bluuebunny/crossref_metadata_2025 huggingface dataset:
Telomere Length as an Indicator of Biological Aging
Authors: Benetos Athanase , Okuda Koji , Lajemi Malika , Kimura Masayuki , Thomas Frederique , Skurnick Joan , Labat Carlos , Bean Kathryn , Aviv Abraham
Published: June 2012

Chronological age is the primary determinant of stiffness of central arteries. Increased stiffness is an independent indicator of cardiovascular risk. The aim of this study was to determine whether telomere length, a possible index of biological aging, provides a better account than chronological age for variation in arterial stiffness, evaluated by measuring pulse pressure and aortic pulse wave velocity. The study population included 193 French subjects (120 men, 73 women), with a mean age of 56±11 years, who were not on any antihypertensive medications. Telomere length was evaluated in white blood cells by measuring the mean length of the terminal restriction fragments. Age-adjusted telomere length was longer in women than in men (8.67±0.09 versus 8.37±0.07 kb;
P
=0.016). In both genders, telomere length was inversely correlated with age (
P
<0.01). Multivariate analysis showed that in men, but not in women, telomere length significantly contributed to pulse pressure and pulse wave velocity variations. In conclusion, telomere length provides an additional account to chronological age of variations in both pulse pressure and pulse wave velocity among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and pulse wave velocity, which are indices of large artery stiffness. The longer telomere length in women suggests that for a given chronological age, biological aging of men is more advanced than that of women.
Identification of Peptides That Target the Endothelial Cell–Specific LOX-1 Receptor
Authors: White Steve J. , Nicklin Stuart A. , Sawamura Tatsuya , Baker Andrew H.
Published: June 2012

Current gene delivery vectors demonstrate inefficient and nonselective gene transfer to vascular endothelial cells, limiting their use in cardiovascular gene transfer and therapy. The lectinlike oxidized LDL receptor (LOX-1) is expressed selectively at low levels on endothelial cells but is strongly upregulated in dysfunctional endothelial cells associated with hypertension and atherogenesis. Using LOX-1 as a target receptor, we have sought to isolate peptide ligands that mediate binding to the extracellular domain of LOX-1 as a definitive step in the development of targeted gene transfer aimed at dysfunctional endothelium. To achieve this, we ectopically overexpressed LOX-1 in cells lacking endogenous LOX-1 by using an episomally maintained expression system and designed a novel subtractive phage display strategy to identify peptides selective for LOX-1. After extensive biopanning, we sequenced individual phage and identified 60 novel peptides. This population of peptides contained a number of potential consensus motifs. To define the selectivity of individual peptides for LOX-1 with the use of an independent gene transfer system, we developed a novel adenoviral vector to overexpress LOX-1 transiently in primary cells and cell lines. We then quantified recovery of each peptide from LOX-1–positive and LOX-1–negative cells after adenovirus-mediated gene transfer. This strategy confirmed selectivity to LOX-1 for many peptides and highlighted the peptides LSIPPKA, FQTPPQL, and LTPATAI as principal candidates. These peptides will be useful for the selective targeting of viral and nonviral gene transfer vectors to endothelial cells expressing the LOX-1 receptor in vitro and in vivo and in particular dysfunctional endothelial cells associated with hypertension and atherosclerosis.
Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat
Authors: Cowley Allen W. , Roman Richard J. , Kaldunski Mary L. , Dumas Pierre , Dickhout Jeffrey G. , Greene Andrew S. , Jacob Howard J.
Published: June 2012

Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170±3.3 mm Hg in SS/Mcw rats, 119±2.1 mm Hg in SS.BN13 rats, and 103±1.3 mm Hg in BN/Mcw rats. After salt depletion, MAP fell an average of 27±4.5 mm Hg in SS/Mcw rats, 9±2.6 mm Hg in SS.BN13 rats, and 11±3.0 mm Hg in BN/Mcw rats. Protein excretion of SS/Mcw rats on a high salt diet averaged 189±30 mg/24 h, 63±18 mg/24 h in SS.BN13 rats, and 40±6.4 mg/24 h in BN/Mcw rats. Compared with SS.BN13 and BN/Mcw rats, SS/Mcw rats exhibited significantly greater increases of renal vascular resistance in response to intravenous norepinephrine and angiotensin II. Severe medullary interstitial fibrosis and tubular necrosis after a high salt diet were found consistently in SS/Mcw rat kidneys but were largely absent in the SS.BN13 and BN/Mcw rat kidneys. A similar degree of glomerular sclerosis was found in both SS/Mcw and SS.BN13 rats. In rats fed a 0.4% salt diet, the glomerular filtration rate of SS/Mcw rats was significantly less than that of BN/Mcw and SS.BN13 rats. These results reveal a powerful gene, or set of genes, within chromosome 13 of BN/Mcw rats that confers protection from the detrimental effects of high salt to the SS/Mcw rats.
Role of Endothelin in Intermittent Hypoxia-Induced Hypertension
Authors: Kanagy Nancy L. , Walker Benjimen R. , Nelin Leif D.
Published: June 2012

Clinical studies suggest that sleep apnea causes systemic hypertension. In addition, patients with sleep apnea have elevated plasma levels of endothelin-1 (ET-1). We hypothesized that the intermittent hypoxia/hypercapnia (IH) associated with sleep apnea causes hypertension by increasing ET-1 production. To test this hypothesis, rats with arterial and venous catheters were placed in Plexiglas chambers. IH rat chambers were flushed with an N
2
-CO
2
mixture for 90 seconds to achieve hypoxia/hypercapnia (5% O
2
–5% CO
2
) followed by 90 seconds of compressed air to achieve normoxia (21% O
2
–0% CO
2
). Control rat chambers were flushed with 90 seconds of air-air cycles. Cycles for both groups were repeated 8 hours per day for 11 days. Resting mean arterial pressure (MAP) and heart rate were recorded daily before the start of exposure. After 11 days, MAP was significantly elevated in IH rats compared with initial MAP (109±5 mm Hg initial, 139±11 mm Hg day 11) and compared with air-air rats (110±4 mm Hg). On day 11, cumulative doses of
PD145065
(a nonselective ET-receptor antagonist) were administered intravenously to the rats breathing room air.
PD145065
caused a dose-dependent decrease in MAP in IH rats but did not alter MAP in air-air rats. Plasma ET-1 measured by radioimmunoassay was significantly increased on days 5 and 11 in the IH rats compared with day 1 and compared with air-air rats. There was no significant change in plasma ET-1 over time in air-air rats. We conclude that IH exposure increases both MAP and plasma ET-1 and that the increased ET-1 may contribute to the hypertension.
Reactive Oxygen Species–Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor mRNA by Angiotensin II
Authors: Ichiki Toshihiro , Takeda Kotaro , Tokunou Tomotake , Funakoshi Yuko , Ito Kiyoko , Iino Naoko , Takeshita Akira
Published: June 2012

Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of angiotensin (Ang) II through Ang II type 1 receptor (AT
1
-R). However, the role of ROS in the regulation of AT
1
-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT
1
-R by Ang II. Ang II (10
−6
mol/L) decreased AT
1
-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells. Preincubation of vascular smooth muscle cells with
N
-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II–induced downregulation of AT
1
-R mRNA. The effect of NAC was due to stabilization of the AT
1
-R mRNA that was destabilized by Ang II. The Ang II–induced AT
1
-R mRNA downregulation was also blocked by PD98059, an extracellular signal–regulated protein kinase (ERK) kinase inhibitor. Ang II–induced ERK activation was inhibited by NAC as well as by PD98059. Exogenous H
2
O
2
also suppressed AT
1
-R mRNA. These results suggest that the production of ROS and the activation of ERK are critical for the downregulation of AT
1
-R mRNA. The generation of ROS through stimulation of AT
1
-R not only mediates signaling of Ang II but also may play a crucial role in the adaptation process of AT
1
-R to the sustained stimulation of Ang II.
Oxidized-LDL Enhances Coronary Vasoconstriction by Increasing the Activity of Protein Kinase C Isoforms α and ε
Authors: Giardina Jena B. , Tanner Dennis J. , Khalil Raouf A.
Published: June 2012

Oxidized low-density lipoprotein (ox-LDL) plays a critical role in the development of atherosclerotic coronary vasospasm; however, the cellular mechanisms involved are not fully understood. We tested the hypothesis that ox-LDL enhances coronary vasoconstriction by increasing the activity of specific protein kinase C (PKC) isoforms in coronary smooth muscle. Active stress was measured in de-endothelialized porcine coronary artery strips; cell contraction and [Ca
2+
]
i
were monitored in single coronary smooth muscle cells loaded with fura-2; and the cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific anti-PKC antibodies with Western blots. Ox-LDL (100 μg/mL) caused slow but significant increases in active stress to 1.3±0.4×10
3
N/m
2
and cell contraction (10%) that were completely inhibited by GF109203X (10
−6
mol/L), an inhibitor of Ca
2+
-dependent and -independent PKC isoforms, with no significant change in [Ca
2+
]
i
. 5-Hydroxytryptamine (5-HT; 10
−7
mol/L) and KCl (24 mmol/L) caused increases in cell contraction and [Ca
2+
]
i
that were inhibited by the Ca
2+
channel blocker verapamil (10
−6
mol/L). Ox-LDL enhanced coronary contraction to 5-HT and KCl with no additional increases in [Ca
2+
]
i
. Direct activation of PKC by phorbol 12-myristate13-acetate (PMA; 10
−7
mol/L) caused a contraction similar in magnitude and time course to ox-LDL–induced contraction and enhanced 5-HT– and KCl-induced contraction with no additional increases in [Ca
2+
]
i
. The ox-LDL–induced enhancement of 5-HT and KCl contraction was inhibited by Gö6976 (10
−6
mol/L), an inhibitor of Ca
2+
-dependent PKC isoforms. Both ox-LDL and PMA caused an increase in PKC activity in the particulate fraction, a decrease in the cytosolic fraction, and an increase in the particulate/cytosolic PKC activity ratio. Western blots revealed the Ca
2+
-dependent PKC-α and the Ca
2+
-independent PKC-δ, -ε, and -ζ isoforms. In unstimulated tissues, PKC-α- and -ε were mainly cytosolic, PKC-δ was mainly in the particulate fraction, and PKC-ζ was equally distributed in the cytosolic and particulate fractions. Ox-LDL alone or PMA alone caused translocation of PKC-ε from the cytosolic to particulate fraction, whereas the distribution pattern of PKC-α, -δ, and -ζ remained unchanged. 5-HT (10
−7
mol/L) alone and KCl alone did not change PKC activity. In tissues pretreated with ox-LDL or PMA, 5-HT and KCl caused additional increases in PKC-α activity. Native LDL did not significantly affect coronary contraction, [Ca
2+
]
i
, or PKC activity. These results suggest that ox-LDL causes coronary contraction via activation of the Ca
2+
-independent PKC-ε and enhances the contraction to [Ca
2+
]
i
-increasing agonists by activating the Ca
2+
-dependent PKC-α. Activation of PKC-α and -ε may represent a possible cellular mechanism by which ox-LDL could enhance coronary vasospasm.
Angiotensin II Induces Migration and Pyk2/Paxillin Phosphorylation of Human Monocytes
Authors: Kintscher Ulrich , Wakino Shu , Kim Sarah , Fleck Eckart , Hsueh Willa A. , Law Ronald E.
Published: June 2012

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 μmol/L, with a 3.6±0.6-fold induction in HPBM and a 4.8±0.9-fold induction in THP-1 cells at 1 μmol/L Ang II (both
P
<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 μmol/L) suppressed Ang II–induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R–mediated mechanism. Ang II–directed migration was also blocked by the Src kinase inhibitor PP2 (10 μmol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 μmol/L), and by the p38-MAPK inhibitor SB203580 (10 μmol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II–induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 μmol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7±0.9-fold induction and after 2 minutes for paxillin with a 3.2±0.4-fold induction. Ang II–induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R–dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.
Differential Inhibition of Functional Dilation of Small Arterioles by Indomethacin and Glibenclamide
Authors: Hammer Leah W. , Ligon Alison L. , Hester Robert L.
Published: June 2012

Indomethacin or glibenclamide treatments attenuate functional dilation of larger-diameter “feed” arterioles paired with venules in hamster cremaster muscle. We tested the hypothesis that release of cyclooxygenase products from venules is important for functional dilation of third- and fourth-order arterioles. We also tested whether ATP-sensitive potassium channels are important during functional dilation of smaller arterioles. The microcirculation of hamster cremaster muscle was visualized with in vivo video microscopy. We measured diameter responses of third- and fourth-order arterioles paired and unpaired with venules in response to 2 minutes of muscle field stimulation (40 μs, 10 V, 1 Hz). Control diameters of vessels were 31±2 (n=19), 13±1 (n=12), 12±2 (n=12), and 10±1 (n=12) for paired and unpaired third-order and paired and unpaired fourth-order arterioles, respectively. In all groups, field stimulation resulted in increases in mean control diameter of >80%. Indomethacin (28 μmol/L) superfused on the preparation was used to inhibit cyclooxygenase metabolism, or glibenclamide (10 μmol/L) was used to block ATP-sensitive potassium channels. Indomethacin attenuated arteriolar vasodilations to electrical stimulation in paired third-order vessels only, whereas glibenclamide attenuated this vasodilation in all 4 groups. These results support a role for ATP-sensitive potassium channels in functional dilation of arterioles of all sizes regardless of whether or not they are paired with venules. Conversely, a role for cyclooxygenase products is limited to larger “feed arterioles” paired with venules. This study provides further evidence that venules may be the source of prostaglandin release during functional hyperemia.
Impaired β-Adrenergic Hyperpolarization in Arteries From Prehypertensive Spontaneously Hypertensive Rats
Authors: Goto Kenichi , Fujii Koji , Abe Isao
Published: June 2012

Stimulation of β-adrenoceptors leads to vascular smooth muscle hyperpolarization, presumably through the β-adrenoceptors/Gs protein/adenylate cyclase/ATP-sensitive K
+
-channels (KATP) signaling cascade, which may play an important role in the sympathetic control of membrane potential. β-Adrenoceptor–mediated hyperpolarization has been shown to be impaired in the established stage of experimental hypertension. The present study tested the hypothesis that β-adrenergic hyperpolarization may be defective before the development of hypertension in some forms of genetic hypertension. We evaluated β-adrenoceptor–mediated hyperpolarization using microelectrodes in mesenteric resistance arteries from 5-week-old, prehypertensive, spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Isoproterenol-induced hyperpolarization was significantly smaller in SHR than in WKY (10
−7
mol/L: −4.6±0.6 versus −7.8±0.8 mV,
P
<0.01; 10
−6
mol/L: −7.8±0.5 versus −9.8±0.6 mV,
P
<0.05; n=9). Furthermore, hyperpolarization to cholera toxin, a direct activator of Gs protein, was also impaired in SHR. On the other hand, hyperpolarization to forskolin, an adenylate cyclase activator, and to levcromakalim, a KATP opener, was comparable between groups. These findings suggest that β-adrenoceptor–mediated hyperpolarization is defective in SHR before the development of hypertension, presumably because of an abnormality at the Gs protein site. Considering the importance of membrane potential in the control of vascular tone, altered β-adrenergic control of membrane potential might play a role in the development of hypertension in SHR.
Expression and Function of Peroxisome Proliferator–Activated Receptor-γ in Mesangial Cells
Authors: Nicholas Susanne B. , Kawano Yasuko , Wakino Shu , Collins Alan R. , Hsueh Willa A.
Published: June 2012

Peroxisome proliferator–activated receptor-γ (PPARγ) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARγ are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARγ message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARγ response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARγ is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARγ-PPRE protein complex, confirming specificity of binding of the PPARγ to the PPRE. PPARγ ligands rosiglitazone (1 to 10 μmol/L) and troglitazone (1 to 10 μmol/L) inhibited platelet-derived growth factor–induced DNA synthesis, measured as bromodeoxyuridine incorporation (P
<0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 μg urinary albumin/mg creatinine,
P
<0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARγ activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.
Long-Term Glucose Infusion Increases Arterial Pressure in Dogs With Cyclooxygenase-2 Inhibition
Authors: Brands Michael W. , Hailman Allison E. , Fitzgerald Sharyn M.
Published: June 2012

A series of studies has shown that long-term infusion of insulin and glucose does not increase mean arterial pressure (MAP) in dogs, but we have shown that the same infusion protocol or infusion of glucose alone increases arterial pressure in rats. This study tested the hypothesis that infusing glucose alone in dogs, with all insulin derived from endogenous secretion, would increase arterial pressure. Because fructose feeding in dogs also has been shown not to cause hypertension and because we have shown that prostaglandin production increases during insulin and glucose infusion, this study also tested whether prostaglandins prevent the pressor response in dogs. Dogs were instrumented and assigned in random crossover design to long-term cyclooxygenase-2 (COX-2) inhibition. After baseline measurements, glucose was infused in all dogs for 6 days (≈500 g/d IV). Plasma insulin increased 3- to 4-fold and blood glucose increased significantly in both groups. The MAP (measured 24 h/d) response in control dogs was variable but on average tended to increase, although not significantly. In the dogs with COX-2 inhibition, however, MAP increased significantly to a peak of 9±2 mm Hg and an average of 6±1 mm Hg above control. There was significant sodium and volume retention during glucose infusion and a significant increase in glomerular filtration rate, but there were no between-group differences. Plasma renin activity increased only in the control group. This is the first study to report a long-term pressor response with glucose infusion and hyperinsulinemia in dogs, and it suggests that the inability to detect this relationship previously was due to prostaglandins.
Renal Interstitial ATP Responses to Changes in Arterial Pressure During Alterations in Tubuloglomerular Feedback Activity
Authors: Nishiyama Akira , Majid Dewan S. A. , Walker Matthew , Miyatake Akira , Navar L. Gabriel
Published: June 2012

We recently demonstrated a direct relationship between autoregulation-related changes in renal vascular resistance (RVR) and renal interstitial ATP concentrations. To assess the possible role for extracellular ATP in the regulation of tubuloglomerular feedback (TGF)-mediated autoregulatory adjustments in RVR, renal interstitial ATP concentrations were measured with microdialysis probes in anesthetized dogs at different renal arterial pressures (RAPs) within the autoregulatory range during augmented and diminished activity of the TGF mechanism. Stepwise reductions in RAP from ambient pressure (129±3 mm Hg) to 102±2 mm Hg (step 1) and 75±1 mm Hg (step 2) resulted in significant decreases in ATP concentrations from 9.0±0.8 to 6.3±0.6 nmol/L in step 1 and to 4.2±0.5 nmol/L in step 2. Changes in RVR were highly correlated with changes in ATP concentrations (
r
=0.86,
P
<0.001, n=12). Acetazolamide (100 μg · kg
−1
· min
−1
, n=6), which increases solute delivery to the macula densa, thus augmenting TGF activity, significantly decreased renal blood flow (RBF) by −16±2% and glomerular filtration rate (GFR) by −22±4% and increased ATP concentrations from 8.4±0.7 to 15.5±1.4 nmol/L. Although basal RBF and GFR levels were reduced by the acetazolamide infusion, autoregulation efficiency was maintained, and interstitial ATP concentrations were significantly decreased in response to reductions in RAP by −36±4% in step 1 and by −54±2% in step 2. The relationship between changes in RVR and interstitial ATP concentrations was preserved during acetazolamide treatment (
r
=0.80,
P
<0.01). Inhibition of the TGF mechanism by furosemide significantly increased RBF by 33±6% and GFR by 13±2% and decreased ATP concentrations from 8.9±1.4 to 5.0±0.8 nmol/L (n=6). Furosemide caused marked impairment of RBF and GFR autoregulatory efficiency (by −14±3% and −11±3% in step 1 and by −26±2% and −18±4% in step 2, respectively). In the furosemide-treated kidneys, interstitial ATP levels remained low and were not altered during reductions in RAP (4.7±0.7 nmol/L in step 1 and 4.7±0.8 nmol/L in step 2), and changes in RVR did not exhibit a correlation with changes in ATP concentrations (
r
=0.22,
P
=0.30). These data support the hypothesis that extracellular ATP contributes to autoregulatory adjustments in RVR that are mediated by changes in activity of the TGF mechanism.
Antifibrotic Effects of
N
-Acetyl-Seryl-Aspartyl-Lysyl-Proline on the Heart and Kidney in Aldosterone-Salt Hypertensive Rats
Authors: Peng Hongmei , Carretero Oscar A. , Raij Leopoldo , Yang Fang , Kapke Alissa , Rhaleb Nour-Eddine
Published: June 2012

N
-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits not only hematopoietic cell proliferation but also fibroblast proliferation and collagen synthesis in vitro. Ac-SDKP also prevents collagen deposition and cell proliferation in the left ventricle (LV) in rats with renovascular hypertension (renin dependent). However, it is not clear whether Ac-SDKP has similar effects in a model of renin-independent hypertension (aldosterone-salt). Using a hypertensive rat model of cardiac and renal fibrosis created by chronic elevation of circulating aldosterone (ALDO) levels, we examined the effect of Ac-SDKP on blood pressure, cardiac and renal fibrosis and hypertrophy, and proliferating cell nuclear antigen (PCNA) expression in the LV and left kidney. Uninephrectomized rats were divided into 4 groups: (1) controls that received tap water, (2) rats that received ALDO (0.75 μg/h SC) and 1% NaCl/0.2% KCl in drinking water (ALDO-salt), (3) rats that received ALDO-salt plus Ac-SDKP 400 μg · kg
−1
· day
−1
SC, and (4) rats that received ALDO-salt plus Ac-SDKP 800 μg · kg
−1
· d
−1
SC. After 6 weeks of treatment, the ALDO-salt group was found to have significantly increased blood pressure with decreased body weight and plasma renin concentration (
P
<0.05), LV and renal hypertrophy as well as renal injury, significantly increased collagen content in both ventricles and kidney as well as increased collagen volume fraction in the LV (
P
<0.0001), and significantly increased interstitial and perivascular PCNA-positive cells in the LV and kidney (
P
<0.0001). Ac-SDKP at 800 μg · kg
−1
· d
−1
markedly prevented cardiac and renal fibrosis (
P
<0.005) without affecting blood pressure or organ hypertrophy. It also suppressed PCNA expression in the LV and kidney in a dose-dependent manner. We concluded that Ac-SDKP prevents increased collagen deposition and cell proliferation in the heart and kidney in ALDO-salt hypertensive rats. Because ACE inhibitors increase plasma and tissue Ac-SDKP and decrease cardiac and renal fibrosis, we speculate that Ac-SDKP may participate in the antifibrotic effect of ACE inhibitors.
Arterial Pressure, Left Ventricular Mass, and Aldosterone in Essential Hypertension
Authors: El-Gharbawy Areeg H. , Nadig Vishwanatha S. , Kotchen Jane Morley , Grim Clarence E. , Sagar Kiran B. , Kaldunski Mary , Hamet Pavel , Pausova Zdenka , Gaudet Daniel , Gossard Francis , Kotchen Theodore A.
Published: June 2012

The purpose of the present study was to evaluate the relationship of aldosterone to blood pressure and left ventricular size in black American (n=109) and white French Canadian (n=73) patients with essential hypertension. Measurements were obtained with patients off antihypertensive medications and included 24-hour blood pressure monitoring, plasma renin activity and aldosterone, and an echocardiogram. Compared with the French Canadians, the black Americans had higher body mass indexes, higher systolic blood pressures, attenuated nighttime reduction of blood pressure, and lower serum potassium concentrations (
P
<0.01 for each). Left ventricular mass index, posterior wall thickness, interventricular septal thickness, and relative wall thickness were also greater (
P
<0.01 for each) in the black American patients. Supine and standing plasma renin activity was lower (
P
<0.01 and
P
<0.05, respectively) in the black Americans, whereas supine plasma aldosterone concentrations did not differ, and standing plasma aldosterone was greater (
P
<0.05) in the black Americans (9.2±0.7 ng/dL) than in the French Canadians (7.3±0.6 ng/dL). In the black Americans, supine plasma aldosterone was positively correlated with nighttime systolic (
r
=0.30;
P
<0.01) and diastolic (
r
=0.39;
P
<0.001) blood pressures and inversely correlated with the nocturnal decline of systolic (
r
=−0.29;
P
<0.01) and diastolic (
r
=−0.37;
P
<0.001) blood pressures. In the black Americans, standing plasma aldosterone was positively correlated with left ventricular mass index (
r
=0.36;
P
<0.001), posterior wall thickness (
r
=0.33;
P
<0.01), and interventricular septal thickness (
r
=0.26;
P
<0.05). When the black American patients were divided into obese and nonobese groups, significant correlations between plasma aldosterone and both blood pressure and cardiac mass were observed only in the obese. In the French Canadians, overall, plasma aldosterone did not correlate with either blood pressure or any measures of heart size. However, among obese French Canadians, supine plasma aldosterone correlated with nighttime diastolic (
r
=0.53,
P
<0.02) and systolic (
r
=0.44,
P
<0.01) blood pressures but not with cardiac mass. These results are consistent with the hypothesis that aldosterone contributes to elevated arterial pressure in obese black American and obese white French Canadian patients with essential hypertension and to the attenuated nocturnal decline of blood pressure and left ventricular hypertrophy in obese, hypertensive black Americans.
Antiadrenergic Effects of Adenosine in Pressure Overload Hypertrophy
Authors: Meyer Theo E. , Chung Eugene S. , Perlini Stefano , Norton Gavin R. , Woodiwiss Angela J. , Lorbar Mojca , Fenton Richard A. , Dobson James G.
Published: June 2012

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to β-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A
1
receptor agonist chloro-
N
6
-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A
2A
receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A
2A
receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca
2+
]
i
transients in the presence of adenosine and the A
2A
receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A
1
receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.
Abnormal Renal Vascular Responses to Dipyridamole-Induced Vasodilation in Spontaneously Hypertensive Rats
Authors: Susic Dinko , Varagic Jasmina , Frohlich Edward D.
Published: June 2012

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg · kg
−1
· min
−1
) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by ≈20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.
Genetic Influences on Baroreflex Function in Normal Twins
Authors: Tank Jens , Jordan Jens , Diedrich Andre , Stoffels Mandy , Franke Gabriele , Faulhaber Hans-Dieter , Luft Friedrich C. , Busjahn Andreas
Published: June 2012

Blood pressure and heart rate are strongly influenced by genetic factors; however, despite the pivotal role of genetics in short-term cardiovascular regulation, little is known about the genetic contribution to baroreflex function. We assessed genetic influence on baroreflex sensitivity (BRS) in 149 twin pairs (88 monozygotic of age 33±13 years and BMI 23±4 kg/m
2
and 61 dizygotic of age 33±11 years and BMI 24±4 kg/m
2
). ECG and finger arterial blood pressures were measured continuously under resting conditions. BRS values were calculated by use of cross-spectral analysis (baroreflex slope calculated as mean value of transfer function between systolic blood pressure and the R-R interval in the low-frequency band [BRSLF] and baroreflex slope calculated as the mean value of transfer function between systolic blood pressure and R-R interval in the respiratory frequency band [BRSHF]) and the sequence technique (BRS+, BRS-). Heritability (
h
2
) was estimated with a path-modeling approach. BRS values did not differ significantly between groups (monozygotic, BRSLF, 17±13; BRSHF, 21±18; BRS+, 19±16; and BRS-, 21±15, and dizygotic, BRSLF, 16±9; BRSHF, 20±14; BRS+, 18±10; and BRS-, 20±11 ms/mm Hg), and were significantly correlated (
P
<0.001). When variances and covariances for monozygotic and dizygotic twins were compared, significant correlations were found for BRS in monozygotic (range,
r
=0.38 to 0.48) but not in dizygotic twin pairs (
r
=-0.03 to 0.09). Thus, BRS is heritable; the variability can be explained by genetic influences (
P
<0.01;
h
2
range, 0.36 to 0.44). The genetic influence on BRS remained strong after correction for BMI and blood pressure. Therefore, BRS is strongly genetically determined, probably by different genes than are resting blood pressure and BMI.
Familial Factors of Blood Pressure and Adiposity Covariation
Authors: Livshits Gregory , Gerber Linda M.
Published: June 2012

In the present study, we used the maximum likelihood approach as implemented by variance analysis and attempted to quantify genetic and environmental components of variance in systolic (SBP) and diastolic (DBP) blood pressure in 514 individuals who belonged to a total of 135 nuclear families of Chuvasha, Russia, ethnic origin. The extent to which these interindividual differences depend on age, gender, body mass index (BMI) and other anthropometric measurements was investigated. Major findings include the following. (1) The variation in both SBP and DBP was significantly affected by genetic factors (h
2
SBP
=0.51±0.13, h
2
DBP
=0.20±0.09), shared household environment, and age. These effects were stronger with respect to SBP, which also showed significant gender differences in baseline values and rate of SBP increase with age. (2) Genetic and common household factors, as well as undetected residual effects, were not completely independent. The respective 3 facets of correlation between SBP and DBP were significant: 0.66±0.10, 0.76±0.11, and 0.55±0.14. (3) SBP and DBP each showed significant phenotypic correlations with BMI and anthropometric factors. These correlations had a substantial genetic component but were not equal for SBP and DBP. SBP showed the highest genetic correlation with arm circumference (r
G
=0.63), whereas for DBP, this was found with hip skinfold (r
G=
0.88). (4) Bivariate heritability estimates, as well as adjustment of BP measurements for BMI and selected anthropometrics, indicated that DBP likely does not have independent genetic heritability. The residual genetic variance of adjusted SBP remained significant, although substantially lower in comparison with the nonadjusted h
2
.
Effects of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Type 1 Receptor Antagonist in Deoxycorticosterone Acetate–Salt Hypertensive Mice Lacking
Ren-2 Gene
Authors: Peng Hongmei , Carretero Oscar A. , Alfie Marcos E. , Masura Julie A. , Rhaleb Nour-Eddine
Published: June 2012

We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate–salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2
). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the
Ren-1
gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg · kg
−
1
· d
−
1
) and an angiotensin type 1 (AT
1
) receptor antagonist (L-158809, 4 mg · kg
−
1
· d
−
1
) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128±2 mm Hg) compared with controls (109±2 mm Hg) (
P
<0.001), while plasma renin concentration was decreased by 97% (
P
<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (
P
<0.001). Urinary albumin (
P
<0.05) and proliferating cell nucleic antigen–positive cells in the tubules and interstitium of the renal cortex (
P
<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT
1
antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT
1
antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT
1
antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT
1
antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.
Endogenous Cyclic AMP-Adenosine Pathway Regulates Cardiac Fibroblast Growth
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Mi Zaichuan , Jackson Edwin K.
Published: June 2012

Abstract
—Our previous studies show that cardiac fibroblasts express the extracellular “cAMP-adenosine pathway,” that is, the generation of adenosine from extracelluar cAMP. The goal of this study was to assess whether activation of the cAMP-adenosine pathway by stimulation of endogenous cAMP synthesis regulates cardiac fibroblast growth. Cardiac fibroblasts in 3D cultures were used as the model system. Treatment of cardiac fibroblasts with forskolin, isoproterenol, or norepinephrine increased cAMP production and extracellular levels of adenosine, and these effects were prevented by inhibition of adenylyl cyclase (2′,5′-dideoxyadenosine). Treatment with forskolin, isoproterenol, or norepinephrine for 24 hours inhibited DNA synthesis (
3
H-thymidine incorporation), and this effect was enhanced by combined inhibition of adenosine deaminase (erythro-9-[2-hydroxy-3-nonyl] adenine) plus adenosine kinase (iodotubercidin). Inhibition of adenylyl cyclase or adenosine receptors (1,3-dipropyl-8-
p
-sulfophenylxanthine or KF17837) prevented the effects of forskolin, isoproterenol, and norepinephrine on DNA synthesis. Forskolin also inhibited protein synthesis (
3
H-leucine incorporation) and cell proliferation, and these effects were blocked by adenosine receptor antagonism. Treatment of cardiac fibroblasts with norepinephrine for >48 hours but not <48 hours increased DNA synthesis, protein synthesis, and cell number. However, blockade of adenylyl cyclase or antagonism of adenosine receptors caused norepinephrine to induce proliferation in <48 hours. Our findings indicate that the endogenous cAMP-adenosine pathway regulates cardiac fibroblast growth.
Activation of NF-κB in Tubular Epithelial Cells of Rats With Intense Proteinuria
Authors: Gómez-Garre Dulcenombre , Largo Raquel , Tejera Nuria , Fortes José , Manzarbeitia Félix , Egido Jesús
Published: June 2012

Abstract
—The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-κB (NF-κB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-κB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-κB at all time periods studied. By in situ Southwestern histochemistry, NF-κB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET
A
/ET
B
receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-κB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-κB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT
1
: losartan and AT
2
: PD-123,319) or ET-1 (ET
A
: BQ123 and ET
B
: IRL1038) inhibited significantly the BSA-induced NF-κB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-κB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.
Reduced Uterine Perfusion Pressure During Pregnancy in the Rat Is Associated With Increases in Arterial Pressure and Changes in Renal Nitric Oxide
Authors: Alexander Barbara T. , Kassab Salah E. , Miller M. Todd , Abram Sean R. , Reckelhoff Jane F. , Bennett William A. , Granger Joey P.
Published: June 2012

Abstract
—A reduction in nitric oxide (NO) synthesis has been suggested to play a role in pregnancy-induced hypertension. We have recently reported that normal pregnancy in the rat is associated with significant increases in whole-body NO production and renal protein expression of neuronal and inducible NO synthase. The purpose of this study was to determine whether whole-body and renal NO production is reduced in a rat model of pregnancy-induced hypertension produced by chronically reducing uterine perfusion pressure starting at day 14 of gestation. Chronic reductions in uterine perfusion pressure resulted in increases in arterial pressure of 20 to 25 mm Hg, decreases in renal plasma flow (<23%) and glomerular filtration rate (<40%), but no difference in urinary nitrite/nitrate excretion relative to control pregnant rats. In contrast, reductions in uterine perfusion pressure in virgin rats resulted in no significant effects on arterial pressure. Renal endothelial (<4%) and inducible (<11%) NO synthase protein expression did not decrease significantly in the chronically reduced uterine perfusion pressure rats relative to normal pregnant rats; however, significant reductions in neuronal NO synthase were observed (<30%). The results of this study indicate that the reduction in renal hemodynamics and the increase in arterial pressure observed in response to chronic decreases in uterine perfusion pressure in pregnant rats are associated with no change in whole-body NO production and a decrease in renal protein expression of neuronal NO synthase.
Mechanisms of Carvedilol Action in Human Congestive Heart Failure
Authors: Kaye David M. , Johnston Leonie , Vaddadi Gautam , Brunner-LaRocca Hanspeter , Jennings Garry L. , Esler Murray D.
Published: June 2012

Abstract
—The precise mechanism by which β-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, β2-adrenoceptor–mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17±1% to 28±3%;
P
<0.01) and left ventricular stroke work (87±13 to 119±21 g · m per beat;
P
<0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33±0.04 to 0.42±0.04;
P
=0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.