bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspirin and Urinary 11-Dehydrothromboxane B
2
in African American Stroke Patients
Authors: Bruno Askiel , McConnell Joseph P. , Mansbach, III Harry H. , Cohen Stanley N. , Tietjen Gretchen E. , Bang Nils U.
Published: July 2002

Background and Purpose

—

The aim of the study was to evaluate the relationship between daily aspirin use and urinary excretion of a stable thromboxane metabolite, 11-dehydrothromboxane B
2
(11-DTB2), in African American stroke patients.

Methods

—

Subjects were a subgroup of those screened for the African American Antiplatelet Stroke Prevention Study. Subjects were within 4 months of noncardioembolic ischemic stroke and were not being treated with anticoagulants. Antithrombotic therapy at the time of urine collection varied according to the practice patterns of various attending physicians who treated the patients during their acute strokes. 11-DTB2 was measured by enzyme immunoassay in random urine samples 1 to 4 months after the stroke.

Results

—

Eighty-seven of 92 patients enrolled were able to give a urine sample at the time of enrollment. There were 51 men and 36 women aged 36 to 87 (mean 62) years. On the basis of antithrombotic treatment before the sample collection, we divided patients into 4 groups: (1) 16 patients treated with no aspirin (no antithrombotic drugs [n=4] or ticlopidine [n=12]), (2) 21 patients treated with 81 to 325 mg aspirin per day (81 mg/d [n=2], 325 mg/d [n=19]), (3) 20 patients treated with 650 mg aspirin per day, and (4) 30 patients treated with 975 to 1300 mg aspirin per day (975 mg/d [n=2] and 1300 mg/d [n=28]). In patients taking daily aspirin at any dose, the median urinary 11-DTB2 was 783 pg/mg creatinine compared with 1386 pg/mg creatinine in patients not taking daily aspirin (
P
=0.01 by Wilcoxon rank sum test). In multivariate regression analysis, aspirin use remained significantly associated with lower urinary 11-DTB2 (
P
=0.008). There was no dose-response effect between the 3 aspirin dose groups and urinary 11-DTB2 (
P
=0.70).

Conclusions

—

In African American stroke patients, aspirin use is associated with significantly lower urinary 11-DTB2 independent of other vascular factors, and there does not appear to be a dose-response effect for aspirin doses of 325 to 1300 mg daily. The clinical significance of these finding remains to be determined.
Intracranial Venous Hemodynamics in Patients With Midline Dislocation Due to Postischemic Brain Edema
Authors: Stolz Erwin , Gerriets Tibo , Babacan Sait Seymen , Jauss Marek , Kraus Jörg , Kaps Manfred
Published: July 2002

Background and Purpose

—

Cerebral venous pressure is governed by intracranial pressure, cerebral perfusion pressure, and venous outflow resistance. Therefore, changes in venous flow velocities are to be expected because of changes in intracranial pressure and brain tissue dislocation in patients with ischemic stroke and space-occupying brain edema.

Methods

—

In 21 prospectively recruited patients with middle cerebral artery stroke and postischemic edema, flow velocities in the basal veins, the vein of Galen, the straight sinus, and the P2 segment of the posterior cerebral artery were recorded every 0.9±0.5 days during the first 5 days after symptom onset with the use of transcranial color-coded duplex sonography. The midline shift of the third ventricle was determined by B-mode imaging.

Results

—

We observed an initial increase of flow velocity in the basal vein ipsilateral to the lesion, followed by a significant decrease within 5 days after symptom onset and with increasing midline shift in patients with brain herniation. In the straight sinus, flow velocity showed a biphasic U-shaped response to increasing dislocation of the third ventricle, with an initial decrease followed by an increase in the course of mass movement (midline shift 1 to 1.5 cm). A steep increase of flow velocity in the vein of Galen took place with a midline shift >1.5 cm. In the survivors these changes could not be observed. Flow velocity in the P2 segment of the posterior cerebral artery followed a typical course in neither the fatal cases nor the survivors.

ConclusionsA

—

Monitoring of flow velocities in the basal cerebral veins and in the straight sinus can provide additional pathophysiological information in patients with space-occupying brain edema after acute stroke.
Ang II Accumulation in Rat Renal Endosomes During Ang II-Induced Hypertension
Authors: Zhuo Jia L. , Imig John D. , Hammond Timothy G. , Orengo Sheyla , Benes Edmund , Navar L. Gabriel
Published: July 2002

Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT
1
receptor–dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT
1
receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114±2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185±4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348±58 versus 119±16 fmol/mL) and 2-fold (399±39 versus 186±26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100±283 versus 71±12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88±22 versus 37±7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT
1A
receptor antibody binding in endosomal and intermicrovillar clefts of Ang II–infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119±3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215±19 fmol/g), endosomal (96±29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11±2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II–dependent hypertension via an AT
1
receptor–mediated process.
Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine
Authors: Omura Takashi , Yoshiyama Minoru , Yoshida Ken , Nakamura Yasuhiro , Kim Shokei , Iwao Hiroshi , Takeuchi Kazuhide , Yoshikawa Junichi
Published: July 2002

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 μmol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours,
P
<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of
3
H-phenylalanine (1.4-fold by ET and 1.5-fold by PE,
P
<0.01), cell size (2.3-fold and 2.5-fold,
P
<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold,
P
<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold,
P
<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of
3
H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
Proprotein Convertase PC5 Regulation by PDGF-BB Involves PI3-Kinase/p70
s6
-Kinase Activation in Vascular Smooth Muscle Cells
Authors: Stawowy Philipp , Blaschke Florian , Kilimnik Adam , Goetze Stephan , Kallisch Heike , Chrétien Michel , Marcinkiewicz Mieczyslaw , Fleck Eckart , Graf Kristof
Published: July 2002

We have recently demonstrated that furin, PC5, and PC7, members of the subtilisin/kexin-like mammalian proprotein convertases (PCs), are found in rodent aorta. These PCs have been identified to activate several growth factors, adhesion molecules and extracellular matrix compounds by endoproteolytic cleavage. In the present study, we investigated the regulation of PC5 in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Stimulation of rat aortic VSMCs with platelet-derived growth factor (PDGF)-BB (20 ng/mL), angiotensin II (Ang II, 1 μmol/L), or 10% fetal calf serum (FCS) for 48 hours increased DNA synthesis, as assessed by proliferating cell nuclear antigen (PCNA) immunoblotting. PC5 was strongly upregulated by PDGF-BB and 10% FCS (both 8-fold,
P
<0.05), whereas Ang II had no effect on PC5 protein levels compared with controls. The PCs furin and PC7, which display a comparable subcellular localization and cleavage activity, were found in VSMCs, but their levels did not increase following PDGF-BB, Ang II, or FCS stimulation. Time-course analysis revealed a rapid increase in PC5 levels after 30 minutes of PDGF-stimulation of VSMCs. PDGF-stimulated PC5 induction was inhibited by the PI3-kinase inhibitor wortmannin, and by rapamycin, an inhibitor of mTOR/p70
s6
-kinase (both
P
<0.05). In contrast, the mitogen-activated protein kinase (MAPK)-pathway inhibitor PD98059 did not inhibit PDGF-stimulated PC5 induction. Immunocytochemistry and in situ hybridization revealed low PC5 protein and mRNA levels in intact rat aorta in vivo. After balloon injury, PC5 protein and mRNA levels were strongly increased in proliferating PCNA-positive VSMCs. The present data demonstrate that PC5 is upregulated during proliferation of VSMCs in vivo and in vitro. We show that PDGF-induced PC5 expression is PI3-kinase/p70
s6
-kinase dependent. Thus, growth factors regulate the proprotein convertase PC5, which may play an important role during VSMC growth.
Thyrotropin-Releasing Hormone Decreases Leptin and Mediates the Leptin-Induced Pressor Effect
Authors: García Silvia I. , Landa María S. , Porto Patricia I. , Alvarez Azucena L. , Schuman Mariano , Finkielman Samuel , Pirola Carlos J.
Published: July 2002

Abstract—

Leptin, an adipocyte-released hormone, modifies food intake and energy expenditure regulating hypothalamic-pituitary-thyroid axis function. We previously reported that thyrotropin-releasing hormone (TRH) precursor gene overexpression induces hypertension in the normal rat and that spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In both models, intracerebroventricular antisense (AS) treatment against the TRH precursor produced a dose-dependent reduction of the increased diencephalic TRH content while normalizing high arterial blood pressure. In this article, we report that male Wistar rats that were made hypertensive by intracerebroventricular injection of a eucaryotic expression plasmid containing the pre-TRH cDNA showed decreased leptin plasma levels and that pre-TRH AS treatment reversed this phenomenon. In addition, male and female spontaneously hypertensive rats showed lower levels of circulating leptin than did sex-matched Wistar-Kyoto control rats. This difference also was abated by the pre-TRH AS treatment. Conversely, 20 μg ICV leptin induced a long-lasting pressor effect (18±5 mm Hg, n=6,

P

<0.01, >60 minutes) that was not observed in pre-TRH AS pretreated rats (2±3 mm Hg, n=6) but persisted in rats used as controls that were treated with inverted oligonucleotide (20±6 mm Hg, n=4,

P

<0.01). These data suggest that in rats with TRH-induced hypertension, leptin is decreased, inducing compensatory adiposity. We propose that because leptin produces central TRH synthesis and release, obesity may induce hypertension through TRH system activation and that the TRH-leptin interaction may thus contribute to the strong association between hypertension and obesity.
Obligatory Role of Protein Kinase Cβ and MARCKS in Vesicular Trafficking in Living Neurons
Authors: Yang Hong , Wang Xiangyu , Sumners Colin , Raizada Mohan K.
Published: July 2002

Neurotransmitter release from neurons involves both vesicular trafficking and subsequent fusion of synaptic vesicles with the plasma membrane. The mechanisms involving the formation and fusion of vesicles that allow the exocytotic release of transmitters are understood well. Little is known, however, about the signaling mechanism involved in the trafficking of vesicles along the neurites. In this study, we used real-time confocal microscopy to search for evidence that vesicular trafficking in neurons requires the activation of protein kinase Cβ (PKCβ) and the myristoylated alanine-rich C kinase substrate (MARCKS) signaling pathway. Dopamine-β-hydroxylase fused to green fluorescent protein has been used to trace vesicular movement. Angiotensin II, an established neuromodulatory hormone, stimulates translocation of green fluorescent protein-dopamine-β-hydroxylase vesicles from the cell body to neurites. This translocation was blocked by an antisense oligonucleotide to PKCβ and MARCKS. Stimulation of PKC by other means, such as phorbol-12-myristate-13-acetate or carbachol, also resulted in the redistribution of fluorescence in a manner similar to that observed for angiotensin II. These observations demonstrate that PKCβ-MARCKS signaling may be a general mechanism for the stimulation of vesicular trafficking in brain neurons.
α-Adducin 460Trp Allele Is Associated With Erythrocyte Na Transport Rate in North Sardinian Primary Hypertensives
Authors: Glorioso Nicola , Filigheddu Fabiana , Cusi Daniele , Troffa Chiara , Conti Milena , Natalizio Marcella , Argiolas Giuseppe , Barlassina Cristina , Bianchi Giuseppe
Published: July 2002

Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if α-adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V
max
were faster (
P
<0.0001), whereas intracellular Na concentration was lower (
P
<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp α-adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp α-adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients.
Expression of Human Angiotensinogen-Renin in Rat
Authors: Bartel Sabine , Hoch Brigitte , Vetter Donathe , Krause Ernst-Georg
Published: July 2002

In double transgenic rats (dTGR) harboring the human angiotensinogen (hAOGEN) and human renin (hREN) genes, we studied cardiac transcript levels of hypertrophy-related, Ca
2+
regulatory, and β-adrenoceptor–associated proteins. The contractile properties and the cellular signaling of isolated hearts exposed to (-)isoproterenol and/or angiotensin (Ang) I were evaluated. dTGR developed hypertension of 174.1±7.6 versus 109.6±2.0 mm Hg (
P
<0.05) in Sprague-Dawley rats and heart hypertrophy. In hearts of dTGR, the transcript levels of ANP, β-MHC, and α-MHC were altered (percentage versus Sprague-Dawley rats, 100%) by 304%, 178%, and 78%, respectively. Transcript levels of L-type Ca
2+
channel, Ca
2+
release channel, SERCA2a, phospholamban, G
i
- and G
s
-proteins were unchanged. Isolated hearts of dTGR indicated higher baseline contractility versus Sprague-Dawley rats. (-)Isoproterenol-modified contractility occurred in both groups; however, the extent (predrug value, 100%) was less in hearts of dTGR versus Sprague-Dawley rats (+dP/dt, 310±42% versus 534±63%;
P
<0.05). Interestingly, (-)isoproterenol shortened the relaxation time by ≈25% in both groups. This finding was reflected by a protein kinase A–related phospholamban phosphorylation. Ang I depressed the heart contractility but did not interact with the protein kinase A pathway. In conclusion, we have found that expression of the hAOGEN-hREN complex in dTGR elicited specific effects on transcripts of ANP and myofibrillar proteins. Although the β-adrenergically mediated relaxation was not impaired in the hypertrophied hearts, the extent of β-adrenergic inotropic responsiveness was reduced.
Neprilysin Inhibitors Potentiate Effects of Bradykinin on B2 Receptor
Authors: Deddish Peter A. , Marcic Branislav M. , Tan Fulong , Jackman Herbert L. , Chen Zhenlong , Erdös Ervin G.
Published: July 2002

Some beneficial effects of angiotensin-I–converting enzyme (ACE, kininase II) inhibitor therapy are attributed to enhancing the activity of bradykinin on its B
2
receptor. Independent of inhibition of bradykinin hydrolysis, ACE inhibitors enhance the action of bradykinin on its B
2
receptor by inducing crosstalk between ACE and the receptor. We investigated whether inhibitors of another kininase II-type enzyme, neprilysin (neutral endopeptidase 24.11; NEP), could augment bradykinin effects unrelated to blocking its breakdown using a NEP-resistant bradykinin analog as ligand. We used transfected Chinese hamster ovary (CHO) cells stably expressing human B
2
receptor and NEP (CHO/NEP-B
2
) or only B
2
(CHO/B
2
) as control and human pulmonary fibroblasts (IMR90), expressing B
2
, but more NEP than ACE. NEP inhibitor phosphoramidon (100 nmol/L), or omapatrilat, which inhibits both NEP and ACE, did not potentiate bradykinin in CHO/B
2
cells. In IMR90 cells, 10 nmol/L bradykinin elevated [Ca
2+
]
i
and desensitized the receptor. Adding either 100 nmol/L omapatrilat or phosphoramidon resensitized the receptor to the ligand, which was abolished by receptor blocker HOE 140. Arachidonic acid release by bradykinin from CHO/NEP-B
2
cells was also augmented by 100 nmol/L phosphoramidon or omapatrilat about 3-fold, and again, the inhibitors resensitized the desensitized B
2
receptor. The inhibitors did not potentiate bradykinin when soluble rNEP was added to the medium of CHO/B
2
cells. Similar to ACE, NEP inhibitors potentiated bradykinin independent of inhibiting inactivation. Consequently, omapatrilat could augment bradykinin effects on B
2
, when either ACE or NEP is expressed close to receptor on cell membrane.
Increased Renal Medullary Oxidative Stress Produces Hypertension
Authors: Makino Ayako , Skelton Meredith M. , Zou Ai-Ping , Roman Richard J. , Cowley Allen W.
Published: July 2002

The present study examined whether chronic increased oxidative stress within the medulla of the kidney lowers medullary blood flow and leads to hypertension. Optical fibers were implanted into the renal cortex and medulla of uninephrectomized Sprague-Dawley rats (Harlan Sprague-Dawley, Madison, Wis) for the daily measurement of blood flow to these regions using laser-Doppler flowmetry techniques, while arterial pressure was measured from an indwelling aortic catheter. A renal medullary interstitial catheter was implanted for the continuous delivery of the superoxide dismutase (SOD) inhibitor, diethyldithiocarbamic acid (DETC), at a dose of 7.5 mg/kg/d. Renal interstitial superoxide (O
2
−
) levels were determined by perfusing an O
2
−
sensitive fluorescent dye, dihydroethidium, through a microdialysis probe implanted into the medulla. Urine samples (24 hours) were collected for measurements of isoprostane excretion. The results indicate that medullary DETC infusions increased tissue O
2
−
concentrations in the renal medulla (93.4±22.3,n=8, saline and 867.3±260.2, n=8, DETC; fluorescence units) and increased urinary 8-isoprostane excretion (4.1±0.4 ng/d, n=9, saline and 8.8±1.6 ng/d, n=10, DETC). Mean arterial pressure increased 24 hours after the start of intrarenal DETC infusion and remained nearly 20 mm Hg above control pressure throughout the 5 days of medullary SOD inhibition. During chronic medullary DETC infusion, medullary blood flow was significantly reduced (42.7%), whereas cortical blood flow was unchanged. Intravenous infusion of the same dose of DETC produced no changes in renal medullary or cortical blood flow or arterial blood pressure. The present experiments indicate that an increase in superoxide concentration within the renal medulla selectively reduces medullary blood flow resulting in chronic hypertension.
Blood Pressure Variability and Organ Damage in a General Population
Authors: Sega Roberto , Corrao Giovanni , Bombelli Michele , Beltrame Luca , Facchetti Rita , Grassi Guido , Ferrario Marco , Mancia Giuseppe
Published: July 2002

In hypertensive patients, 24-hour blood pressure (BP) variability (V) shows a positive relationship with organ damage, organ damage progression, and cardiovascular morbidity. The clinical relevance of BPV in the population has never been investigated. In a sample of 3200 individuals, randomly selected from the general population of Monza (Milan, Italy), we evaluated BP by an automatic oscillometric device every 20 minutes for 24 hours and left ventricular mass index (LVMI) by echocardiography. In each subject, individual systolic and diastolic BP readings were averaged to obtain a 24-hour mean. Systolic BPV was obtained by calculating (1) the standard deviation of the 24-hour mean, which was taken as the overall BPV, (2) the cyclic components (Fourier spectral analysis) that in the population as a whole explained >95% of the overall BPV, and (3) the fraction of the overall BPV that in each subject was not accounted for by the 2 cyclic components, termed individual residual BPV. A similar procedure was used for diastolic BP and heart rate. Participation rate was 64.1%. Patients receiving antihypertensive therapy (n=403) were excluded from the analysis, which was therefore limited to 1648 participants. In the population as a whole, LVMI significantly related to 24-hour systolic and diastolic BP mean (β=0.40 and β=0.37, respectively,
P
<0.001 for both) but not to the 2 cyclic components that accounted for most of the BPV. On the other hand, the individual residual BPV (which accounts on average for about 50% of overall BPV) showed a significant positive relationship with LVMI (β =0.38 and β=0.88 for systolic and diastolic BP, respectively,
P
<0.05 and
P
<0.01). No relationship was found between LVMI and heart rate values. These findings provide evidence that there is a relationship between LVMI and 24-hour average BP values in the population. They also provide the first demonstration that in the population there is also a positive independent association between LVMI and BPV. This association, however, can be exclusively seen with the BPV component that has an erratic rather than a cyclic nature.
Effect of ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists on Endothelial NO Synthase Knockout Mice With Heart Failure
Authors: Liu Yun-He , Xu Jiang , Yang Xiao-Ping , Yang Fang , Shesely Edward , Carretero Oscar A.
Published: July 2002

The beneficial effects of ACE inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT
1
-ant) are reportedly mediated by NO in heart failure (HF). We hypothesized that in the absence of endothelial NO synthase (eNOS), (1) left ventricular (LV) dysfunction and myocardial remodeling would be more severe after myocardial infarction (MI), and (2) the cardioprotective effect of ACEi and AT
1
-ant would be diminished or absent in mice with HF after MI. eNOS knockout mice (eNOS−/−) and wild-type C57BL/6J (C57) mice (+/+) were subjected to MI by ligating the left coronary artery. One month after MI, each strain was treated with vehicle, ACEi (enalapril, 20 mg/kg per day), or AT
1
-ant (valsartan, 50 mg/kg per day) for 5 months. Echocardiography was performed, and systolic blood pressure was measured before MI and monthly thereafter. Interstitial collagen fraction and myocyte cross-sectional area were examined histologically. We found that (1) compared with C57 mice, eNOS−/− mice that underwent sham surgery had significantly increased systolic blood pressure (
P
<0.05) and increased LV mass both initially and at 1 to 3 months, although cardiac function and histological findings did not differ between strains; (2) the development of HF and myocardial remodeling were similar after MI in both strains; and (3) ACEi improved cardiac function and remodeling in C57 mice, as evidenced by increased LV ejection fraction (LVEF) and LV shortening fraction (LVSF) and decreased diastolic LV dimension, mass, myocyte cross-sectional area, and interstitial collagen fraction, but these benefits were absent or diminished in eNOS−/− mice (for C57 versus eNOS−/−: increase in LVEF after ACEi, 14.2±2% versus −4.9±2.5%, respectively [
P
<0.001]; increase in LVSF, 8.6±2.1% versus −7.2±2.8%, respectively [
P
<0.01]; and decrease in LV mass, −16.6±15 versus 73±23 mm
3
, respectively [
P
<0.01]). AT
1
-ant had benefits similar to those of ACEi, which were also absent or diminished in eNOS−/− mice (for C57 versus eNOS−/−: increase in LVEF after AT
1
-ant, 13.5±1.8% versus −9.8±3%, respectively [
P
<0.001]; increase in LVSF, 6.1±1.6% versus −3.8±3.1%, respectively [
P
<0.01]). Our data suggest that the absence of NO does not alter the development of HF after MI; however, it significantly decreases the cardioprotective effects of ACEi or AT
1
-ant.
Phospholipase D Contributes to Transmural Pressure Control of Prorenin Processing in Juxtaglomerular Cell
Authors: Hirota Nobuhisa , Ichihara Atsuhiro , Koura Yukako , Hayashi Matsuhiko , Saruta Takao
Published: July 2002

This study was designed to delineate the involvement of phospholipase C (PLC) and phospholipase D (PLD) in transmural pressure control of renin synthesis and secretion. Primary cultures of rat juxtaglomerular (JG) cells were applied to a transmural pressure-loading apparatus for 12 hours, and the renin secretion rate (RSR), active renin content (ARC), and total (active + inactive) renin content (TRC) were determined. Under control conditions (n=5), transmural pressure decreased RSR (78.1±3.0 and 64.6±4.4% for 0 or 40 mm Hg, respectively;
P
<0.05) and ARC (42.8±3.3 and 26.0±3.9 ng of angiotensin I per hour per million cells for 0 or 40 mm Hg, respectively;
P
<0.05) but did not have a significant effect on TRC (99.5±6.7 and 89.2±4.6 ng of angiotensin I per hour per million cells for 0 or 40 mm Hg, respectively). Treatment with PLC inhibitors, 2-nitro-4-carboxyphenyl-
N,N
-diphenyl-carbamate (200 μmol/L) and U73122 (10 μmol/L) did not alter RSR but prevented the RSR decrease with transmural pressure, whereas neither 2-nitro-4-carboxyphenyl-
N,N
-diphenyl-carbamate nor U73122 altered ARC, TRC, or the decrease in ARC with transmural pressure. Experiments were also performed using JG cells (n=5) treated with a PLD inhibitor, 4-(2-aminoethyl)-benzensulfonyl fluoride (AEBSF, 100 μmol/L). Treatment with AEBSF did not influence basal levels of RSR, ARC, and TRC or the RSR decrease with transmural pressure. However, AEBSF did inhibit the decrease in ARC with transmural pressure. These results indicate that transmural pressure inhibits renin secretion via PLC-dependent pathways and prevents conversion of inactive renin to active renin via PLD-dependent mechanisms in JG cells.
Vasopressin Increases Intracellular NO Concentration via Ca
2+
Signaling in Inner Medullary Collecting Duct
Authors: Mori Takefumi , Dickhout Jeffrey G. , Cowley Allen W.
Published: July 2002

The present study was designed to determine whether arginine vasopressin (AVP) stimulates NO production in the epithelial collecting duct cells of the inner medulla (IMCDs) and if this is mediated through Ca
2+
signaling. Thin tissue layers containing IMCDs were dissected from Sprague-Dawley rats. Intracellular Ca
2+
concentration ([Ca
2+
]
i
) and NO production were measured in IMCDs by a fluorescence imaging system with the use of fura 2-AM and the cell-permeable form of the NO-sensitive dye 4,5-diaminofluorescein (DAF-2), respectively. AVP (100 nmol/L) produced a rapid peak increase in [Ca
2+
]
i
of 320±70 nmol/L within a few seconds and a sustained increase of 120±62 nmol/L. The peak increase in [Ca
2+
]
i
was followed by a significant increase of NO production (34±7 U). This was similar to that produced by 20 μmol/L of the NO donor DETA-NONOate (42±11 U). The NO scavenger carboxy-PTIO (100 μmol/L) or depletion of [Ca
2+
]
i
by preincubation with 5 μmol/L of the Ca
2+
-ATPase inhibitor thapsigargin in Ca
2+
-free buffer abolished the NO response to AVP. We conclude that AVP mobilizes Ca
2+
to produce NO in IMCDs.
Intracellular Angiotensin II Stimulates Voltage-Operated Ca
2+
Channels in Arterial Myocytes
Authors: Eto Kimika , Ohya Yusuke , Nakamura Yoshito , Abe Isao , Iida Mitsuo
Published: July 2002

Although the presence of intracellular angiotensin II (Ang II) and of Ang II-binding sites has been reported, their roles in cell function have not been fully clarified. The purpose of the present study was to test the hypothesis that intracellular Ang II modifies voltage-operated Ca
2+
channels in vascular smooth muscle. Ca
2+
channel currents were recorded in guinea pig mesenteric arterial myocytes with the whole-cell patch-clamp method. Intracellular dialysis of Ang II increased the amplitudes of Ca
2+
channel current (133±9% of the control with 10 nmol/L Ang II, n=16). Concomitant dialysis of the Ang II type 1 receptor antagonist, CV-11974 (1 μmol/L, n=11), but not the bath application of this drug, suppressed this Ang II action. In contrast, the dialysis of the Ang II type 2 receptor antagonist, PD123319 (1 μmol/L, n=5), failed to affect the Ang II action. Dialysis of either a phospholipase C inhibitor (U-73122, 10 μmol/L, n=5) or protein kinase C inhibitors (calphostin C, 100 nmol/L, n=5; protein kinase C inhibitor peptide-[19-36], 1 μmol/L, n=5) suppressed the Ang II action. Dialysis of KT5720 (100 nmol/L, n=5), an inhibitor of cAMP-dependent protein kinase, did not affect the Ang II action. Intracellular dialysis of angiotensin I (10 nmol/L) enhanced Ca
2+
channel currents (13 3±8%, n=6), which were sensitive to intracellular enalaprilat (1 μmol/L, n=5) or CV-11974 (n=5). These results suggest that intracellular Ang II has a stimulating action on voltage-operated Ca
2+
channels in vascular smooth muscle, possibly through intracellular binding sites similar to the Ang II type 1 receptor, which are associated with phospholipase C and protein kinase C.
Aldosterone and
d
-Glucose Stimulate the Proliferation of Human Cardiac Myofibroblasts In Vitro
Authors: Neumann Susanne , Huse Klaus , Semrau Robert , Diegeler Anno , Gebhardt Rolf , Buniatian Gayane Hrachia , Scholz Gerhard H.
Published: July 2002

The renin-angiotensin-aldosterone-system appears to be involved in the development of cardiac fibrosis in rodents, characterized by nonepithelial cell proliferation and changes in the extracellular matrix. The aim of our study was to investigate the effect of high aldosterone concentrations on the proliferation of human cardiac interstitial cells in vitro. In addition, the effect of
d
-glucose as another risk factor for fibrosis, eg, in the diabetic heart, was investigated. Human cardiac myofibroblast cultures were established, and growth rates were measured by WST-1 assay in fetal calf serum-free Dulbecco’s modified Eagle’s medium (DMEM). Cells in culture showed a significant increase in number between 24 to 72 hours of cultivation under basal conditions (DMEM, 10% fetal calf serum). Aldosterone at high concentrations (10
−8
and 10
−7
mol/L) significantly (
P
<0.01) increased the proliferation of cultured cardiac myofibroblasts. Comparable effects were observed after incubation of the cells with high
d
-glucose concentrations (15 and 25 mmol/L,
P
<0.01). No additive growth stimulation was evident when the cells were incubated in medium containing both aldosterone and
d
-glucose. These results suggest a role for aldosterone and glucose in mediating the cardiac fibrosis through stimulation of myofibroblast growth in patients with dysregulated renin-angiotensin-aldosterone-system (especially hyperaldosteronism) and impaired glucose homeostasis.
Insulin Inhibits Acetylcholine Responses in Rat Isolated Mesenteric Arteries via a Non-Nitric Oxide Nonprostanoid Pathway
Authors: Kimura Masahiko , Jefferis Ann-Maree , Watanabe Hiroshi , Chin-Dusting Jaye
Published: July 2002

Hyperinsulinemia is a risk factor for hypertension and arteriosclerosis. The mechanism by which it contributes to disease progression is not known. The present study examines the effects of insulin on endothelium-derived relaxing factors. Segments of rat mesenteric arterioles and aorta were set up for isometric recordings. The effect of insulin (1 mU/mL) on acetylcholine responses was examined with and without nitro-
l
-arginine, indomethacin, KCl (40 mmol/L), and apamin+charybdotoxin. Incubation with insulin (maximum response to acetylcholine 90.9±8.7% versus 90.7±4.5% for before versus after insulin, respectively), nitro-
l
-arginine, indomethacin, or high K
+
alone had no effect on these responses in mesenteric arterioles. Apamin+charybdotoxin significantly blunted responses to acetylcholine. When coincubated with nitro-
l
-arginine but not with indomethacin or high K
+
, insulin blunted the maximum response to acetylcholine (from 84.8±8.2% to 40.7±10.2% for before versus after insulin, respectively;
P
<0.01). When coincubated with apamin+charybdotoxin, insulin had no further effect. Coadministration of indomethacin with nitro-
l
-arginine had no greater effect than did nitro-
l
-arginine alone. The addition of insulin, together with nitro-
l
-arginine and indomethacin, significantly decreased the maximal response to acetylcholine from 96.6±5.3% to 52.9±10.8% (
P
<0.01). In the aorta, nitro-
l
-arginine abolished acetylcholine responses. Coadministration with insulin had no further effect. We conclude that insulin attenuates acetylcholine responses mediated by endothelium-derived hyperpolarizing factor in small but not large arteries. This effect of insulin is apparent only when NO is blocked and may be important in the development of hypertension or arteriosclerosis when reduced NO function has been reported.
Development of Predictive Models for Long-Term Cardiovascular Risk Associated With Systolic and Diastolic Blood Pressure
Authors: Glynn Robert J. , L’Italien Gilbert J. , Sesso Howard D. , Jackson Elizabeth A. , Buring Julie E.
Published: July 2002

Most existing risk prediction models have not considered the joint contribution of systolic and diastolic blood pressure to cardiovascular risk, and some suggest that there are thresholds below which further reductions of blood pressure yield no additional benefit. We developed multivariate risk prediction models that quantify the risk associated with both systolic and diastolic blood pressure and that can be used to infer the benefits of antihypertensive therapy in populations. Two large clinical trial cohorts, the Physicians’ Health Study, composed of 22 071 males (mean age, 53.2 years; median follow-up, 13.0 years), and the Women’s Health Study, composed of 39 876 females (mean age, 53.8 years; median follow-up, 6.2 years), were used to develop gender-specific predictive models via Cox regression. End points included myocardial infarction, stroke, coronary artery bypass, angioplasty, and cardiovascular death. Risk reduction estimates were derived by computing reductions associated with incremental lowering of systolic and diastolic blood pressures. In both populations, lower levels of blood pressure predicted lower event rates, with no evidence of a plateau or a J-shaped curve. In males, both systolic and diastolic blood pressures were significantly associated with events (
P
<0.001), whereas in females, only systolic blood pressure (
P
<0.001) predicted outcome after multivariate adjustment. Correction for measurement error in blood pressure increased risk estimates by ≈50%. Differences in systolic blood pressure yielded greater relative risk reductions than did differences in diastolic blood pressure in a combined population of males and females. These predictive models may be useful for risk estimation associated with hypertension in similar populations and may also be used to infer the benefits of antihypertensive therapy.
Increased Sympathetic Activation in Idiopathic Orthostatic Intolerance
Authors: Jordan Jens , Shannon John R. , Diedrich Andre , Black Bonnie K. , Robertson David
Published: July 2002

Idiopathic orthostatic intolerance (OI) is characterized by adrenergic symptoms with standing. Changes in central sympathetic tone or in adrenoreceptor sensitivity could contribute to this syndrome. In OI patients and control subjects, we determined heart rate (HR) and systolic blood pressure (SBP) changes after incremental bolus doses of isoproterenol and phenylephrine before and during ganglionic blockade with trimethaphan. SBP decreased by 17±1.6 mm Hg in patients and 3.9±3.8 mm Hg in control subjects (
P
<0.01) with trimethaphan. Patients with a larger decrease (28±3.8 mm Hg, n=7) in SBP with trimethaphan had greater supine SBP and supine and upright plasma norepinephrine levels than did patients with a lesser decrease (3.0±3.0 mm Hg, n=7) in SBP. Supine and orthostatic HRs were similar for the groups. The majority of patients had a normal HR response to isoproterenol before and during ganglionic blockade. Phenylephrine increased SBP similarly in patients and control subjects before and during blockade. Sympathetic support is increased in a subgroup of OI patients. Hyperadrenergic and nonhyperadrenergic subgroups have similar degrees of orthostatic tachycardia. Our findings suggest that the hyperadrenergic features of OI cannot be completely explained by systemic hypersensitivity of postsynaptic α
1
- and β-adrenoreceptors but rather originates in enhanced sympathetic activation.
Relationship Between Muscle Sympathetic Nerve Activity and Diurnal Blood Pressure Profile
Authors: Narkiewicz Krzysztof , Winnicki Mikolaj , Schroeder Kathleen , Phillips Bradley G. , Kato Masahiko , Cwalina Elzbieta , Somers Virend K.
Published: July 2002

The physiological mechanisms mediating the variability and diurnal rhythm of blood pressure are unclear. We tested the hypothesis that resting sympathetic activity is linked to the variability characteristics and 24-hour profile of ambulatory blood pressure measurements. We evaluated the relationship between muscle sympathetic nerve activity (MSNA) and the level, variability, and nocturnal fall of ambulatory blood pressure in 69 normal men. Subjects were subdivided according to the tertiles of MSNA distributions. Mean 24-hour blood pressure was not significantly different across the 3 groups. Compared with subjects in the first tertile (lowest MSNA, <18 bursts/min), subjects in the third tertile (highest MSNA, >25 bursts/min) had significantly greater daytime blood pressure variability, whether expressed as absolute values (10.2±0.5 versus 8.1±0.4 mm Hg for systolic blood pressure and 9.4±0.4 versus 7.2±0.4 mm Hg for diastolic blood pressure;
P
<0.01 for both comparisons) or as variation coefficients (8.1±0.4% versus 6.6±0.3% for systolic blood pressure and 12.7±0.7% versus 10.1±0.6% for diastolic blood pressure;
P
<0.01 for both comparisons). Subjects in the third tertile also had a more striking absolute and percentage fall in systolic blood pressure from daytime to nighttime than subjects in the first tertile (17±2 versus 10±2 mm Hg,
P
=0.02, or 13±1% versus 8.2±1.4%,
P
=0.02). In conclusion, higher resting measurements of sympathetic traffic are associated with greater daytime blood pressure variability and a more marked nocturnal decline in blood pressure in normal subjects. These findings suggest that sympathetic neural mechanisms may contribute importantly to the regulation of blood pressure over the 24-hour period.
The Settlement of the United States from 1790 to 1990: Divergent Rates of Growth and the End of the Frontier
Authors: Otterstrom Samuel M. , Earle Carville
Published: July 2002

The timing of the American frontier's closing can be determined through an analysis of the patterns and rates of settlement growth in the United States—based on historical county boundaries, population data from U.S. censuses, and a minimum of two people per square mile to classify a region as settled. Trends in the settlement of the contiguous areas of the country indicate three periods of population settlement—1790 to 1840, 1840 to 1910, and 1910 to 1990. The first period of rapid frontier growth ended in 1840, and a second, more moderate, one ended in 1910, marking the final closure of the frontier.
Spatiotemporal Spike Encoding of a Continuous External Signal
Authors: Masuda Naoki , Aihara Kazuyuki
Published: July 2002

Interspike intervals of spikes emitted from an integrator neuron model of sensory neurons can encode input information represented as a continuous signal from a deterministic system. If a real brain uses spike timing as a means of information processing, other neurons receiving spatiotemporal spikes from such sensory neurons must also be capable of treating information included in deterministic interspike intervals. In this article, we examine functions of neurons modeling cortical neurons receiving spatiotemporal spikes from many sensory neurons. We show that such neuron models can encode stimulus information passed from the sensory model neurons in the form of interspike intervals. Each sensory neuron connected to the cortical neuron contributes equally to the information collection by the cortical neuron. Although the incident spike train to the cortical neuron is a superimposition of spike trains from many sensory neurons, it need not be decomposed into spike trains according to the input neurons. These results are also preserved for generalizations of sensory neurons such as a small amount of leak, noise, inhomogeneity in firing rates, or biases introduced in the phase distributions.
Attractor Reliability Reveals Deterministic Structure in Neuronal Spike Trains
Authors: Tiesinga P. H. E. , Fellous J.-M. , Sejnowski Terrence J.
Published: July 2002

When periodic current is injected into an integrate-and-fire model neuron, the voltage as a function of time converges from different initial conditions to an attractor that produces reproducible sequences of spikes. The attractor reliability is a measure of the stability of spike trains against intrinsic noise and is quantified here as the inverse of the number of distinct spike trains obtained in response to repeated presentations of the same stimulus. High reliability characterizes neurons that can support a spike-time code, unlike neurons with discharges forming a renewal process (such as a Poisson process). These two classes of responses cannot be distinguished using measures based on the spike-time histogram, but they can be identified by the attractor dynamics of spike trains, as shown here using a new method for calculating the attractor reliability.

We applied these methods to spike trains obtained from current injection into cortical neurons recorded in vitro. These spike trains did not form a renewal process and had a higher reliability compared to renewal-like processes with the same spike-time histogram.
Traveling Waves of Excitation in Neural Field Models: Equivalence of Rate Descriptions and Integrate-and-Fire Dynamics
Authors: Cremers Daniel , Herz Andreas V. M.
Published: July 2002

Field models provide an elegant mathematical framework to analyze large-scale patterns of neural activity. On the microscopic level, these models are usually based on either a firing-rate picture or integrate-andfire dynamics. This article shows that in spite of the large conceptual differences between the two types of dynamics, both generate closely related plane-wave solutions. Furthermore, for a large group of models, estimates about the network connectivity derived from the speed of these plane waves only marginally depend on the assumed class of microscopic dynamics. We derive quantitative results about this phenomenon and discuss consequences for the interpretation of experimental data.
Attentional Recruitment of Inter-Areal Recurrent Networks for Selective Gain Control
Authors: Hahnloser Richard H. R. , Douglas Rodney J. , Hepp Klaus
Published: July 2002

There is strong anatomical and physiological evidence that neurons with large receptive fields located in higher visual areas are recurrently connected to neurons with smaller receptive fields in lower areas. We have previously described a minimal neuronal network architecture in which top-down attentional signals to large receptive field neurons can bias and selectively read out the bottom-up sensory information to small receptive field neurons (Hahnloser, Douglas, Mahowald, & Hepp, 1999). Here we study an enhanced model, where the role of attention is to recruit specific inter-areal feedback loops (e.g., drive neurons above firing threshold). We first illustrate the operation of recruitment on a simple example of visual stimulus selection. In the subsequent analysis, we find that attentional recruitment operates by dynamical modulation of signal amplification and response multistability. In particular, we find that attentional stimulus selection necessitates increased recruitment when the stimulus to be selected is of small contrast and of small distance away from distractor stimuli. The selectability of a low-contrast stimulus is dependent on the gain of attentional effects; for example, low-contrast stimuli can be selected only when attention enhances neural responses. However, the dependence of attentional selection on stimulus-distractor distance is not contingent on whether attention enhances or suppresses responses. The computational implications of attentional recruitment are that cortical circuits can behave as winner-take-all mechanisms of variable strength and can achieve close to optimal signal discrimination in the presence of external noise.
Using Noise to Compute Error Surfaces in Connectionist Networks: A Novel Means of Reducing Catastrophic Forgetting
Authors: French Robert M. , Chater Nick
Published: July 2002

In error-driven distributed feedforward networks, new information typically interferes, sometimes severely, with previously learned information. We show how noise can be used to approximate the error surface of previously learned information. By combining this approximated error surface with the error surface associated with the new information to be learned, the network's retention of previously learned items can be improved and catastrophic interference significantly reduced. Further, we show that the noise-generated error surface is produced using only first-derivative information and without recourse to any explicit error information.