
v
, β
1
, β
3
, and β
5
integrins; osteopontin; and α-actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to β
3
and α
v
β
5
attenuated Ang II–induced adhesion. In SHR, ventricular α
v
and β
5
integrin expression and α-actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, α-actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated β-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and α-actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT
1
receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and α-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT
1
receptor.
Endothelin-1 Attenuates ω3 Fatty Acid–Induced Apoptosis by Inhibition of Caspase 3
Authors: Diep Quy N. , Intengan Hope D. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Endothelin-1 (ET-1) may be involved in the induction of vascular hypertrophy in hypertension. ET-1 may also modulate vascular growth through the exertion of antiapoptotic effects. The ω3 fatty acids (ω3 FAs), which have antiproliferative effects in various cell types, may have a beneficial role in hypertension. We tested the hypothesis that ET-1 could act as a survival factor against ω3 FA–induced apoptosis and attempted to elucidate possible molecular mechanisms underlying the protective action of ET-1 on docosahexaenoic acid (DHA)-induced apoptosis. Mesenteric vascular smooth muscle cells were stimulated with DHA, a representative ω3 FA. Dose-response curves of DHA at different apoptotic stages were assessed with the use of flow cytometry: (1) very early: plasma membrane phosphatidylserine (PS) translocation; (2) early: change in mitochondrial transmembrane potential (ΔΨm); and (3) late: cell cycle analysis. Expression of the proapoptotic protein bax and the antiapoptotic protein bcl-2 was determined with Western blot assay. The activity and the expression of caspase 3, which is a critical proteolytic enzyme involved in the death-signaling pathway, were evaluated with a fluorometric immunosorbent enzyme assay and Western blot analysis, respectively. Apoptosis, which was detected with PS translocation, ΔΨm disruption, and cell cycle analysis, was increased dose dependently by DHA. DHA-induced apoptosis was attenuated through exposure to ET-1 for 1 hour before DHA in cell cycle analysis. The interference of ET-1 with DHA-induced apoptosis, as detected with cell cycle analysis, was not apparent at the membrane (PS translocation) or the mitochondrial (ΔΨm) level. The increase in bax/bcl-2 ratio in DHA-stimulated cells was not affected by ET-1. However, DHA increased both caspase 3 activity and the active forms of caspase 3 (20 and 17 kDa), resulting in enhanced DNA fragmentation as shown through Hoechst staining and fluorescence microscopy, which were attenuated by ET-1 pretreatment. In conclusion, DHA, an ω3 FA, induced apoptosis in vascular smooth muscle cells in a dose-dependent manner. ET-1 exerted important protective effects through the attenuation of DHA-induced caspase 3 activation and subsequent DNA fragmentation in the late stages of apoptosis.
Nitric Oxide Synthase Activity and Isoforms in Rat Renal Vasculature
Authors: Mattson David L. , Wu Feng
Published: June 2012

Abstract
—Experiments were performed to quantify nitric oxide synthase (NOS) activity and identify the NOS isoforms present in the Sprague-Dawley rat renal vasculature. NOS enzymatic activity was measured by adding [
3
H]arginine to microdissected renal blood vessels and quantifying the conversion to [
3
H]citrulline by reverse-phase high-performance liquid chromatography. Total NOS activity was greatest in microdissected vasa recta (123±41 pmol · mg
−1
· h
−1
, n=5) and significantly less in glomeruli (46±9 pmol · mg
−1
· h
−1
, n=6) and afferent arterioles (42±10 pmol · mg
−1
· h
−1
, n=6) and averaged <5 pmol · mg
−1
· h
−1
in arcuate (n=8) and interlobular (n=9) arteries. Addition of 1.0 mmol/L EDTA to the reaction decreased NOS activity to <5 pmol · mg
−1
· h
−1
in afferent arterioles, glomeruli, and vasa recta (n=5 each), indicating that the NOS enzymatic activity in these segments is primarily a result of constitutive NOS. Both neuronal and endothelial NOS mRNA were identified in each vascular segment by reverse transcription—polymerase chain reaction, but inducible NOS mRNA was detected only in microdissected arcuate arteries. The present experiments indicate that the vasa recta, glomeruli, and afferent arterioles contain large amounts of calcium-dependent NOS enzymatic activity and that neuronal NOS and endothelial NOS mRNA are present in these segments.
Sympathetic Control of Arterial Membrane Potential by ATP-Sensitive K
+
-Channels
Authors: Goto Kenichi , Fujii Koji , Abe Isao , Fujishima Masatoshi
Published: June 2012

Abstract
—Stimulation of perivascular nerve terminals leads to a release of various neurotransmitters such as norepinephrine, epinephrine, acetylcholine, nitric oxide, and calcitonin gene-related peptide (CGRP). Because some of these substances have been shown to cause smooth muscle hyperpolarization by direct or endothelium-dependent mechanisms, we hypothesized that the liberation of 1 or more of these transmitters may lead to neurogenic hyperpolarization in arterial muscle cells. The present study was designed to determine the presence or absence of neurogenic hyperpolarization and, if present, its underlying mechanisms in isolated rat mesenteric resistance arteries, through the use of conventional microelectrode techniques. The experiments were performed under the combined blockade of α-adrenoceptors and purinoceptors with phentolamine and suramin to eliminate depolarizing responses to nerve stimulation. Under these conditions, perivascular nerve stimulation (5 Hz, 30 seconds) evoked smooth muscle hyperpolarization (−3.3±0.3 mV, n=15), which was abolished by tetrodotoxin, indicating the neurogenic origin of the response. This neurogenic hyperpolarization was resistant to atropine, nitro-
l
-arginine, or CGRP8-37, a CGRP antagonist, but was abolished by guanethidine and β-blocker propranolol. This hyperpolarization was also abolished by glibenclamide, an ATP-sensitive K
+
channel (K
ATP
) blocker, but was unaffected by apamin, a Ca
2+
-activated K
+
channel blocker. In separate experiments, exogenous norepinephrine caused glibenclamide-sensitive hyperpolarization in the presence of phentolamine. On the other hand, norepinephrine-induced depolarization in the absence of phentolamine was enhanced by propranolol. These findings suggest that neurally released catecholamines cause membrane hyperpolarization through the activation of K
ATP
by β-adrenoceptors. Such hyperpolarization may play an important role in the control of arterial membrane potential by opposing α-adrenergic depolarization.
Endothelin Enhances and Inhibits Adrenal Catecholamine Release in Deoxycorticosterone Acetate-Salt Hypertensive Rats
Authors: Lange Darrell L. , Haywood Joseph R. , Hinojosa-Laborde Carmen
Published: June 2012

Abstract
—Endothelin (ET) and the sympathoadrenal system contribute to the development and maintenance of deoxycorticosterone acetate (DOCA)-salt hypertension. ET can act directly on the adrenal medulla to enhance the release of catecholamines. In addition, the level of ET peptide is increased in the adrenal glands of DOCA-salt hypertensive rats. Therefore, we tested the hypothesis that ET enhances adrenal medullary catecholamine release during DOCA-salt hypertension. The infusion of exogenous ET-1 into an isolated, perfused adrenal gland preparation resulted in an increase in the basal release of norepinephrine (NE) and epinephrine (EPI) in control and DOCA-salt hypertensive rats. Nerve-stimulated (0.3 Hz) release of NE was significantly inhibited during ET-1 infusion in the DOCA-salt hypertensive rats but not in the control rats. The role of endogenous ET on basal and nerve-stimulated NE and EPI release was also examined. An infusion of either BQ-123 (10
−7
mol/L), an ET
A
receptor antagonist, or BQ-788 (10
−7
mol/L), an ET
B
receptor antagonist, did not alter basal NE or EPI release in either control or DOCA-salt hypertensive rats. BQ-788 did not alter nerve-stimulated release of NE and EPI. In contrast, the nerve-stimulated release of EPI, but not NE, was enhanced during BQ-123 infusion in DOCA-salt hypertensive rats. Nerve-stimulated NE and EPI release was unaffected by BQ-123 in the control rats. These data suggest that ET can stimulate adrenal medullary catecholamine release in normotensive and DOCA-salt hypertensive rats. However, ET also inhibits adrenal medullary catecholamine release in DOCA-salt hypertensive rats.
Endothelin-A Blockade Attenuates Systemic and Renal Hemodynamic Effects of L-NAME in Humans
Authors: Montanari Alberto , Biggi Almerina , Carra Nicoletta , Fasoli Elena , Calzolari Massimo , Corsini Francesca , Perinotto Patrizia , Novarini Almerico
Published: June 2012

Abstract
—Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either
N
G
-nitro-
l
-arginine methyl ester (L-NAME) 3.0 mg · kg
−1
· min
−1
or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol · kg
−1
· min
−1
or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (
P
<0.001 versus b) in period 1, to 9.9% (
P
<0.001) in period 2 with L-NAME, and by 3.3% (
P
<0.01) to 6.6% (
P
<0.001) with L-NAME plus BQ (
P
=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%;
P
<0.001) but not with coinfused BQ (2.1%;
P
=NA versus b,
P
=0.005 versus L-NAME alone). RBF declined by 12.2% (
P
<0.001) to 18.3% (
P
<0.001) with L-NAME and by 4.6% (
P
<0.005) to 8.2% (
P
<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (
P
<0.05 in period 1 and
P
<0.02 in period 2). Blunted changes were also seen for RVR (
P
<0.005 in period 1 and
P
<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.
Extracellular Signal-Regulated Kinase Pathway Is Involved in Basic Fibroblast Growth Factor Effect on Angiotensin II–Induced Ca
2+
Transient in Vascular Smooth Muscle Cell From Wistar-Kyoto and Spontaneously Hypertensive Rats
Authors: Samain Emmanuel , Bouillier Hélène , Miserey Stéphanie , Perret Claudine , Renaud Jean-François , Safar Michel , Dagher Georges
Published: June 2012

Abstract
—We studied the effect of basic fibroblast growth factor (b-FGF) on different Ca
2+
mechanisms elicited by angiotensin II (Ang II) in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Intracellular Ca
2+
(Ca
2+
i
) variations were studied in cultured vascular smooth muscle cells (VSMCs) isolated from the aorta of 5- to 6-week-old WKY rats and SHR. Ca
2+
i
was assessed in Fura-2–loaded cells with fluorescent imaging microscopy. Ang II subtype 1 receptor activation by Ang II (1 μmol/L) induced a transient increase in Ca
2+
i
that was partially attenuated by genistein, a tyrosine kinase inhibitor. Pretreatment of VSMCs with b-FGF for 24 hours markedly stimulated the Ang II–induced Ca
2+
i
release from the internal stores in WKY rats, whereas it was without effect in SHR. This was not consequent to a change in the affinity of Ang II subtype 1 receptors or an increase in their density. Inhibition of mitogen-activated protein kinase with PD 98059 reduced this stimulatory effect of the cytokine in the WKY rats. On the other hand, b-FGF stimulated the Ang II–induced Ca
2+
influx in both strains. Similar results were observed when Ca
2+
influx was induced with thapsigargin. Genistein and PD 98059 abolished the effect of b-FGF. These results show for the first time that b-FGF regulates Ca
2+
mechanisms induced by Ang II and that this regulation is different in SHR than in normotensive control animals. The extracellular signal-regulated kinase cascade is implicated in this cross-regulation with G protein–signaling pathway at 2 levels and possibly more: 1 at the tyrosine kinases and the other downstream of the extracellular signal–regulated kinase family. These results may prove useful in understanding the interaction between these 2 pathways and their implication in genetic hypertension.
Blood Pressure Is Related to Placental Volume and Birth Weight
Authors: Thame Minerva , Osmond Clive , Wilks Rainford J. , Bennett Franklyn I. , McFarlane-Anderson Norma , Forrester Terrence E.
Published: June 2012

Abstract
—The objective of this study was to determine whether maternal nutrition and fetal and placental size program blood pressure. A longitudinal study linking the maternal anthropometric measurements of the first antenatal visit, ultrasound data of placental and fetal size, anthropometry at birth, and childhood growth and blood pressure was performed. The subjects were 428 women who attended the antenatal clinic at the University Hospital of the West Indies, Kingston, Jamaica, and their children, who were subsequently followed up. Systolic blood pressure at ages 1, 2, 2.5, 3, and 3.5 years was the main outcome measure. Pooling the data across ages, systolic blood pressure fell by 1.4 mm Hg for every 1-kg increase in birth weight (95% CI 0.2 to 2.7,
P
=0.02) and by 1.2 mm Hg for every 100-mL increase in placental volume at 20 weeks of gestation (95% CI 0.4 to 2.0,
P
=0.004). Blood pressure was also negatively associated with placental volume at 17 weeks and fetal abdominal circumference at 20 weeks. Measures of maternal nutritional status were strongly related to birth weight and placental volume but not directly to childhood blood pressure at these young ages. In conclusion, blood pressure is associated with fetal size in this population, as previously described among Europeans. We found associations between placental volume and abdominal circumference in the second trimester and childhood blood pressure, suggesting that the initiating events of blood pressure programming occur early in pregnancy. Measures of maternal nutritional status were not directly related to childhood blood pressure at these young ages but were strong predictors of both birth weight and placental volume, suggesting an indirect relation.
Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice
Authors: Járai Zoltán , Wagner Jens A. , Goparaju Sravan Kumar , Wang Lei , Razdan Raj K. , Sugiura Takayuki , Zimmer Ann M. , Bonner Tom I. , Zimmer Andreas , Kunos George
Published: June 2012

Abstract
—Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1
−/−
) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1
−/−
mice and their homozygous (CB1
+/+
) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1
−/−
mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor–mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.
Vascular Response to Angiotensin II in Atherosclerosis
Authors: Wilfert Klaus , Drischel Klaus , Unbehaun Axel , Guski Hans , Persson Pontus B. , Stauss Harald M.
Published: June 2012

Abstract
—High-cholesterol alimentation is associated with an induction of angiotensin-converting enzyme and angiotensin II receptor expression within the vascular wall of the aorta. Despite an enhanced pressure response to angiotensin II in atherosclerotic conscious rabbits, angiotensin II–induced contraction was reduced in isolated vascular rings from the aorta and unchanged in those from the iliac artery. We, therefore, investigated whether cholesterol-induced atherosclerosis enhances overall vascular responsiveness to angiotensin II in intact animals and whether an altered arterial baroreflex sensitivity can explain the discrepancy between experiments in intact animals and isolated blood vessels. Rabbits were maintained on a high-cholesterol diet (2 g/d cholesterol plus 20 mL/d sunflower seed oil, n=11) or on a standard diet (n=12) for 12 weeks. Total serum lipids markedly increased (
P
<0.05). Tissue examinations 6 weeks after termination of the high-cholesterol diet revealed distinct atherosclerosis and elevated cholesterol content in the aorta (
P
<0.05). A high-cholesterol diet did not change baseline hemodynamic parameters. However, angiotensin II–induced increases in total peripheral resistance were larger in the atherosclerotic animals (86.3±13.0 versus 41.9±9.7 mm Hg · L
−1
· min,
P
<0.05). In addition, the blood pressure pulse interval relationship was markedly reduced (slope: 0.80±0.14 versus 0.49±0.06 ms/mm Hg,
P
<0.05), which suggested that the baroreflex blunted the angiotensin II response to a lesser extent in atherosclerotic animals. In conclusion, the overall vascular responsiveness to angiotensin II is increased in the atherosclerotic rabbit as indicated by the larger increase in total peripheral resistance. An attenuation of the arterial baroreflex sensitivity may contribute to this effect.
Nitric Oxide in the Renal Medulla Protects From Vasopressin-Induced Hypertension
Authors: Szentiványi Mátyás , Park Frank , Maeda Celso Y. , Cowley Allen W.
Published: June 2012

Abstract
—In the present study, we assessed whether activation of the nitric oxide (NO) system within the renal medulla could serve as a buffer against the chronic hypertensive effects of arginine vasopressin (AVP). NO concentration in the renal medulla of Sprague-Dawley rats was measured with in vivo microdialysis/oxyhemoglobin NO trapping. The results showed that medullary interstitial [NO] was increased after 2 hours of AVP infusion and remained elevated even after 10 days (by 62±8% and 42±13%, respectively). Western blot analysis showed that 2 days of AVP infusion was insufficient to increase protein expression of any of the NO synthase (NOS) isoforms, but after 10 days of AVP infusion, endothelial NOS expression was significantly increased in the inner medulla with no significant changes in noninducible NOS and inducible NOS levels. When renal medullary NOS enzyme activity was blunted with a nonpressor dose of
N
G
-nitro-
l
-arginine methyl ester (75 μg · kg
−1
· h
−1
) that was chronically infused locally into the renal medulla, intravenous AVP infusion (which was shown earlier to be subpressor in chronic studies) produced a sustained elevation in arterial pressure (from 107±2 to 121±2 mm Hg). These data indicate that chronic elevations in plasma AVP enhance renal medullary endothelial NOS protein expression, which enables sustained elevations of NO concentrations in this region of the kidney to buffer the hypertensive effects of AVP.
Interaction Between Nitric Oxide and Mineralocorticoids in the Long-Term Control of Blood Pressure
Authors: Alvarez Gracia , Osuna Antonio , Wangensteen Rosemary , Vargas Félix
Published: June 2012

Abstract
—We analyzed the effects of a possible interaction between nitric oxide deficiency and mineralocorticoids on the long-term control of blood pressure and renal and endocrine variables. Six groups of uninephrectomized male Wistar rats were used: control animals and rats that received (1)
N
G
-nitro-
l
-arginine methyl ester (L-NAME) subpressor (0.5 mg/100 mL drinking fluid), (2) L-NAME pressor (35 mg/100 mL drinking fluid), (3) deoxycorticosterone acetate (DOCA; 12.5 mg/wk per rat), (4) DOCA plus L-NAME subpressor, or (5) L-NAME pressor plus DOCA. For all groups, the drinking fluid was tap water or 1% NaCl solution. We measured the time course of tail systolic blood pressure (SBP) and body weight for 3 weeks in all rats. At the end of the experimental period, we measured mean arterial pressure (direct recording) and endocrine and renal variables. Tail SBP rose significantly in the DOCA plus L-NAME subpressor–treated group but remained at normotensive levels in the DOCA-treated group. The addition of L-NAME to the subpressor dose accelerated the blood pressure increase in DOCA-salt hypertensive rats. The simultaneous administration of DOCA and L-NAME increased blood pressure and mortality rates in rats that drank water or saline compared with the rats treated with L-NAME alone. The subpressor dose of L-NAME did not increase blood pressure in saline-drinking rats. We conclude that impaired NO synthesis results in increased sensitivity to the pressor effect of mineralocorticoids in the presence or absence of an increased saline intake. Hence, nitric oxide contributes to the adaptative response to mineralocorticoid excess, perhaps through the facilitation of natriuresis and, thus, control of blood pressure.