bluuebunny/crossref_metadata_2025 huggingface dataset:
TRUST RISK AND CONTROL IN THE MANAGEMENT OF COLLABORATIVE TECHNOLOGY DEVELOPMENT
Authors: HOECHT ANDREAS , TROTT PAUL
Published: February 2003

The technology management literature has recently started to show more interest in trust as a precondition and facilitator for collaborative research and technology development (Das & Teng, 1998; Dodgson, 1993). This renewed interest in trust in the social sciences should inspire research interest in the benefits of collaborative research and development in the technology management literature. There is a danger, however, that the risks of such collaborations may be underestimated. This paper sets out to explore the relationship between risk, trust and control in relation to the risk of information leakage. We identify a strong link between successful cooperative learning, trust and risk as well as the autonomy of individuals working in collaborative projects. We concentrate on the risk of information leakage and analyse this risk and its relationship with trust, and legal and bureaucratic control mechanisms for different technology development strategies and activities, which we group along an "inward/outward-looking" axis. The more "outward-looking" the technology development strategy, the less effective the legal control instruments and the more important the "social" control mechanisms, such as reputation, become. At the same time, higher levels of mutual trust have to be developed.
DEVELOPMENT OF INNOVATIVE PRODUCTS USING KANO'S MODEL AND QUALITY FUNCTION DEPLOYMENT
Authors: TAN KAY CHUAN , XIE MIN , SHEN XIAO-XIANG
Published: February 2003

Quality and innovation are two main issues involved in product development. When faced with increasingly intense competition from both national and international competitors, organisations usually consider quality and innovation as sources of competitive advantage. Customer satisfaction can be met and exceeded by providing customers with innovative products of high quality. Focusing on the early phases of product development, this paper suggests the combined use of quality function deployment and Kano's model. A case example is presented by employing the proposed method in a World Wide Web page design process. Customer requirements on Web pages were clearly recognised and deeply analysed. Also, further technical features were identified for delivering attractive Web pages. The results from the case example support the proposed framework as a means of innovative product development and attractive quality creation.
RESEARCH ON THE DETERMINANTS OF TECHNOLOGICAL INNOVATION: A CONTINGENCY APPROACH
Authors: SOUITARIS VANGELIS
Published: February 2003

This paper examines different methodologies used in quantitative empirical studies attempting to identify the distinctive characteristics of innovative firms. Despite the research effort, the statistical analysis results are inconsistent. The reasons for this inconsistency were explored and can be attributed to (i) methodological differences in the studies, such as the varying definitions and measurements of innovation and (ii) different characteristics of firms targeted such as size, sector and geographical region. A portfolio model synthesising the various research results is developed, which is not meant to be universally applicable but instead can be used as a platform for country or industry specific studies. To illustrate the application of the proposed contingency approach, the author presents a comparative review of results from two recent studies using portfolio models in Iran and Greece.
Nitric Oxide Opposes Glucose-Induced Hypertension by Suppressing Sympathetic Activity
Authors: Claxton Christie R. , Brands Michael W.
Published: February 2003

We have reported that glucose infusion in L-NAME–treated rats increased arterial pressure more than the additive responses to glucose and L-NAME alone. This suggested that nitric oxide synthesis inhibition potentiated the hypertensive response to chronic glucose infusion, and the heart rate data suggested an important role for the sympathetic nervous system. This study tested the role of the sympathetic nervous system by infusing glucose for 7 days in 4 groups of rats: L-NAME (L), L-NAME plus α- and β-adrenergic receptor blockade (LB), vehicle, or vehicle plus adrenergic receptor blockade (blockers). Mean arterial pressure (MAP, 24 hours per day) increased significantly in both the vehicle and blockers groups, confirming our previous reports. Likewise, MAP increased significantly more during glucose infusion in the L rats, from 120±3 mm Hg to 158±4 mm Hg by day 7, which was >3 times the increase in the vehicle rats. Heart rate also increased significantly in the L rats, from 391±4 to 426±8 bpm, and that increase was prevented completely in the LB rats. However, although the increase in MAP in the LB rats was significantly less than in the L rats, the hypertension was not prevented completely. The explanation for that partial inhibition is not clear, but the overall effectiveness of adrenergic receptor blockade to attenuate the potentiated hypertensive and tachycardic responses to glucose infusion in the L-NAME–treated rats versus the normal rats suggests that nitric oxide may help protect against hypertension during glucose infusion through suppression of sympathetic activity.
Renal Sympathetic Nerve Responses to Tempol in Spontaneously Hypertensive Rats
Authors: Shokoji Takatomi , Nishiyama Akira , Fujisawa Yoshihide , Hitomi Hirofumi , Kiyomoto Hideyasu , Takahashi Norihiro , Kimura Shoji , Kohno Masakazu , Abe Youichi
Published: February 2003

Recent studies have implicated a contribution of oxidative stress to the development of hypertension. Studies were performed to determine the effects of the superoxide dismutase (SOD) mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-
N
-oxyl (Tempol) on vascular superoxide production and renal sympathetic nerve activity (RSNA) in anesthetized Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Compared with WKY rats (n=6), SHR showed a doubled vascular superoxide production, which was normalized by treatment with Tempol (3 mmol/L, n=7). In WKY rats (n=6), Tempol (30 mg/kg IV) significantly decreased mean arterial pressure (MAP) from 108±5 to 88±6 mm Hg and HR from 304±9 to 282±6 beats/min. In SHR (n=6), Tempol significantly decreased MAP from 166±4 to 123±9 mm Hg and HR from 380±7 to 329±12 beats/min. Furthermore, Tempol significantly decreased RSNA in both WKY rats and SHR. On the basis of group comparisons, the percentage decreases in MAP (−28±4%), HR (−16±3%) and integrated RSNA (−63±6%) in SHR were significantly greater than in WKY rats (−17±3%, −9±2%, and −30±4%, respectively). In SHR, changes in integrated RSNA were highly correlated with changes in MAP (r=0.85,
P
<0.0001) during administration of Tempol (3, 10, and 30 mg/kg IV). In both WKY rats and SHR (n=4, respectively), intracerebroventricular injection of Tempol (300 μg/1 μL) did not alter MAP, HR, or RSNA. Intravenous administration of a SOD inhibitor, diethyldithio-carbamic acid (30 mg/kg), significantly increased MAP, HR, and integrated RSNA in both WKY rats and SHR (n=6, respectively). These results suggest that augmented superoxide production contributes to the development of hypertension through activation of the sympathetic nervous system.
Wall Stiffness Suppresses Akt/eNOS and Cytoprotection in Pulse-Perfused Endothelium
Authors: Peng Xinqi , Haldar Saptarsi , Deshpande Shailesh , Irani Kaikobad , Kass David A.
Published: February 2003

Increased steady shear stress stimulates nitric oxide synthase (eNOS) in part by Akt-dependent phosphorylation. Arteries in vivo are exposed to pulse perfusion (PP) combining phasic shear with stretch. In compliant vessels, enhancing PP lowers vascular tone by stimulating eNOS; whereas in aged, stiff arteries, flow-mediated dilation declines and PP is a prominent risk factor. Here, we tested the hypothesis that reduced wall distensibility alters PP-induced eNOS/Akt mechano-signaling. Bovine aortic endothelial cells cultured within distensible tubes were exposed to physiological nonreversing steady or PP (7 dynes/cm
2
mean shear, pulse pressure 0 or 90 mm Hg×2 hours) in a custom servo-system. In compliant tubes, PP doubled Akt phosphorylation above nonpulsatile flow levels, whereas P-Akt declined to static levels from PP in stiffer tubes. eNOS phosphorylation (S-1179) similarly increased with PP in compliant tubes but was nearly undetectable with increased PP in stiffer tubes. After PP, brief exposure of cells to ultraviolet irradiation (oxidant stress) and subsequent culture revealed cytoprotection in compliant tubes but diffuse cytotoxicity and cell detachment in stiffer tubes. NOS inhibition by L-NAME converted compliant-tube post-UV behavior to that of stiffer tubes. These data provide novel evidence that wall compliance can directionally mediate endothelial Akt/eNOS phosphorylation and mechano-signaling. This may help explain increased vascular risks resulting from artery stiffening.
Renoprotection by ACE Inhibition or Aldosterone Blockade Is Blood Pressure–Dependent
Authors: Griffin Karen A. , Abu-Amarah Isam , Picken Maria , Bidani Anil K.
Published: February 2003

Renin-angiotensin-aldosterone system blockade has been shown to protect against renal damage in salt-supplemented, stroke-prone spontaneously hypertensive rats (SHRsp). Based on intermittent tail-cuff blood pressure (BP) measurements, it has been claimed that such protection is BP-independent and mediated by a blockade of the direct tissue-damaging effects of angiotensin and/or aldosterone. BP radiotelemetry was performed for 8 weeks in ≈10-week-old male SHRsp who received a standard diet and either tap water (n=10) or 1% NaCl to drink. Saline-drinking SHRsp were either left untreated (n=12), received enalapril (50 mg/L) in drinking fluid (n=9), or had subcutaneous implantation of time-release 200-mg pellets of aldactone (n=10). The average systolic BP (mean±SEM) during the final 3 weeks was significantly higher (
P
<0.05) in untreated saline-drinking (215±6 mm Hg) SHRsp but not aldactone-treated (198±4 mm Hg) or enalapril-treated treated SHRsp (173±1 mm Hg), as compared with tap water–drinking SHRsp (197±3 mm Hg). Histological renal damage scores at 8 weeks paralleled the BP in all groups, with an excellent correlation (
r
=0.8,
P
<0.001, n=41). Moreover, a renal damage score of >5 was only observed in SHRsp whose average systolic BP during the final 3 weeks exceeded 200 mm Hg, indicating a threshold relation with BP. These data show that protection by renin-angiotensin-aldosterone system blockade in this model is BP-dependent and mediated by preventing the severe increases in BP seen in untreated salt-supplemented SHRsp and further underscore the limitations of interpretations based on conventional tail-cuff BP measurements.
Adrenomedullin Overexpression to Inhibit Cuff-Induced Arterial Intimal Formation
Authors: Yamasaki Masao , Kawai Junsuke , Nakaoka Takashi , Ogita Teruhiko , Tojo Akihiro , Fujita Toshiro
Published: February 2003

Adrenomedullin (AM) inhibits vascular smooth muscle cell proliferation stimulated by fetal calf serum and platelet-derived growth factor in vitro. In this study, an adenovirus expressing AM (AxCAAM) was created to examine the in vivo action of AM. Femoral arteries of Wistar rats were wrapped with a silicone cuff and treated with adenovirus expressing
Escherichia coli
β-galactosidase (AxCALacZ) or AxCAAM. Immunoreactivity for endothelial nitric oxide synthase (eNOS) was reduced in the endothelium of cuff-injured arteries and was associated with increased local DNA synthesis. Consequently, the intimal formation measured by the intimal-to-medial ratio was significantly increased at 14 and 28 days after the cuff placement. AxCAAM-infected arteries increased the expression of eNOS in the endothelium and inducible NOS in the media and the adventitia. AxCAAM significantly decreased the intimal-to-medial ratio by 40% at 14 days and 51% at 28 days, whereas AxCALacZ showed no changes compared with cuff-injured control arteries. AM overexpression effectively limits intimal hyperplasia by reducing cell proliferation through a nitric oxide–dependent pathway of eNOS. Our findings suggest the possibility of a therapeutic use of the AM gene for the prevention of vascular proliferative disorders.
Overexpression of eNOS in RVLM Improves Impaired Baroreflex Control of Heart Rate in SHRSP
Authors: Kishi Takuya , Hirooka Yoshitaka , Kimura Yoshikuni , Sakai Koji , Ito Koji , Shimokawa Hiroaki , Takeshita Akira
Published: February 2003

We previously demonstrated that the overexpression of endothelial nitric oxide synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate (HR), and sympathetic nerve activity and that these effects are enhanced in stroke-prone spontaneously hypertensive rats (SHRSP). The aim of this study was to determine if an increase in NO production in the RVLM caused by the overexpression of eNOS improves the impaired baroreflex control of HR in SHRSP. We transfected adenovirus vectors encoding eNOS (AdeNOS) into the RVLM of SHRSP or Wistar-Kyoto rats (WKY). Mean arterial pressure and HR were measured by a radio-telemetry system in the conscious state. Reflex changes in HR were elicited by intravenous infusion of either phenylephrine, sodium nitroprusside, or hydralazine at day 7 after the gene transfer. The maximum gain of the baroreflex control of HR was significantly decreased in SHRSP compared with WKY. Overexpression of eNOS in the RVLM of SHRSP improved the impaired maximum gain of the baroreflex control of HR. After treatment with atropine, the maximum gain was still significantly greater in SHRSP in the AdeNOS-transfected group than in the nontransfected group, although it was decreased in both groups. In contrast, after treatment with metoprolol, the maximum gain did not differ between the two groups. These results indicate that an increase in NO production in the RVLM improves the impaired baroreflex control of HR in SHRSP and that these effects may have resulted from a cardiac sympathoinhibitory effect of NO in the RVLM of SHRSP.
Morning Blood Pressure Peak, QT Intervals, and Sympathetic Activity in Hypertensive Patients
Authors: Marfella Raffaele , Gualdiero Pasquale , Siniscalchi Mario , Carusone Caterina , Verza Mario , Marzano Salvatore , Esposito Katherine , Giugliano Dario
Published: February 2003

We investigated the relation between morning blood pressure (BP) variations, sympathetic activity, and QT intervals in 156 never-treated subjects with essential hypertension and different patterns of morning BP increase. The morning BP peak (MP) was defined as a rise in systolic BP ≥50 mm Hg and/or diastolic BP ≥22 mm Hg during early morning (6:00 to 10:00
am
) compared with mean BP during the night. Clinical characteristics of patients with morning BP peak (MP+, n= 69, morning systolic BP=+54±4, diastolic BP=+32±5 mm Hg) did not differ from patients without BP peak (MP−, n= 87, morning systolic BP=+24±5, diastolic BP=+19±3 mm Hg). The daytime (10:00
am
to 10:00
pm
) and the nighttime (10:00
pm
to 6:00
am
) BP profile did not differ between the two groups. During daytime and nighttime ECG monitoring, the corrected QT (QTc) interval, and QTc dispersion did not differ significantly between the two groups, whereas during the morning period the QT values were significantly broader in the MP+ group compared with the MP− group (
P
≤0.001). Morning LF/HF ratio was significantly higher in MP+ patients than in MP− patients (
P
≤0.02). Both systolic and diastolic morning BP, in combination with ratio LF/HF power, were significant predictors of QTc dispersion (adjusted
R
2
=0.59,
P
≤0.01) and QTc interval (adjusted
R
2
=0.41,
P
≤0.01), whereas inclusion of physical activity and echocardiographic parameters did not add explanatory information. The prolongation of cardiac repolarization times and morning sympathetic overactivity coexist in hypertensive patients with morning BP peaks, and they might contribute to raised cardiovascular risk in these patients.
Nephron Number, Renal Function, and Arterial Pressure in Aged GDNF Heterozygous Mice
Authors: Cullen-McEwen Luise A. , Kett Michelle M. , Dowling John , Anderson Warwick P. , Bertram John F.
Published: February 2003

The loss of one allele for glial cell line–derived neurotrophic factor (GDNF) results in ≈30% fewer but normal sized glomeruli in young mice. Low nephron number, inherited or acquired, has been linked to increased risk of development of hypertension and renal failure. This study examines whether GDNF heterozygous mice, with an inherent reduction in nephron number, demonstrate a deterioration in renal structure and function and rise in arterial pressure in later life. Fourteen-month-old male GDNF heterozygous (n=7) and wild-type (n=6) mice were anesthetized and prepared for measurement of mean arterial pressure, glomerular filtration rate (GFR), and renal blood flow. After measurement of renal function, kidneys were fixed for stereological determination of total glomerular number and mean glomerular volume. Mean arterial pressure was, on average, 18 mm Hg higher in GDNF heterozygous (98±4 mm Hg) than wild-type mice (80±2 mm Hg;
P
<0.01). However, GFR (0.656±0.054 versus 0.688±0.076 mL/min per g kidney wt) and renal blood flow (5.29±0.42 versus 4.70±0.34 mL/min per g kidney wt) were not different between groups. Fourteen-month-old GDNF heterozygous mice had ≈30% fewer glomeruli than wild-type mice (9206±934 versus 13440±1275;
P
<0.01) and significantly larger glomeruli (4.51±0.39 versus 3.72±0.63×10
−4
mm
3
;
P
<0.01). Thus, aged GDNF heterozygous mice maintained a normal GFR and renal blood flow despite reduced nephron numbers. The elevated arterial pressure, glomerular hypertrophy, and hyperfiltration demonstrated in the GDNF heterozygous mice at this age may indicate a compensatory mechanism whereby GFR is maintained in the presence of a reduced nephron endowment.
Peroxisome Proliferator–Activated Receptor-γ Coactivator-1 Gene Locus
Authors: Oberkofler Hannes , Hölzl Bertram , Esterbauer Harald , Xie Mingqiang , Iglseder Bernhard , Krempler Franz , Paulweber Bernhard , Patsch Wolfgang
Published: February 2003

Peroxisome proliferator–activated receptor-γ coactivator-1 (PPARGC1/PGC-1) is a transcriptional coactivator of nuclear hormone receptors implicated in blood pressure regulation. We therefore ascertained whether the
PPARGC1
gene locus is associated with hypertension. We studied associations of 3 polymorphisms in PPARGC1 transcripts with hypertension in 683 middle-aged men and 530 middle-aged women of a cross-sectional Austrian population. Hypertension was defined by average values of systolic or diastolic ambulatory blood pressure readings (taken between 7
am
and 10
pm
) above 140 and/or 90 and/or use of antihypertensive medication. Among the 3 polymorphic sites, genotype distributions associated with Gly482Ser differed by hypertension status in men (
P
=0.0038), but not in women. The less common Ser482 allele was associated with a modest, but significant, reduction in the prevalence of hypertension in men. The distribution of 3 loci haplotypes also differed in men with and without hypertension (
P
=0.015). Despite its moderate effect, but because of its high frequency (≈64%), the more common risk allele contributed to hypertension in 35% (95% CI 16% to 54%) of our male population. These results suggest, but do not prove, that PPARGC1 participates in blood pressure control, and sequence substitutions at its gene locus confer an increased risk of hypertension to a substantial proportion of men.
NOS3 Genotype–Dependent Correlation Between Blood Pressure and Physical Activity
Authors: Kimura Tomomi , Yokoyama Tetsuji , Matsumura Yasuhiro , Yoshiike Nobuo , Date Chigusa , Muramatsu Masaaki , Tanaka Heizo
Published: February 2003

Endothelium-dependent vasorelaxation plays an important role in reduction of blood pressure and is mediated through release of nitric oxide (NO), which is generated by constitutively expressed endothelial nitric oxide synthase (NOS3). Exercise also augments NO release and has been recommended for primary prevention and improvement of hypertension, but individual responses are highly variable. We therefore postulated that genetic polymorphisms of NOS3 might interact with physical activity level to differentially influence blood pressure level. We genotyped 832 healthy Japanese (mean age of 54.4±8.6 years, 372 men and 460 women) for a polymorphism of NOS3 in intron 4 (ecNOS4a/b), using the polymerase chain reaction method, and scored their habitual physical activity level by using the rate of energy expenditure per resting metabolic rate through an interview according to a semiquantitative assessment method. Only in the subjects who had the rarer
a
allele (
aa
+
ba
type), systolic blood pressure was found to be inversely correlated with physical activity level (
P
for linear trend=0.0496, for interaction=0.0071). Eventually, this polymorphism was significantly associated with the prevalence of systolic hypertension only in the subjects who were in the lowest tertile of physical activity level (OR=2.4, 95% CI, 1.1 to 5.6,
P
for interaction=0.0474). In the present study, we found a significant interaction between the genotype and physical activity level on systolic blood pressure. These results might allow a better understanding of the mechanism to improve hypertension by exercise and to thereby reduce the risk of cardiovascular disease.
Myocardial Ultrasonic Backscatter in Hypertension
Authors: Kozàkovà Michaela , Buralli Simona , Palombo Carlo , Bernini Giampaolo , Moretti Angelica , Favilla Stefania , Taddei Stefano , Salvetti Antonio
Published: February 2003

A disproportionate accumulation of fibrillar collagen is a characteristic feature of hypertensive heart disease, but the extent of myocardial fibrosis may differ in different models of hypertension. In experimental studies, aldosterone and endothelins emerge as important determinants of myocardial fibrosis. Changes in myocardial extracellular matrix and collagen deposition can be estimated noninvasively by analysis of the ultrasonic backscatter signal, which arises from tissue heterogeneity within the myocardium and describes myocardial texture. This study was designed to investigate the relations between myocardial integrated backscatter and circulating aldosterone and immunoreactive endothelin in human hypertension. The study population consisted of 56 subjects: 14 healthy normotensive volunteers and 42 hypertensive patients (14 with primary aldosteronism, 7 with renovascular hypertension, and 21 with essential hypertension). The patients with essential and secondary hypertension were matched for age, gender, body mass index, and blood pressure. Myocardial integrated backscatter at diastole was 19.8±2.0 and 20.8±2.9 decibels in normotensive control subjects and patients with essential hypertension and significantly higher in patients with primary aldosteronism (27.4±3.8 decibels,
P
<0.01) and renovascular hypertension (26.8±4.8 decibels,
P
<0.01). In the population as a whole, as well as in the hypertensive subpopulation, myocardial integrated backscatter was directly related to plasma aldosterone (
r
=0.73 and 0.71,
P
<0.01 for both) and immunoreactive endothelin (
r
=0.60 and 0.56,
P
<0.01 for both). The data of this study suggest that in human hypertension, circulating aldosterone and immunoreactive endothelin may induce alterations in left ventricular myocardial texture, possibly related to increased myocardial collagen content.
Effect of Sodium Intake on Sympathetic and Hemodynamic Response to Thermal Receptor Stimulation
Authors: DiBona Gerald F. , Jones Susan Y.
Published: February 2003

Low dietary sodium intake increases central nervous system angiotensin activity, which increases basal renal sympathetic nerve activity and shifts its arterial baroreflex control to a higher level of arterial pressure. This results in a higher level of renal sympathetic nerve activity for a given level of arterial pressure during low dietary sodium intake than during either normal or high dietary sodium intake, in which there is less central angiotensin activity. Peripheral thermal receptor stimulation overrides arterial baroreflex control and produces a pressor response, tachycardia, increased renal sympathetic nerve activity, and renal vasoconstriction. To test the hypothesis that increased central angiotensin activity would enhance the responses to peripheral thermal receptor stimulation, anesthetized normal rats in balance on low, normal, and high dietary sodium intake were subjected to acute peripheral thermal receptor stimulation. Low sodium rats had greater increases in renal sympathetic nerve activity, greater decreases in RBF, and greater increases in renal vascular resistance than high sodium rats. Responses of normal sodium rats were between those of low and high sodium rats. Arterial pressure and heart rate responses were not different among dietary groups. Spontaneously hypertensive rats, known to have increased central nervous system angiotensin activity, also had greater renal sympathoexcitatory and vasoconstrictor responses than normotensive Wistar-Kyoto rats. These results support the view that increased central nervous system angiotensin activity alters arterial baroreflex control of renal sympathetic nerve activity such that the renal sympathoexcitatory and vasoconstrictor responses to peripheral thermoreceptor stimulation are enhanced.
β
2
-Adrenergic Receptor Gene Polymorphism, Age, and Cardiovascular Phenotypes
Authors: Castellano Maurizio , Rossi Federica , Giacchè Mara , Perani Cristiano , Rivadossi Francesca , Muiesan Maria Lorenza , Salvetti Massimo , Beschi Marina , Rizzoni Damiano , Agabiti-Rosei Enrico
Published: February 2003

Previous studies suggest that variants of the β
2
-adrenergic receptor (ADRB2) may differently affect functional responses to adrenergic stimulation, thereby possibly modulating cardiovascular and metabolic phenotypes. We examined the hypothesis that G/R16 and Q/E27 polymorphism of ADRB2, or their haplotypes, may modulate blood pressure, cardiovascular structure, and function or metabolic cardiovascular risk factors in the general population. We examined a random sample of the general population (n=571; age, 35 to 64 years). Neither clinic nor 24-hour ambulatory blood pressure was significantly associated with ADRB2 genotypes in the overall population. Cardiac structure and function were also not influenced by ADRB2 polymorphism. After adjustment for potential confounders, association of the R16 allele with higher systolic blood pressure was observed in the subgroup of younger people (below age of 50 years). Haplotype analysis showed that higher blood pressure values were more specifically associated with the presence of R16-Q27. Younger people carrying the R16-Q27 haplotype also showed a trend toward lower heart rate, higher BMI, lower glycemia, and higher trygliceridemia, which is consistent with the hypothesis of a genetic predisposition to reduced cardiovascular and metabolic response to ADRB2 stimulation. This study does not provide evidence of a major role of ADRB2 gene variability in blood pressure modulation. However, association of ADRB2 polymorphism with cardiovascular and metabolic effects can be observed in younger subjects, before the development of age-related decline of ADRB2-mediated activity. Our study emphasizes the necessity of taking into account (patho)-physiological changes related to aging (in this case, decreased efficiency of ADRB2 signaling) when analyzing phenotypic effects of genetic variants.
Increased Systolic Performance With Diastolic Dysfunction in Adult Spontaneously Hypertensive Rats
Authors: Cingolani Oscar H. , Yang Xiao-Ping , Cavasin Maria A. , Carretero Oscar A.
Published: February 2003

Hypertensive heart disease is characterized by early development of hypertrophy and fibrosis that leads to heart failure (HF). HF develops in spontaneously hypertensive rats (SHR) after 18 months; however, it is not clear whether hypertrophy leads to altered cardiac performance at an earlier age in these rats. We studied cardiac performance in 10- to 11-month-old SHR and age-matched Wistar-Kyoto rats (WKY), using presssure-volume (PV) conductance catheter system to evaluate systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), +dP/dt, and its relation to end-diastolic volume (+dP/dt–EDV) and preload-adjusted maximal power (PWR
max
–EDV
2
) as well as the time constant of left ventricular pressure decay, tau (τ), as an index of relaxation. The slope of the end-diastolic pressure-volume relation (EDPVR) and the ex vivo PV relation, both indexes of stiffness, were also calculated for each heart, and the Doppler E/A ratio was determined. In addition, plasma samples were obtained to assess B-type natriuretic peptide levels (BNP). We found that PRSW was higher in SHR than in WKY (174.5±15.6 versus 92.6±18.9 mm Hg;
P
<0.01). +dP/dt and +dP/dt–EDV were also enhanced in SHR versus WKY (9125±662 versus 6633±392 mm Hg/sec,
P
<0.01, and 28.14±4.35 versus 12.7±2.8 mm Hg/s per μL,
P
<0.02). In addition, PWR-EDV
2
was elevated in SHR (7.3±1.5 versus 3.1±0.6 mW/μL
2
). τ was prolonged in SHR (14.5±1 ms versus 10.8±0.8 for WKY,
P
<0.02) and EDPVR was significantly greater in SHR than in WKY (0.01±0.005 versus 0.004±0.001,
P
<0.05). The ex vivo pressure-volume relation was also steeper for SHR and the E/A ratio was 2.53±0.15 for SHR versus 1.67±0.08 for WKY (
P
<0.02). BNP was 45±2.5 pg/mL for SHR and 33.3±1.8 pg/mL for WKY (
P
<0.02). Taken together, these data suggest that at 10 to 11 months of age, before HF develops, SHR have increased systolic performance accompanied by delayed relaxation and increased diastolic stiffness.
Antioxidant-Rich Diet Relieves Hypertension and Reduces Renal Immune Infiltration in Spontaneously Hypertensive Rats
Authors: Rodriguez-Iturbe Bernardo , Zhan Chang-De , Quiroz Yasmir , Sindhu Ram K. , Vaziri Nosratola D.
Published: February 2003

Previous studies have demonstrated that oxidative stress contributes to hypertension and treatments with either antioxidant or immunosuppressive/anti-inflammatory agents improve hypertension in spontaneously hypertensive rats (SHR). The present study was performed to determine if the antihypertensive effects of an antioxidant-rich diet are associated with reduction in the renal immune infiltration. Rats were divided into experimental groups (n=5 each) that were followed 7 months after birth, during which they were fed either a regular or antioxidant-enriched (test) diet as follows: SHR-R group=regular diet; SHR-T group=test diet throughout the experiment; SHR-S group=test diet for 4 months switched to regular diet thereafter; WKY group=control rats given regular diet. The SHR-T rats showed a significant reduction in systolic blood pressure (mm Hg): SHR-T=179.6±12.9 versus SHR-R=207.5±9.6 (
P
<0.001) and plasma hydrogen peroxide concentration (SHR-T=15±4 μmol/L versus 34±9 in SHR-R rats). This was accompanied by significant reductions of renal tissue nitrotyrosine abundance, tubulointerstitial infiltration (cells/mm
2
) of lymphocytes (SHR-T=18±3 versus SHR-R=30±4,
P
<0.001), macrophages (SHR-T= 17±3 versus SHR-R=22±3), and angiotensin II–positive cells (SHR-T= 17±2 versus SHR-R=25±5,
P
<0.01). Results in the SHR-S group were intermediate between the SHR-R and SHR-T groups. The intensity of the infiltration of lymphocytes, macrophages, and angiotensin II–positive cells significantly correlated with systolic blood pressure. Thus, the present study demonstrates that an antioxidant-enriched diet reduces the renal interstitial inflammation and improves hypertension in SHR. These findings point to interrelation between oxidative stress and inflammatory reactivity in the pathogenesis of hypertension.
Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E–Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression
Authors: van Royen N. , Hoefer I. , Böttinger M. , Hua J. , Grundmann S. , Voskuil M. , Bode C. , Schaper W. , Buschmann I. , Piek J.J.
Published: February 2003

Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E–deficient (apoE
−/−
) mice and whether it affects the systemic development of atherosclerosis. A total of 78 apoE
−/−
mice were treated with local infusion of low-dose MCP-1 (1 μg/kg per week), high-dose MCP-1 (10 μg/kg per week), or PBS as a control after unilateral ligation of the femoral artery. Collateral hindlimb flow, measured with fluorescent microspheres, significantly increased on a 1-week high-dose MCP-1 treatment (PBS 22.6±7.2%, MCP-1 31.3±10.3%;
P
<0.05). These effects were still present 2 months after the treatment (PBS 44.3±4.6%, MCP-1 56.5±10.4%;
P
<0.001). The increase in collateral flow was accompanied by an increase in the number of perivascular monocytes/macrophages on MCP-1 treatment. However, systemic CD11b expression by monocytes also increased, as did monocyte adhesion at the aortic endothelium and neointimal formation (intima/media ratio, 0.097±0.011 [PBS] versus 0.257±0.022 [MCP-1];
P
<0.0001). Moreover, Sudan IV staining revealed an increase in aortic atherosclerotic plaque surface (24.3±5.2% [PBS] versus 38.2±9.5% [MCP-1];
P
<0.01). Finally, a significant decrease in the percentage of smooth muscle cells was found in plaques (15.0±5.2% [PBS] versus 5.8±2.3% [MCP-1];
P
<0.001). In conclusion, local infusion of MCP-1 significantly increases collateral flow on femoral artery ligation in apoE
−/−
mice up to 2 months after the treatment. However, the local treatment did not preclude systemic effects on atherogenesis, leading to increased atherosclerotic plaque formation and changes in cellular content of plaques.
Compound Heterozygosity for Mutations (W156X and R225W) in
SCN5A
Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System
Authors: Bezzina Connie R. , Rook Martin B. , Groenewegen W.Antoinette , Herfst Lucas J. , van der Wal Allard C. , Lam Jan , Jongsma Habo J. , Wilde Arthur A.M. , Mannens Marcel M.A.M.
Published: February 2003

Cardiac conduction defects associate with mutations in
SCN5A
, the gene encoding the cardiac Na
+
channel. In the present study, we characterized a family in which the proband was born in severe distress with irregular wide complex tachycardia. His older sister died at 1 year of age from severe conduction disease with similarly widened QRS-complexes. Mutational analysis of
SCN5A
in the proband demonstrated compound heterozygosity for a nonsense mutation (W156X), inherited from the father, and a missense mutation (R225W), inherited from the mother. Genotyping on DNA extracted from tissue from the deceased sibling revealed the same
SCN5A
genotype. Injection of cRNA encoding the W156X mutation in
Xenopus
oocytes did not produce any current. The R225W substitution neutralizes the third Arg residue within the voltage-sensing segment of domain I. Expression studies showed that this mutation leads to a severe reduction in
I
Na
and is also associated with gating changes. Histological examination of the heart from the deceased sibling revealed changes consistent with a dilated type of cardiomyopathy and severe degenerative abnormalities of the specialized conduction system. The occurrence of compound heterozygosity for these two mutations implies that the proband carries solely severely dysfunctional cardiac Na
+
channels. This explains his severe phenotype and that of his deceased sister who had been a carrier of the same genotype. The morphological changes within the heart of the deceased sibling may have occurred secondary to the Na
+
channel abnormality and contributed to the severity of the disorder in this individual.
Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine
Authors: Ueda Seiji , Kato Seiya , Matsuoka Hidehiro , Kimoto Masumi , Okuda Seiya , Morimatsu Minoru , Imaizumi Tsutomu
Published: February 2003

In response to vascular insults, inflammatory cytokines stimulate vascular smooth muscle cells (SMCs) to express an inducible isoform of nitric oxide synthase (iNOS). Asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To determine whether the ADMA-DDAH system regulates cytokine-induced NO production, cultured rat SMCs were exposed to interleukin-1β (IL-1β). IL-1β (1 to 100 U/mL) dose-dependently stimulated not only iNOS but also DDAH expression and enzyme activity, accompanied by an increase in NO metabolite and by a decrease in ADMA content in culture media. A DDAH inhibitor (4124W, 5 mmol/L) augmented ADMA production (
P
<0.01) and decreased NO synthesis (
P
<0.01) in IL-1β–stimulated SMCs. On the other hand, an adenovirus-mediated overexpression of DDAH reduced ADMA and enhanced NO production. Exogenous administration of NO donors (SNAP and SIN-1) dose-dependently increased NO metabolite in the culture media but had no effect on ADMA. Our results indicate two mechanisms of IL-1β–induced NO synthesis: the direct stimulation of the expression of iNOS and the indirect stimulation of iNOS activity by upregulating DDAH and reducing ADMA. The ADMA-DDAH system may be another regulatory mechanism of inflammation-mediated NO production for human vascular diseases.
Load-Induced Transcriptional Activation of c-
jun
in Rat Myocardium
Authors: Nadruz Wilson , Kobarg Claudia B. , Constancio Sábata S. , Corat Patrícia D.C. , Franchini Kleber G.
Published: February 2003

The increased expression of immediate-early genes is a key feature of the myocardial response to hypertrophic stimuli. In this study, we investigated whether pressure overload or phenylephrine treatment stimulated myocyte enhancer factor 2 (MEF2)-dependent transcriptional activation of c-
jun
in cardiac myocytes. Western blotting and immunohistochemical analysis of rat myocardium demonstrated that p70
MEF2
is highly expressed in the rat heart and is predominantly located at the nuclei of cardiac myocytes. Electrophoretic mobility shift assays of myocardial nuclear extracts revealed a consistent DNA binding activation of MEF2 after 1 and 2 hours of pressure overload. We further showed that pressure overload induced a progressive nuclear translocation and activation of extracellular signal–regulated kinase 5 (ERK5). Coimmunoprecipitation and in vitro kinase assays indicated that the activation of ERK5 was paralleled by increased association of ERK5/p70
MEF2
and by enhanced ability of ERK5 to phosphorylate p70
MEF2
. Experiments with in vivo transfection of the left ventricle with the c-
jun
promoter reporter gene showed that pressure overload induced a consistent increase of c-
jun
transcriptional activity in the rat myocardium. Rendering the MEF2 site of the c-
jun
plasmid inactive by mutation abolished the load-induced activation of the c-
jun
promoter reporter gene. Mutation of the MEF2 site also abolished the phenylephrine-induced c-
jun
promoter activation in neonatal rat ventricular myocytes. In addition, we demonstrated that neonatal rat ventricular myocyte transfection with ERK5-antisense oligodeoxynucleotide inhibited the phenylephrine-induced c-
jun
promoter activation. These findings identify MEF2 as a potential regulator of c-
jun
transactivation and suggest that ERK5 might be an important mediator of MEF2 and c-
jun
promoter activation in response to hypertrophic stimuli in cardiac myocytes.
Myocyte Death, Growth, and Regeneration in Cardiac Hypertrophy and Failure
Authors: Nadal-Ginard Bernardo , Kajstura Jan , Leri Annarosa , Anversa Piero
Published: February 2003

The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number of myocytes from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult myocytes are terminally differentiated, there is a small and continuously renewed subpopulation of cycling myocytes produced by the differentiation of cardiac stem-like cells. Myocyte death and myocyte regeneration are introduced as major determinants of cardiac homeostasis and alterations of ventricular anatomy and function in physiological and pathological states. The possibility of reconstituting dead myocardium by stem-like cells is advanced and proposed as a major area of future research.
β-Adrenergic Receptor–Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH
2
-Terminal Kinase–Dependent Activation of the Mitochondrial Pathway
Authors: Remondino Andrea , Kwon Susan H. , Communal Catherine , Pimentel David R. , Sawyer Douglas B. , Singh Krishna , Colucci Wilson S.
Published: February 2003

Stimulation of β-adrenergic receptors (βARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating βAR-stimulated apoptosis is not known. Stimulation of βARs with norepinephrine (10 μmol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 μmol/L) and Euk-134 decreased βAR-stimulated apoptosis by 89±6% and 76±10%, respectively. Infection with an adenovirus expressing catalase decreased βAR-stimulated apoptosis by 82±15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 μmol/L) decreased βAR-stimulated apoptosis by 76±8%, and the caspase inhibitor zVAD-fmk (25 μmol/L) decreased βAR-stimulated apoptosis by 62±11%. βAR-stimulated cytochrome
c
release was inhibited by MnTMPyP. βAR stimulation caused c-Jun NH
2
-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited βAR-stimulated apoptosis by 81±12%, and the JNK inhibitor SP600125 inhibited both βAR-stimulated apoptosis and cytochrome
c
release. Thus, βAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
Onset of Cardiac Function During Early Mouse Embryogenesis Coincides With Entry of Primitive Erythroblasts Into the Embryo Proper
Authors: Ji Rui Ping , Phoon Colin K.L. , Aristizábal Orlando , McGrath Kathleen E. , Palis James , Turnbull Daniel H.
Published: February 2003

When cardiac function and blood flow are first established are fundamental questions in mammalian embryogenesis. The earliest erythroblasts arise in yolk sac blood islands and subsequently enter the embryo proper to initiate circulation. Embryos staged 0 to 30 somites (S) were examined in utero with 40- to 50-MHz ultrasound biomicroscopy (UBM)-Doppler, to determine onset of embryonic heartbeat and blood flow and to characterize basic physiology of the very early mouse embryonic circulation. A heartbeat was first detected at 5 S, and blood vascular flow at 7 S. Heart rate, peak arterial velocity, and velocity-time integral showed progressive increases that indicated a dramatically increasing cardiac output from even the earliest stages. In situ hybridization revealed an onset of the heartbeat coincident with the appearance of yolk sac–derived erythroblasts in the embryo proper at 5 S. Early maturation of the circulation follows a tightly coordinated program.
Visual Rating of Age-Related White Matter Changes on Magnetic Resonance Imaging
Authors: Kapeller P. , Barber R. , Vermeulen R.J. , Adèr H. , Scheltens P. , Freidl W. , Almkvist O. , Moretti M. , del Ser T. , Vaghfeldt P. , Enzinger C. , Barkhof F. , Inzitari D. , Erkinjunti T. , Schmidt R. , Fazekas F.
Published: February 2003

Background and Purpose—

To provide further insight into the MRI assessment of age-related white matter changes (ARWMCs) with visual rating scales, 3 raters with different levels of experience tested the interrater agreement and comparability of 3 widely used rating scales in a cross-sectional and follow-up setting. Furthermore, the correlation between visual ratings and quantitative volumetric measurement was assessed.

Methods—

Three raters from different sites using 3 established rating scales (Manolio, Fazekas and Schmidt, Scheltens) evaluated 74 baseline and follow-up scans from 5 European centers. One investigator also rated baseline scans in a set of 255 participants of the Austrian Stroke Prevention Study (ASPS) and measured the volume of ARWMCs.

Results—

The interrater agreement for the baseline investigation was fair to good for all scales (κ values, 0.59 to 0.78). On the follow-up scans, all 3 raters depicted significant ARWMC progression; however, the direct interrater agreement for this task was poor (κ, 0.19 to 0.39). Comparison of the interrater reliability between the 3 scales revealed a statistical significant difference between the scale of Manolio and that of Fazekas and Schmidt for the baseline investigation (
z
value, −2.9676;
P
=0.003), demonstrating better interrater agreement for the Fazekas and Schmidt scale. The rating results obtained with all 3 scales were highly correlated with each other (Spearman rank correlation, 0.712 to 0.806;
P
≤0.01), and there was significant agreement between all 3 visual rating scales and the quantitative volumetric measurement of ARWMC (Kendall
W
, 0.37, 0.48, and 0.57;
P
<0.001).

Conclusions—

Our data demonstrate that the 3 rating scales studied reflect the actual volume of ARWMCs well. The 2 scales that provide more detailed information on ARWMCs seemed preferential compared with the 1 that yields more global information. The visual assessment of ARWMC progression remains problematic and may require modifications or extensions of existing rating scales.
Racial Differences in Thoracic Aorta Atherosclerosis Among Ischemic Stroke Patients
Authors: Gupta Vishal , Nanda Navin C. , Yesilbursa Dilek , Huang Wen Ying , Gupta Vijaya , Li Qing , Gomez Camilo R.
Published: February 2003

Background and Purpose—

Atherosclerosis of the thoracic aorta is an independent risk factor for stroke. There is little information on the impact of race in the prevalence of thoracic aorta atherosclerotic plaques among ischemic stroke patients. This study was an attempt to objectively assess the prevalence, thickness, and burden of thoracic aorta atherosclerotic plaques in a large population of ischemic stroke patients and to compare the differences between American blacks and whites.

Methods—

This is a retrospective study of clinical data and transesophageal echocardiography (TEE) of 1553 ischemic stroke patients (664 blacks, 889 whites) over a period of 4.5 years. Atherosclerotic plaque prevalence, thickness, morphology, and burden (sum of maximum thickness in ascending aorta [AA], aortic arch [AO], and descending aorta [DA]) were assessed with TEE. Charts were reviewed for clinical information.

Results—

Age and sex were similar among blacks and whites. Analyses of clinical data found that blacks had significantly higher hypertension (odds ratio [OR], 2.61;
P
<0.0001) and diabetes mellitus (OR, 1.99;
P
<0.0001) and significantly lower coronary artery disease (OR, 0.75;
P
=0.017) and carotid artery disease (OR, 0.62;
P
=0.0008) compared with whites. TEE showed that whites had significantly greater plaque prevalence (AA: OR, 1.37;
P
=0.04; AO: OR, 1.26;
P
=0.03; DA: OR, 1.39;
P
=0.002) and plaque burden (blacks, 4.28 mm; whites, 4.97 mm;
P
=0.007). Whites also had a trend of increased complex plaques and plaques >4 mm thick in all regions of the thoracic aorta.

Conclusions—

Among ischemic stroke patients, blacks had a lower prevalence of extra cranial atherosclerotic disease even though they had significantly higher hypertension and diabetes mellitus compared with whites. This difference cannot be explained by the existing risk factors in ischemic stroke patients.