bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin Enhances Endothelial α
2
-Adrenergic Vasorelaxation by a Pertussis Toxin Mechanism
Authors: Lembo Giuseppe , Iaccarino Guido , Vecchione Carmine , Barbato Emanuele , Morisco Carmine , Monti Francesco , Parrella Lucia , Trimarco Bruno
Published: June 2012

Abstract
To investigate whether insulin effect on endothelium is related to a specific signal transduction pathway or reflects a more generalized action of the hormone, we studied in aortic rings of Wistar-Kyoto (WKY) rats the effects of the hormone on endothelium-dependent relaxations generated by acetylcholine, adenosine diphosphate, the selective α
2
-adrenergic agonist UK 14,304, and the calcium ionophore ionomycin. The responses were evaluated both in control conditions and after 30 minutes of exposure to three different levels of insulin (30, 100, and 500 μU/mL). Insulin failed to modify the phenylephrine aortic contractions and the relaxations induced by acetylcholine, adenosine diphosphate, and ionomycin. In contrast, both 100 and 500 μU/mL insulin were able to potentiate the UK 14,304–induced vasorelaxation (+96±19% and +91±12%, respectively). Pertussis toxin, which causes α
2
-adrenergic receptor G
i
uncoupling, reduced the α
2
-adrenergic vasorelaxation and prevented the insulin potentiation of the response to UK 14,304. Furthermore, in primary cultured aortic endothelial cells from WKY, we evaluated the conversion of [
3
H]arginine to [
3
H]citrulline in response to acetylcholine, ionomycin, and UK 14,304, both in control conditions and during insulin exposure. Again, insulin did not affect basal citrulline production or the increase induced by acetylcholine and ionomycin, whereas it potentiated the response to UK 14,304. Finally, in aortic rings of spontaneously hypertensive rats, insulin treatment (100 and 500 μU/mL) was unable to enhance the α
2
-adrenergic vasodilator response; in vascular endothelial cells from spontaneously hypertensive rats, insulin did not potentiate the increase in citrulline production evoked by UK 14,304. In conclusion, insulin selectively enhances α
2
-adrenergic endothelial vasorelaxation through a pertussis toxin–sensitive mechanism, by potentiating endothelial nitric oxide production. This vasorelaxant mechanism is altered in spontaneously hypertensive rats.
Analysis of the Effects of Candesartan in the Mesenteric Vascular Bed of the Cat
Authors: Champion Hunter C. , Kadowitz Philip J.
Published: June 2012

Abstract
The effects of the nonpeptide angiotensin II AT
1
receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 μg/kg IV. After administration of the AT
1
receptor antagonist in a dose of 3 μg/kg IV, the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT
1
receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, α,β-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT
2
receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose. These results indicate that candesartan is a potent, selective, long-acting AT
1
receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.
A Mouse View of Hypertension
Authors: Smithies Oliver
Published: June 2012

Abstract
Essential hypertension probably results from combinations of genetic variations, not necessarily the same in all afflicted persons, which individually may not cause sufficient deviation from normality to be significantly harmful.

Genes contributing to hypertension are being sought by analytic experiments aimed at identifying candidate genes associated or segregating with the phenotype in humans and animals and by synthetic experiments in which changes are made in candidate genes in animals and their effects on blood pressure are determined.

We have used gene targeting to vary the amounts of angiotensinogen and angiotensin-converting enzyme (ACE) synthesized from their genes (
Agt
and
Ace
). These “gene titration” experiments establish that changes in
Agt
gene expression cause changes in the blood pressures of mice. Surprisingly, quantitative changes in
Ace
gene expression over a threefold range do not affect blood pressures.

Computer simulations with a simple version of the renin-angiotensin system predict that changes in
Agt
function alter the steady state levels of both angiotensin I (Ang I) and angiotensin II (Ang II). In contrast, modest changes in
Ace
function alter Ang I levels considerably but scarcely affect Ang II levels. Simulations over the ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II levels will decrease only when Ang I levels have plateaued.

Comparisons of the computer simulations with our genetic experiments and with prior work of others using wide dose ranges of ACE inhibitor show a satisfactory agreement and help reconcile the apparent contradictions between the genetic and pharmacological experiments.
Pulse Pressure
Authors: Benetos Athanase , Safar Michel , Rudnichi Annie , Smulyan Harold , Richard Jacques-Lucien , Ducimetière Pierre , Guize Louis
Published: June 2012

Abstract
Studies on the usefulness of blood pressure as a prognostic factor in cardiovascular disease have more often involved investigations of the levels of diastolic or systolic blood pressure. However, blood pressure may be divided into two other components: steady (mean pressure) and pulsatile (pulse pressure). In this study, the relationship of pulse pressure to cardiovascular mortality was investigated in 19 083 men 40 to 69 years old who were undergoing a routine systematic health examination and were being followed up after a mean period of 19.5 years. Subjects were divided into four groups according to age (40 to 54 and 55 to 69 years) and mean arterial pressure (<107 and ≥107 mm Hg). Each group was further divided into four subgroups according to the pulse pressure level. A wide pulse pressure (evaluated according to the quartile group or as a continuous quantitative variable) was an independent and significant predictor of all-cause, total cardiovascular, and, especially, coronary mortality in all age and mean pressure groups. No significant association between pulse pressure and cerebrvascular mortality was observed. In conclusion, in a large population of men with a relatively low cardiovascular risk, a wide pulse pressure is a significant independent predictor of all-cause, cardiovascular, and, especially, coronary mortality.
Endothelin Converting Enzyme-1 Gene Expression in the Kidney of Spontaneously Hypertensive Rats
Authors: Disashi Tumba , Nonoguchi Hiroshi , Iwaoka Taisuke , Naomi Shojiro , Nakayama Yushi , Shimada Kohei , Tanzawa Kazuhiko , Tomita Kimio
Published: June 2012

Abstract
Abnormal renal handling of water and sodium is implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Alteration of renal endothelin-1 synthesis is also reported in SHR. Endothelin-1, a potent vasoconstrictor and regulator of sodium reabsorption in the nephron, has a pathophysiological potential in the development of hypertension. Because synthesis of bioactive endothelin-1 requires endothelin converting enzyme-1 (ECE-1), we investigated whether renal ECE-1 gene expression is altered in the kidney of SHR. Kidneys from both 4- and 12-week-old SHR and age-matched Wistar-Kyoto rats (WKY) were studied. ECE-1 mRNA in microdissected nephron segments was assessed by reverse transcription–competitive polymerase chain reaction, and ECE-1 protein level by Western blot. In 4-week-old SHR, ECE-1 mRNA was significantly increased in the proximal straight tubule, medullary thick ascending limb, cortical thick ascending limb, and inner medullary collecting duct. ECE-1 protein level was increased in both the outer and inner medulla. In 12-week-old SHR, ECE-1 gene expression was significantly increased in the proximal straight tubule, medullary thick ascending limb, and also in the glomeruli. Glomerular preproendothelin-1 mRNA expression was not different between the two strains at both 4 and 12 weeks. We conclude that high ECE-1 gene expression in the nephron, via increase of endothelin-1 synthesis, may promote sodium retention that contributes to the development and/or maintenance of hypertension in SHR.
Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade
Authors: Takemoto Masao , Egashira Kensuke , Tomita Hideharu , Usui Makoto , Okamoto Hiroshi , Kitabatake Akira , Shimokawa Hiroaki , Sueishi Katsuo , Takeshita Akira
Published: June 2012

Abstract
We have shown previously that angiotensin-converting enzyme (ACE) inhibitors prevent coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and hypertrophy) in rats induced by long-term inhibition of nitric oxide (NO) synthesis with oral administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME). ACE inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin. In this study, we aimed to determine the relative contribution of the latter two mechanisms to the beneficial effects of an ACE inhibitor on structural remodeling. First, we examined the effects of the ACE inhibitor temocapril and the angiotensin II AT
1
subtype receptor antagonist CS-866 on the structural remodeling induced by administering L-NAME for 8 weeks. Temocapril and CS-866 were equally effective in preventing remodeling. Second, we examined whether the effect of temocapril on the remodeling induced by L-NAME was reduced by the bradykinin receptor antagonist HOE140. The latter drug did not alter the beneficial effect of temocapril on remodeling. In conclusion, although species differences must be considered to apply our conclusion to clinical conditions, the present results suggest that the inhibition of angiotensin II activity, mediated via the AT
1
receptors, is responsible for the beneficial effects of an ACE inhibitor in our animal model of coronary vascular and myocardial remodeling induced by the long-term inhibition of NO synthesis.
Cyclic Strain–Induced Reactive Oxygen Species Involved in ICAM-1 Gene Induction in Endothelial Cells
Authors: Cheng Jing-Jy , Wung Being-Sun , Chao Yeun-Jen , Wang Danny Ling
Published: June 2012

Abstract
—Vascular endothelial cells (ECs) are constantly subjected to pressure-induced strain. We have previously demonstrated that strain can induce intercellular adhesion molecule-1 (ICAM-1) expression in ECs. The molecular mechanisms of gene induction by strain, however, remain unclear. Recent evidence suggests that intracellular reactive oxygen species (ROS) may act as second messengers. The potential role of ROS in strain-induced ICAM-1 expression was examined. ECs grown on a flexible membrane base were deformed with various sinusoidal negative pressures to produce an average strain of 12%. Cyclic strain induced an increase in intracellular ROS measured by fluorescent intensity of dichlorofluorescein formed after peroxidation. Maximal levels of ROS were seen after 30 minutes. Levels subsequently decreased but remained elevated compared with unstrained groups. Concomitantly, a sustained increase of H
2
O
2
decomposition activity was observed in strained ECs. Both ROS and H
2
O
2
decomposition activity returned to basal levels after removal of the strain. ECs treated with an antioxidant (
N
-acetylcysteine or catalase) inhibited strain-induced ROS generation and ICAM-1 mRNA levels followed by decreased ICAM-1 expression on EC surfaces. This inhibition may account for the reduced monocytic cell adhesion in antioxidant-treated ECs but not in strained controls. Our findings indicate that cyclic strain–induced monocyte adhesion to ECs is mediated, at least in part, by an increase of ICAM-1 gene expression via the elevation of ROS levels in strained ECs. Our results support the importance of intracellular ROS in the modulation of hemodynamic force–induced endothelial responses.
Inducible Nitric Oxide Synthase and Blood Pressure
Authors: Mattson David L. , Maeda Celso Y. , Bachman Timothy D. , Cowley Allen W.
Published: June 2012

Abstract
—In the present studies, the influence of inducible nitric oxide synthase (NOS) inhibition with aminoguanidine on renal function and blood pressure was examined in rats. Intravenous aminoguanidine infusion (60 mg · kg
−1
· hr
−1
) for 40 minutes to anesthetized Sprague-Dawley rats (n=7) resulted in no significant changes in mean arterial pressure or renal cortical blood flow, while medullary blood flow was slightly increased. Despite minimal effects on renal blood flow, urine flow was significantly decreased from 14.2±2.7 to 10.4±2.3 μL · min
−1
· g kidney wt
−1
during aminoguanidine infusion. To examine the possible effects of inducible NOS on blood pressure, aminoguanidine (10 mg · kg
−1
· h
−1
IV) was infused chronically into uninephrectomized rats maintained on a high salt (4.0% NaCl) diet. Mean arterial pressure significantly increased from 104±2 to 118±3 mm Hg after 6 days of aminoguanidine infusion (n=7) and returned to levels not different from those in the control group after 2 days of postcontrol infusion. Calcium-independent NOS activity in the renal medulla, a tissue that expresses inducible NOS in normal rats, was significantly decreased by 49% in the aminoguanidine-infused group (n=6) compared with that activity in the vehicle-infused control animals (n=6). In contrast, calcium-dependent NOS activity in the renal medulla was not significantly altered by aminoguanidine infusion, indicating specificity of aminoguanidine for inducible NOS in these experiments. In a final group of rats (n=5), oral
l
-arginine administration in drinking water (2% wt/vol) increased plasma arginine levels from 118±5 to 232±16 μmol/L and blocked the increase in arterial pressure after 6 days of aminoguanidine infusion. The present experiments provide evidence supporting a role for inducible NOS in the control of arterial pressure, possibly by renal tubular effects.
Nitric Oxide in Hypertension: Relationship With Renal Injury and Left Ventricular Hypertrophy
Authors: Raij Leopoldo
Published: June 2012

Hypertension is accompanied by architectural changes in the kidney, heart, and vessels that are often maladaptive and can eventually contribute to end-organ disease such as renal failure, heart failure, and coronary disease. Nitric oxide, an endogenous vasodilator and antithrombotic agent synthesized in the endothelium by a constitutive nitric oxide synthase, inhibits growth-related responses to injury in vascular cells. Specifically, in the presence of hypertension, nitric oxide may work in the kidney by inhibiting both mesangial cell hypertrophy and hyperplasia as well as synthesis of extracellular matrix and in the heart and systemic vessels by modulating smooth muscle cell hypertrophy and hyperplasia. The effects of nitric oxide are antagonistic of the effects of angiotensin II. Shear stress and cyclic strain, physical forces known to operate in hypertension, are accompanied by increases in endothelial nitric oxide synthase expression, nitric oxide synthase protein, and nitric oxide synthase activity in endothelial cells. Experimental studies using genetic models of hypertension show a variation in hypertension-modulated vascular nitric oxide synthase activity in different strains of rats. These studies suggest that upregulation of vascular nitric oxide synthase activity is a homeostatic adaptation to increased hemodynamic workload in hypertension and that this may help prevent end-organ damage. If these findings apply to humans, differences in end-organ disease seen in patients with similar degrees of hypertension may be due in part to genetic differences in vascular nitric oxide synthase activity in response to hypertension.
Cytochrome P-450 Metabolites Mediate Norepinephrine-Induced Mitogenic Signaling
Authors: Uddin Mohammed R. , Muthalif Mubarack M. , Karzoun Nour A. , Benter Ibrahim F. , Malik Kafait U.
Published: June 2012

Norepinephrine (NE) stimulates release of arachidonic acid (AA) from tissue lipids in blood vessels, which is metabolized via cyclooxygenase, lipoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to biologically active products. Moreover, NE and AA have been shown to stimulate proliferation of vascular smooth muscle cells (VSMCs) of rat aorta. The purpose of this study was to determine the possible contribution of AA and its metabolites to NE-induced mitogenesis in VSMCs of rat aorta and the underlying mechanism of their actions. NE (0.1 to 10 μmol/L) increased DNA synthesis as measured by [
3
H]thymidine incorporation in VSMCs, and this effect was attenuated by inhibitors of CYP-450 (17-octadecynoic acid, 5 μmol/L; 12-diabromododec-11-enoic acid, 10 μmol/L; and dibromo-dodecenyl-methylsulfimide, 10 μmol/L) and by the LO inhibitor (baicalein, 20 μmol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 μmol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to fimide, 10 μmol/L) and by the LO inhibitor (baicalein, 20 μmol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 μmol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to 0.5 μmol/L) and 12(S)-HETE, respectively, increased [
3
H]thymidine incorporation in VSMCs. Both NE and 20-HETE increased mitogen activated protein (MAP) kinase activity as measured by the in-gel kinase assay. The inhibitor of MAP kinase kinase, PD-98059 (50 μmol/L), attenuated NE as well as 20-HETE induced [
3
H]thymidine incorporation and MAP kinase activation in VSMCs. These data suggest that products of AA formed via CYP-450, most likely 20-HETE, and via LO mediate NE induced mitogenesis in VSMCs.
Stretch-Activated Channels in Arterial Smooth Muscle of Genetic Hypertensive Rats
Authors: Ohya Yusuke , Adachi Natsuko , Nakamura Yoshito , Setoguchi Motoko , Abe Isao , Fujishima Masatoshi
Published: June 2012

Electrical and contractile responses of small arteries to mechanical stress are reportedly enhanced in spontaneously hypertensive rats (SHR), compared with those in Wistar Kyoto rats (WKY). We have previously shown that stretch-activated cation channels exist in arterial smooth muscle membrane, of which opening causes Na
+
and Ca
2+
influx and membrane depolarization. We thus hypothesize that activation of stretch-activated channels is enhanced in arterial smooth muscle of SHR compared with WKY. To test this hypothesis, stretch-activated channels is enhanced in arterial smooth muscle cells of resistance mesenteric arteries from SHR and WKY (16 to 24 weeks of age). In the whole-cell recording, membrane stretch was applied by inflating the cell with positive pressure to the recording pipette. Cell-inflation evoked Gd
3+
-sensitive cation currents. This current appeared with less stretch stimulation and its amplitude was larger in SHR cells compared with WKY cells. In the cell-attached recording, suction to the recording pipette evoked single stretch-activated channel currents (conductance of 32 pS with 150 mmol/L Na
+
), which were blocked by Gd
3+
. Channels were activated with less negative pressure and their availability was greater in SHR cells than in WKY cells. Results suggest that the activation of stretch-activated channels is enhanced in smooth muscle of resistance arteries from SHR compared with WKY, which may contribute to the enhanced vascular responses to mechanical stress in SHR.
Protective Effect of Angiotensin II-Induced Increase in Nitric Oxide in the Renal Medullary Circulation
Authors: Zou Ai-Ping , Wu Feng , Cowley Allen W.
Published: June 2012

This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (Po
2
), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of Po
2
with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary Po
2
. N
ο
-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 μg/kg per minute, a dose that did not significantly alter basal levels of MBF or Po
2
. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary Po
2
by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 μg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.
Efficient Inhibition of the Development of Cardiac Remodeling by a Long-Acting Calcium Antagonist Amlodipine
Authors: Yamazaki Tsutomu , Komuro Issei , Zou Yunzeng , Kudoh Sumiyo , Shiojima Ichiro , Mizuno Takehiko , Hiroi Yukio , Nagai Ryozo , Yazaki Yoshio
Published: June 2012

Abstract—
The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of “fetal type” genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of β-myosin heavy chain, skeletal α-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively preveted cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.
Metabolism of Angiotensin-(1–7) by Angiotensin-Converting Enzyme
Authors: Chappell Mark C. , Pirro Nancy T. , Sykes Angela , Ferrario Carlos M.
Published: June 2012

Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1–7) [Ang-(1–7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1–7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1–7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1–7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of
125
I-Ang-(1–7). The primary product of
125
I-Ang-(1–7) metabolism was identified as Ang-(1–5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1–7) to the pentapeptide Ang-(1–5). The ACE inhibitors lisinopril and enalaprilat (1 μmol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1–5) and did not yield other metabolic products. Ang-(1–5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1–7) by ACE revealed a substrate affinity of 0.81 μmol/L and maximal velocity of 0.65 μmols min
−1
mg
−1
. The calculated turnover constant for the peptide was 1.8 sec
−1
with a catalytic efficiency (Kcat/Km) of 2200 sec
−1
mmol/L
−1
. These findings suggest that increased levels of Ang-(1–7) following ACE inhibition may due, in part, to decreased metabolism of the peptide.
Renal Nerves Promote Sodium Excretion in Angiotensin-Induced Hypertension
Authors: Lohmeier Thomas E. , Hildebrandt Drew A.
Published: June 2012

To determine whether the sympathetic nervous system contributes to the hypertension induced by pathophysiological increments in plasma angiotensin II (Ang II) concentration, we determined the neurally induced changes in renal excretory function during chronic intravenous infusion of Ang II. Studies were carried out in five conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from the denervated and innervated kidneys. After control measurements, Ang II was infused for 5 days at a rate of 4.8 pmol/kg per minute (5 ng/kg per minute); this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure (MAP) and for the ratio of denervated to innervated kidneys (DEN/INN) for urinary sodium, potassium, and creatinine excretion were 93±5 mm Hg, 1.17±0.09, 1.10±0.10, and 1.00±0.02, respectively. As expected, Ang II infusion caused sodium retention for several days before sodium balance was achieved at an elevated MAP (day 5=124±4 mm Hg). Moreover, by day 2 of Ang II-induced hypertension, there were significant reductions in the DEN/INN for sodium and potassium, which persisted for the 5 days of Ang II infusion; on day 5, the DEN/INN values for sodium and potassium were 0.71±0.10 and 0.91±0.12, respectively. In contrast, the DEN/INN for creatinine was unchanged from control levels during Ang II infusion, and measurements of renal hemodynamics indicated comparable reductions in glomerular filtration rate (≈13%) and renal plasma flow (≈25%) during Ang II infusion. This indicates that the renal nerves promoted sodium and potassium excretion during Ang II-induced hypertension by inhibiting tubular reabsorption of these electrolytes. Thus, this study provides no support for the hypothesis that increased renal sympathetic nerve activity impairs sodium excretion and contributes to Ang II-induced hypertension.
17β-Estradiol, Its Metabolites, and Progesterone Inhibit Cardiac Fibroblast Growth
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Jackson Edwin K. , Keller Paul J.
Published: June 2012

Postmenopausal women (PMW) have increased incidence of cardiovascular disease, and estrogen substitution therapy has been shown to have cardioprotective effects. Since abnormal growth of cardiac fibroblasts (CFs) is associated with hypertension and myocardial infarction and estrogen inhibits vascular smooth muscle cell (SMC) growth, it is feasible that estrogen may attenuate cardiac remodeling by inhibiting CF growth, and this possibility was investigated by using cultured CFs. 17β-Estradiol and progesterone, but not 17α-estradiol, estrone, or estriol, inhibited 2.5% FCS-induced proliferation (DNA synthesis and cell number) and collagen synthesis (
3
H-proline incorporation) in a concentration-dependent manner and to a similar extent in male and female CFs. Compared to 17β-estradiol, its metabolites 2-hydroxyestradiol and 2-methoxyestradiol were more potent in inhibiting FCS-induced DNA synthesis, collagen synthesis, and cell proliferation. The inhibitory effects of 17β-estradiol and its metabolites were enhanced in presence of progesterone and 4-hydroxytamoxifen (high-affinity estrogen receptor ligand). Moreover, like estrogens, the dietary phytoestrogens biochanin A and daidzein inhibited FCS-induced growth of CFs. In conclusion, 17β-estradiol, its metabolites, and progesterone inhibit CF growth in a gender independent fashion. Moreover, hormone replacement therapy using 17β-estradiol and progesterone may protect PMW against cardiovascular disease by inhibiting CF growth and cardiac remodeling; whereas estrogens that do not inhibit CF growth may be less effective in protecting PMW against cardiovascular disease. Finally, our studies provide evidence that phytoestrogens inhibit CF growth and may be clinically useful as a substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.
Current and Birth Weights Exert Independent Influences on Nocturnal Pressure-Natriuresis Relationships in Normotensive Children
Authors: Lurbe Empar , Redón Josep , Tacons Jose , Torró Isabel , Alvarez Vicente
Published: June 2012

The objective was to study the impact of birth weight on the relationship between ambulatory blood pressure and urinary sodium excretion in children and adolescents. The study included 134 healthy children (61 boys), all Caucasians, who were born at term after a normotensive pregnancy. For each subject, a 24-hour ambulatory blood pressure monitoring and a complete urine collection were simultaneously performed according to the protocols designed. Average ambulatory blood pressure (BP) and the urinary excretion rates for sodium, potassium, and creatinine were calculated separately for 24-hour, awake, and sleep periods defined by a mini-diary. The excretion rate of sodium during sleep time was positively correlated with ambulatory systolic BP; such a positive relationship was not found for waking hours. Consequently, the impact of birth weight on the relationship between blood pressure and the urinary sodium excretion rate was analyzed during sleeping hours. Stepwise multiple regression analysis shows that although current weight was the strongest predictor for the sodium excretion rate during sleep (
P
<.001), there was also an independent significant direct relationship for birth weight (
P
<.04) after controlling for age, sex, and the average of systolic BP during sleep. Adjusted for current weight, a significant difference in the regression slopes relating urinary sodium excretion rate and systolic BP during sleep exists between children in the lowest (<3.100 kg) and the highest tertiles (>3.500 kg) of birth weight (
P
<.02). Differences in sodium excretion rates, adjusted for current weight, between the two extreme tertiles of birth weight became significant at the highest systolic BP (
P
<.04). The children who had the lowest birth weight tended to excrete less sodium during sleep. The results of the present study show a blunted pressure natriuresis curve in children and adolescents with the lowest birth weight. Whether this abnormal renal sodium handling may be present as an initial or as an intermediate mechanism leading to higher BP values must be assessed in additional studies.
Gender Affects Renal Vasoconstrictor Response to Ang I and Ang II
Authors: Gandhi Sanjay K. , Gainer Jay , King Debbie , Brown Nancy J.
Published: June 2012

Abstract
—This study tested the hypothesis that gender affects the pressor and renal vasoconstrictor responses to angiotensin (Ang) I and Ang II in salt-replete normotensive subjects. Ang I and Ang II were infused in graded doses into 9 men and 8 women in a randomized, single-blind, crossover study. There were no differences between genders in baseline blood pressure, heart rate, sodium excretion, renal plasma flow, angiotensin-converting enzyme (ACE) genotype, ACE activity, plasma renin activity, aldosterone, or Ang II levels. Although pressor responses to Ang I and Ang II were similar in men and women, there was a negative relationship between the change in mean arterial pressure and the change in heart rate during Ang I and II infusion in women only. The half-time of the pressor response after discontinuation of Ang I but not Ang II infusion was greater in men than in women (9.5±2.2 versus 4.3±2.1 minutes,
P
<.05). This difference in duration did not result from gender differences in the metabolism of Ang I because Ang II levels measured during Ang I infusion were identical in men and women. In contrast, the renal vasoconstrictor response to Ang I and Ang II was significantly increased in women compared with that in men (Ang I, −243±31 versus −138±13 U/1.73 m
2
; Ang II, −233±25 versus −175±18 U/1.73 m
2
;
P
<.03). These data suggest an effect of gender on baroreflex reactivity during angiotensin infusion. Moreover, in the setting of similar Ang II concentrations, the dramatic difference in the renal vasoconstrictor responses to Ang I and Ang II between salt-replete men and salt-replete women suggests gender differences at a pharmacodynamic level.
Trapidil Inhibits Platelet-Derived Growth Factor–Stimulated Mitogen-Activated Protein Kinase Cascade
Authors: Hoshiya Makiko , Awazu Midori
Published: June 2012

Abstract
—Trapidil, an antiplatelet drug, has been shown to reduce restenosis after angioplasty. It exerts its action, at least in part, by inhibiting vascular smooth muscle cell proliferation, antagonizing platelet-derived growth factor (PDGF). We examined its site of action on PDGF cellular signaling. Exposure of cultured rat vascular smooth muscle cells to increasing concentrations of trapidil for 18 hours resulted in a dose-dependent reduction in PDGF-BB–stimulated [
3
H] thymidine incorporation. Trapidil (400 μg/mL) increased PDGF β-receptor protein by 28±8%, whereas PDGF-induced tyrosine phosphorylation of PDGF β-receptor remained unchanged. PDGF-induced tyrosine phosphorylation of phospholipase Cγ, the p85 regulatory subunit of phosphatidyl-inositol 3 kinase, Ras GTPase–activating protein, and an adaptor molecule Shc were also not altered. On the other hand, trapidil inhibited PDGF-stimulated mitogen-activated protein kinase (MAP kinase) activity by 35±7% at 10 minutes and by 32±10% at 6 hours. Activation of Raf-1, an upstream activator of MAP kinase, by PDGF was also attenuated by trapidil. Moreover, protein content of MAP kinase phosphatase-1, which inactivates MAP kinase, was elevated in trapidil-treated cells. These actions of trapidil may be mediated by cAMP. Thus, there was a 1.9-fold increase in cellular cAMP generation in trapidil-treated cells. The present results demonstrate that trapidil antagonizes PDGF-induced mitogenesis and MAP kinase activation in vascular smooth muscle cells, probably through cAMP.
Salidiuretic Action by Genistein in the Isolated, Perfused Rat Kidney
Authors: Giménez Ignacio , Martinez Rosa M. , Lou Manuel , Mayoral José A. , Garay Ricardo P. , Alda José O.
Published: June 2012

Abstract—
The urinary isoflavonoid genistein inhibits membrane Na-K-Cl cotransporters at similar concentrations as furosemide, but the significance of this action is unknown. Genistein was therefore investigated in rats for its potential salidiuretic actions. In the isolated, perfused rat kidney, genistein induced a maximal salidiuretic action similar to that of furosemide but was 3 to 5 times less potent than furosemide in terms of active doses (natriuresis EC
50
, 237±92 versus 56±20 μmol/L for genistein and furosemide, respectively). Genistein and furosemide had no additive salidiuretic actions. Genistein had no significant effect on glomerular filtration rate but was able to significantly reduce renal vascular resistance with respect to vehicle isolated perfused kidney. Indomethacin (10 μmol/L), a blocker of prostaglandin biosynthesis, reduced salidiuresis and renal vasorelaxation by genistein. Subcutaneous genistein (15 mg/kg) induced a statistically significant increase in diuresis and natriuresis with respect to vehicle during the first 6 hours of administration in rats. In conclusion, genistein compares well with furosemide in vitro for its salidiuretic profile and potency in the isolated perfused rat kidney and is also natriuretic by the subcutaneous route in the rat. Further studies are required to investigate potential natriuretic and perhaps hypotensive actions of dietary genistein.
Prognostic Value of Ambulatory Blood Pressure Monitoring in Refractory Hypertension
Authors: Redon Josep , Campos Carlos , Narciso Maria L. , Rodicio Jose L. , Pascual Jose M. , Ruilope Luis M.
Published: June 2012

Abstract
—The objective of this study was to establish whether ambulatory blood pressure offers a better estimate of cardiovascular risk than does its clinical blood pressure counterpart in refractory hypertension. This prospective study assessed the incidence of cardiovascular events over time during an average follow-up of 49 months (range, 6 to 96). Patients were referred to specialized hypertension clinics (86 essential hypertension patients who had diastolic blood pressure >100 mm Hg during antihypertensive treatment that included three or more antihypertensive drugs, one being a diuretic). Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed at the time of entrance. End-organ damage was monitored yearly, and the incidence of cardiovascular events was recorded. Patients were divided into tertiles of average diastolic blood pressure during activity according to the ABPM, with the lowest tertile <88 mm Hg (LT, n=29), the middle tertile 88 to 97 mm Hg (MT, n=29), and the highest tertile >97 mm Hg (HT, n=28). While significant differences in systolic and diastolic ambulatory blood pressures were observed among groups, no differences were observed at either the beginning or at the time of the last evaluation for office blood pressure. During the last evaluation, a progression in the end-organ damage score was observed for the HT group but not for the two other groups. Twenty-one of the patients had a new cardiovascular event; the incidence of events was significantly lower for the LT group (2.2 per 100 patient-years) than it was for the MT group (9.5 per 100 patient-years) or for the HT group (13.6 per 100 patient-years). The probability of event-free survival was also significantly different when comparing the LT group with the other two groups (LT versus MT log-rank,
P
<.04; LT versus HT log-rank,
P
<.006). The HT group was an independent risk factor for the incidence of cardiovascular events (relative risk, 6.20; 95% confidence interval, 1.38 to 28.1,
P
<.02). Higher values of ambulatory blood pressure result in a worse prognosis in patients with refractory hypertension, supporting the recommendation that ABPM is useful in stratifying the cardiovascular risk in patients with refractory hypertension.
Hypertension Is Related to Cognitive Impairment
Authors: Kilander Lena , Nyman Håkan , Boberg Merike , Hansson Lennart , Lithell Hans
Published: June 2012

Abstract
—Recent findings of a linkage between high blood pressure (BP) and later development of dementia have given new prospects on cerebral target-organ damage in hypertension and have added substance to the concept of “preventable senility.” The aim of this study was to analyze the impact of hypertension, circadian BP profile, and disturbed glucose metabolism on cognitive function. The study population consisted of 999 seventy-year-old men from a population-based cohort study in Uppsala, Sweden, followed with respect to cardiovascular risk factors since the age of 50 years. At the age of 70, 24-hour ambulatory BP was monitored together with measurements of insulin sensitivity, glucose tolerance, serum lipids, and lipoproteins. Cognitive function was assessed by the Mini-Mental State Examination and the Trail-Making Test. High diastolic BP at baseline predicted later impaired cognitive performance, even after excluding men with a previous stroke (n=70). Cross-sectional measurements at age 70 showed that high 24-hour BP, nondipping, insulin resistance, and diabetes all were related to low cognitive function. The relationships between hypertension and cognitive impairment were strongest in untreated men. These data from a general population of healthy elderly men indicate that hypertension and associated metabolic disturbances might be susceptibility factors for cognitive disorders. The findings add support to possibilities of intervention in early stages in cognitive decline, ie, before manifest dementia.
Low-Dose C-Type Natriuretic Peptide Does Not Affect Cardiac and Renal Function in Humans
Authors: Barletta Giuseppe , Lazzeri Chiara , Vecchiarino Sabrina , Del Bene Riccarda , Messeri Gianni , Dello Sbarba Antonio , Mannelli Massimo , La Villa Giorgio
Published: June 2012

Abstract
—In experimental animals, C-type natriuretic peptide (CNP) has vasodilating, hypotensive, and natriuretic activities. The role of circulating CNP in the overall regulation of cardiac and renal function in humans is less defined, in both health and disease. We measured cardiac volumes, diastolic and systolic functions, systemic (Doppler echocardiography) and renal hemodynamics, intrarenal sodium handling (lithium clearance method), plasma and urinary cGMP, plasma renin concentration, and plasma aldosterone level in six healthy volunteers (mean age, 33±3 years) receiving CNP (2 and 4 pmol/kg per minute for 1 hour each) in a single-blind, placebo-controlled, random-order, crossover study. During CNP infusion, plasma CNP increased from 1.17±0.23 to 41.52±4.61 pmol/L (ie, 4- to 10-fold higher levels than those observed in disease states) without affecting plasma and urinary cGMP, cardiac volumes, dynamics of left and right heart filling, cardiac output, arterial pressure, renal hemodynamics, intrarenal sodium handling, sodium excretion, or plasma levels of renin and aldosterone. The finding that increments in plasma CNP within the pathophysiological range have no effects on systemic hemodynamics, renal function, or the renin-angiotensin system do not support the hypothesis that CNP may act as a circulating hormone in humans.
Gene Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 and Type 2 in the Kidneys of Insulin-Dependent Diabetic Rats
Authors: Liu Yan-Jun , Nakagawa Yuichi , Ohzeki Takehiko
Published: June 2012

Abstract
—The presence of 11β-hydroxysteroid dehydrogenase (11β-HSD) activity in the kidney has been suggested to be important in the regulation of glucocorticoid-induced disorders of electrolyte balance and the control of blood pressure. To assess the possible effect of 11β-HSD isoforms in diabetes-related hypertension, we measured the mean systolic blood pressure and the 11β-HSD activity and mRNA levels for both 11β-HSD1 and 11β-HSD2 in the kidney of streptozotocin (STZ)-diabetic female rats. Three weeks after injection of STZ (65 mg/kg), the mean systolic blood pressure of diabetic rats was elevated 13.6% above that of normal rats (
P
<.01). The renal 11β-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats (
P
<.01). However, the treatment of rats with STZ did not decrease the levels of renal 11β-HSD1 activity and mRNA expression in diabetic rats. Insulin administered subcutaneously to diabetic rats for 2 weeks completely reversed the decrease in renal 11β-HSD2 activity and gene expression and prevented the elevation in blood pressure in the diabetic rat. These results indicate that alteration of renal 11β-HSD2 activity and gene expression may be primarily responsible for the changes in blood pressure of STZ-diabetic rats after early treatment with insulin.
Identification of Human Plasma Kallikrein Gene Polymorphisms and Evaluation of Their Role in End-Stage Renal Disease
Authors: Yu Hongrun , Bowden Donald W. , Spray Beverly J. , Rich Stephen S. , Freedman Barry I.
Published: June 2012

Abstract
—Kallikreins are serine proteases that release kinins from kininogens. Kinins, via their effects on cardiovascular and renal function, may be involved in the pathogenesis of hypertension and renal failure. Two groups of kallikreins exist, glandular or tissue kallikrein and plasma kallikrein. In this study, we examined the human plasma kallikrein gene KLK3 to determine whether it contributed to end-stage renal disease (ESRD) susceptibility. We identified two novel polymorphic sequences closely linked to the KLK3 gene, designated KLK3b and KLK3c (heterozygosities: 0.64 to 0.68 and 0.48 to 0.52, respectively). We mapped the KLK3 gene and the marker KLK3c to the long arm of human chromosome 4 between F11 and D4S426 using a radiation hybrid panel. The study population consisted of 142 sibling pairs concordant for ESRD from 121 African American families. The 142 sibling pairs were stratified into 78 pairs with hypertension- and chronic glomerulonephritis–associated ESRD and 64 with non–insulin-dependent diabetes mellitus–associated ESRD. Linkage analyses, using SIBPAL of SAGE, and exclusion analysis, using MAPMAKERS/SIBS, were performed. Linkage analysis of affected sibling pairs did not reveal any evidence of linkage of KLK3 to ESRD in all 142 sib-pairs or in the two stratified subsets. Exclusion analysis indicated that the KLK3 gene could be excluded from contributing to ESRD at a relative risk of 3 when the maximum log of the odds score of −2 was used as the criterion for exclusion. However, an association analysis using the relative predispositional effect technique showed that alleles 7 and 9 of KLK3b were consistently associated with ESRD. Alleles 7 and 9 were present in 11.2% and 10.8% of the 113 unrelated ESRD probands and in 6.6% and 6.6% of the 204 race-matched control subjects without renal disease (allele
P
=.0041 and .0016, respectively). Alleles 7 and 9 were also present in 13% and 10.4% of the proband’s first siblings (allele
P
=.00014 and .0087, respectively). The association of KLK3b alleles with ESRD raises the possibility that polymorphisms in KLK3 may play a role in ESRD susceptibility. The lack of linkage might reflect our relatively small family set.