bluuebunny/crossref_metadata_2025 huggingface dataset:
Ischaemic Tolerance in Aged Mouse Myocardium: The Role of Adenosine and Effects of A1 Adenosine Receptor Overexpression
Authors: Headrick John P. , Willems Laura , Ashton Kevin J. , Holmgren Kirsten , Peart Jason , Matherne G. Paul
Published: April 2003

The genesis of the ischaemia intolerant phenotype in aged myocardium is poorly understood. We tested the hypothesis that impaired adenosine‐mediated protection contributes to ischaemic intolerance, and examined whether this is countered by A1 adenosine receptor (A1AR) overexpression. Responses to 20 min ischaemia and 45 min reperfusion were assessed in perfused hearts from young (2–4 months) and moderately aged (16–18 months) mice. Post‐ischaemic contractility was impaired by ageing with elevated ventricular diastolic (32 ± 2 vs. 18 ± 2 mmHg in young) and reduced developed (37 ± 3 vs. 83 ± 6 mmHg in young) pressures. Lactate dehydrogenase (LDH) loss was exaggerated (27 ± 2 vs. 16 ± 2 IU g−1in young) whereas the incidence of tachyarrhythmias was similar in young (15 ± 1 %) and aged hearts (16 ± 1 %). Functional analysis confirmed equipotent effects of 50 μm adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μm adenosine improved diastolic (5 ± 1 mmHg) and developed pressures (134 ± 7 mmHg) and LDH loss (6 ± 2 IU g−1) in young hearts, it did not alter these variables in the aged group. Adenosine did attenuate arrhythmogenesis for both ages (to ∼10 %). In contrast to adenosine, 50 μm diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti‐necrotic effects of adenosine were limited by 100 μm 5‐hydroxydecanoate (5‐HD) and 3 μm chelerythrine. Anti‐arrhythmic effects were limited by 5‐HD but not chelerythrine. Non‐selective (100 μm 8‐sulfophenyltheophylline) and A1‐selective (150 nm 8‐cyclopentyl‐1,3‐dipropylxanthine) adenosine receptor antagonism impaired ischaemic tolerance in young but not aged hearts. Quantitative real‐time PCR and radioligand analysis indicated that impaired protection is unrelated to changes in A1AR mRNA transcription, or receptor density (∼8 fmol mg−1 protein in both age groups). However, A1AR overexpression improved tolerance for both ages, restoring adenosine‐mediated protection. These data reveal impaired protection via exogenous and endogenous adenosine contributes to ischaemic intolerance with ageing. This is independent of A1AR expression, and involves ineffective activation of a 5‐HD‐/diazoxide‐sensitive process. The effects of A1AR overexpression indicate that the age‐related failure in signalling can be overcome.
Stimulation‐Induced Mitochondrial [Ca2+] Elevations in Mouse Motor Terminals: Comparison of Wild‐Type with SOD1‐G93A
Authors: Vila Lizette , Barrett Ellen F. , Barrett John N.
Published: April 2003

Changes in mitochondrial matrix [Ca2+] evoked by trains of action potentials were studied in levator auris longus motor terminals using Ca2+‐sensitive fluorescent indicator dyes (rhod‐2, rhod‐5F). During a 2500 impulse 50 Hz train, mitochondrial [Ca2+] in most wild‐type terminals increased within 5–10 s to a plateau level that was sustained until stimulation ended. This plateau was not due to dye saturation, but rather reflects a powerful buffering system within the mitochondrial matrix. The amplitude of this plateau was similar for stimulation frequencies in the range 15–100 Hz. Plateau amplitude was sensitive to temperature, with no detectable stimulation‐induced increase in fluorescence at temperatures below 17 °C, and increasing magnitudes as temperature was increased to near‐physiological levels (38 °C). When stimulation ended, mitochondrial [Ca2+] decayed slowly back to prestimulation levels over a time course of hundreds of seconds. Similar measurements were also made in motor terminals of mice expressing the G93A mutation of human superoxide dismutase 1 (SOD1‐G93A). In mice > 100 days old, all of whom exhibited hindlimb paralysis, some terminals continued to show wild‐type mitochondrial [Ca2+] responses, but in other terminals mitochondrial [Ca2+] did not plateau, but rather continued to increase throughout most of the stimulus train. Thus mechanism(s) that limit stimulation‐induced increases in mitochondrial [Ca2+] may be compromised in some SOD1‐G93A terminals.
The Respiratory Response to Carbon Dioxide in Humans with Unilateral and Bilateral Resections of the Carotid Bodies
Authors: Fatemian Marzieh , Nieuwenhuijs Diederik J. F. , Teppema Luc J. , Meinesz Sietske , van der Mey Andel G. L. , Dahan Albert , Robbins Peter A.
Published: April 2003

The acute hypercapnic ventilatory response (AHCVR) arises from both peripheral and central chemoreflexes. In humans, one technique for identifying the separate contributions of these chemoreflexes to AHCVR has been to associate the rapid component of AHCVR with the peripheral chemoreflex and the slow component with the central chemoreflex. Our first aim was to validate this technique further by determining whether a single slow component was sufficient to describe AHCVR in patients with bilateral carotid body resections (BR) for glomus cell tumours. Our second aim was to determine whether the slow component of AHCVR was diminished following carotid body resection as has been suggested by studies in experimental animals. Seven BR subjects were studied together with seven subjects with unilateral resections (UR) and seven healthy controls. A multifrequency binary sequence in end‐tidal PCO2 was employed to stimulate ventilation dynamically under conditions of both euoxia and mild hypoxia. Both two‐ and one‐compartment models of AHCVR were fitted to the data. For BR subjects, the two‐compartment model fitted significantly better on 1 out of 13 occasions compared with 22 out of 28 occasions for the other subjects. Average values for the chemoreflex sensitivity of the slow component of AHCVR differed significantly (P < 0.05) between the groups and were 0.95, 1.38 and 1.50 l min−1 Torr−1 for BR, UR and control subjects, respectively. We conclude that, without the peripheral chemoreflex, AHCVR is adequately described by a single slow component and that BR subjects have sensitivities for the slow component that are lower than those of control subjects.
Sustained Microtubule Treadmilling in
Arabidopsis
Cortical Arrays
Authors: Shaw Sidney L. , Kamyar Roheena , Ehrhardt David W.
Published: April 2003

Plant cells create highly structured microtubule arrays at the cell cortex without a central organizing center to anchor the microtubule ends. In vivo imaging of individual microtubules in
Arabidopsis
plants revealed that new microtubules are initiated at the cell cortex and exhibit dynamics at both ends. Polymerization-biased dynamic instability at one end and slow depolymerization at the other end result in sustained microtubule migration across the cell cortex by a hybrid treadmilling mechanism. This motility causes widespread microtubule repositioning and contributes to changes in array organization through microtubule reorientation and bundling.
Cardiac Sympathetic Nerve Stimulation Triggers Coronary t-PA Release
Authors: Björkman Jan-Arne , Jern Sverker , Jern Christina
Published: April 2003

Objective—

This study was undertaken to determine whether stimulation of sympathetic cardiac nerves induces release of the thrombolytic enzyme tissue-type plasminogen activator (t-PA) in the coronary vascular bed.

Methods and Results—

Anesthetized pigs were studied in an open chest model. Bilateral vagotomy was performed, and sympathetic cardiac nerves were activated by electrical stimulation (1 and 8 Hz). To evaluate possible mediating effects of increased heart rate and enhanced local blood flow, tachycardia was induced by pacing and hyperemia by local infusion of sodium nitroprusside and clevedipine. Furthermore, to study the effects of α- and β-adrenergic receptor stimulation, phenylephrine and isoprenaline were infused locally. In response to low- and high-frequency sympathetic stimulation, mean coronary net release of total t-PA increased approximately 6- and 25-fold, respectively. Active t-PA showed a similar response pattern. Neither tachycardia nor coronary hyperemia stimulated t-PA release. In contrast, β-adrenergic stimulation by isoprenaline induced an approximately 6-fold increase in coronary t-PA release, whereas no significant change in release rates occurred in response to α-adrenergic stimulation by phenylephrine.

Conclusions—

Stimulation of cardiac sympathetic nerves induces a marked coronary release of t-PA, and part of this response may be mediated through stimulation of β-adrenergic receptors.
Isoflavones Reduce Arterial Stiffness
Authors: Teede Helena J. , McGrath Barry P. , DeSilva Lakmini , Cehun Marja , Fassoulakis Andriana , Nestel Paul J.
Published: April 2003

Objective—

This study was undertaken to address the vascular effects of isolated isoflavones as potential contributors to their cardioprotective properties, focusing on biochanin and formononetin.

Methods and Results—

In a randomized, double-blind trial, 80 healthy subjects, 46 men and 34 women, 45 to 75 years of age, received isoflavones enriched in either biochanin or formononetin (precursors of genistein and daidzein; 80 mg/d) crossed over randomly with placebo in two 6-week periods. The end points were measured at baseline and after each intervention and included large artery stiffness (systemic arterial compliance and pulse wave velocity), endothelial function in conduit arteries (flow-mediated vasodilation), 24-hour ambulatory blood pressure, and total peripheral resistance. Isoflavone intervention significantly reduced arterial stiffness with improved systemic arterial compliance (
P
=0.04; repeated-measures ANOVA, Bonferroni correction) attributable to a reduction in total peripheral resistance (
P
=0.03) and a corresponding reduction in central pulse wave velocity (
P
=0.02) compared with placebo. Isoflavones did not affect blood pressure (
P
=0.5) or flow-mediated vasodilation (
P
=0.44). Improvements seemed limited to formononetin-enriched isoflavones (adjusted
P
=0.06). Formononetin treatment also reduced circulating vascular adhesion cell molecule-1 (
P
<0.01).

Conclusions—

In normotensive men and postmenopausal women, red clover isoflavones enriched in formononetin reduced arterial stiffness and total vascular resistance but had no effect on blood pressure. These effects may partly explain the lower cardiovascular risk in populations eating isoflavone-rich diets.
Endothelium-Dependent and -Independent Vascular Dysfunction in Type 1 Diabetes
Authors: Chan Norman Nor , Vallance Patrick , Colhoun Helen Martina
Published: April 2003

Objective—

Defective NO release/response may contribute to increased coronary risk and the loss of sex difference in coronary heart disease in diabetes. We aimed to determine whether NO release/response is impaired in type 1 diabetes and whether any defects are greater in women than men.

Methods and Results—

Forearm blood flow response to vasoactive drugs was assessed by venous plethysmography in 88 diabetic and 69 control subjects aged 30 to 53 years. In diabetic patients, response was 18% lower for acetylcholine (ACh) (
P
=0.002), 6% lower for bradykinin (
P
=0.14), and 17% lower for glyceryl trinitrate (GTN) (
P
<0.001). Women had a higher response to ACh than men (17%,
P
=0.006). The diabetes-associated defect in ACh was greater in women (25% lower,
P
=0.01) than men (13% lower,
P
=0.08), although not significantly (
P
=0.26 for the interaction). Poorer glycemic control was associated with ACh response (
P
=0.003) and contributed to the greater defect in diabetic women than men.

Conclusions—

The diabetes-associated defect in GTN response was similar in men and women. Established coronary heart disease risk factors did not explain any of the defects in ACh or GTN response associated with diabetes. Type 1 diabetes is associated with impaired responsiveness to NO and with an impairment in ACh-stimulated NO release.
Alterations of Arterial Physiology in Osteopontin-Null Mice
Authors: Myers Daniel L. , Harmon Kelley J. , Lindner Volkhard , Liaw Lucy
Published: April 2003

Objective—In this study, we characterized the effects of an osteopontin (OPN)-null mutation in normal arterial function and remodeling in a murine model.

Methods and Results—OPN-null mutant mice were compared with wild-type mice before and after carotid artery ligation. Before ligation, OPN-null mice had increased heart rate, lower blood pressure, and increased circulating lymphocytes compared with wild-type mice. OPN-null vessels also demonstrated greater compliance accompanied by a loosely organized collagen network. After carotid artery ligation, significant differences were also found in the remodeling response of OPN-null animals. At 4 days after ligation, leukocyte adhesion/invasion was diminished by 10-fold in OPN-null mice compared with wild-type mice. At 14 days after ligation, the ligated arteries of OPN-null mice had smaller neointimal lesions but greater constrictive remodeling compared with wild-type mice, resulting in similar lumen areas. Continued remodeling resulted in a similar morphological phenotype in both groups at 28 days.

Conclusions—These data show that endogenous OPN regulates normal vascular physiology and contributes to the vascular remodeling response by regulating vascular compliance and the inflammatory response.
Endothelial Progenitor Cells
Authors: Hristov Mihail , Erl Wolfgang , Weber Peter C.
Published: April 2003

Postnatal bone marrow contains a subtype of progenitor cells that have the capacity to migrate to the peripheral circulation and to differentiate into mature endothelial cells. Therefore, these cells have been termed endothelial progenitor cells (EPCs). The isolation of EPCs by adherence culture or magnetic microbeads has been described. In general, EPCs are characterized by the expression of 3 markers, CD133, CD34, and the vascular endothelial growth factor receptor-2. During differentiation, EPCs obviously lose CD133 and start to express CD31, vascular endothelial cadherin, and von Willebrand factor. EPCs seem to participate in endothelial repair and neovascularization of ischemic organs. Clinical studies using EPCs for neovascularization have just been started; however, the mechanisms stimulating or inhibiting the differentiation of EPC in vivo and the signals causing their migration and homing to sites of injured endothelium or extravascular tissue are largely unknown at present. Thus, future studies will help to explore areas of potential basic research and clinical application of EPCs.
Selective Involvement of p130Cas/Crk/Pyk2/c-Src in Endothelin-1-Induced JNK Activation
Authors: Kodama Hiroaki , Fukuda Keiichi , Takahashi Eiichi , Tahara Satoko , Tomita Yuichi , Ieda Masaki , Kimura Kensuke , Owada Koji M. , Vuori Kristiina , Ogawa Satoshi
Published: April 2003

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca
2+
-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH
2
-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca
2+
([Ca
2+
]
i
) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasΔSD), Crk (CrkSH2m), Pyk2 (PKM), or
C
-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-
jun
promoter luciferase activity was inhibited by overexpression of CasΔSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-
fos
gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.
Genetic Variants of
WNK4
in Whites and African Americans With Hypertension
Authors: Erlich Porat M. , Cui Jing , Chazaro Irmarie , Farrer Lindsay A. , Baldwin Clinton T. , Gavras Haralambos , DeStefano Anita L.
Published: April 2003

Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the
WNK4
gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of
WNK4
in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%,
P
=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (
P
=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (
P
=0.027) or without (
P
=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for
AA
or
AG
individuals vs those with the
GG
genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in
WNK4
influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.
Oxidative Stress in Dahl Salt-Sensitive Hypertension
Authors: Meng Shumei , Cason Garrick W. , Gannon Anthony W. , Racusen Lorraine C. , Manning R. Davis
Published: April 2003

The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 μmol · kg
−1
· h
−1
plus low Na or high Na. After 21 days, mean arterial pressure was 140±3 mm Hg in the high-Na group, 118±1 mm Hg (
P
<0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O
2
·−
release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O
2
·−
release in the high- and low-Na rats, but the decrease in O
2
·−
release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage.
Effect of Treatment With Lercanidipine on Heart of Cohen-Rosenthal Diabetic Hypertensive Rats
Authors: Amenta Francesco , Peleg Edna , Tomassoni Daniele , Sabbatini Maurizio , Rosenthal Talma
Published: April 2003

The influence of treatment with the dihydropyridine-type Ca
2+
antagonist lercanidipine on heart and coronary microanatomic changes was investigated in spontaneously hypertensive rats, Cohen-diabetic rats, and Cohen-Rosenthal diabetic hypertensive rats. At 12 weeks of age, animals were left untreated (control groups) or were treated for 8 weeks with an oral dose of 3 mg/kg per day of lercanidipine. Wistar-Kyoto rats were used as a normotensive reference group. In spontaneously hypertensive rats and diabetic hypertensive rats, systolic blood pressure was higher in comparison with Wistar-Kyoto rats. Augmented pressure values were decreased by lercanidipine treatment. Systolic blood pressure was slightly higher in Cohen-diabetic rats than in Wistar-Kyoto rats, and this increase was countered by treatment with lercanidipine. In spontaneously hypertensive rats, diabetic rats, and diabetic hypertensive rats, the thickness of left ventricle and cardiocyte area were increased. Focal connective tissue areas and diffuse accumulation of connective tissue were observed in the left ventricle of spontaneously hypertensive and Cohen-diabetic rats, respectively. Pharmacological treatment countered left ventricle thickening and restored cardiocyte area values in subendocardium. An increased thickness of tunica media accompanied by luminal narrowing was found in coronary artery branches of control spontaneously hypertensive and diabetic hypertensive rats. Treatment with lercanidipine countered vascular changes primarily in small-sized coronary arteries. These results indicate that hypertensive, diabetic, and diabetic hypertensive rats undergo cardiac hypertrophy and vascular changes affecting small-sized coronary arteries. Treatment with lercanidipine countered hypertension-related cardiac and coronary changes, suggesting that this dihydropyridine-type Ca
2+
antagonist may improve heart and coronary structure in diabetes associated with hypertension.
Different Effect of Antihypertensive Drugs on Conduit Artery Endothelial Function
Authors: Ghiadoni Lorenzo , Magagna Armando , Versari Daniele , Kardasz Isabella , Huang Yale , Taddei Stefano , Salvetti Antonio
Published: April 2003

To compare the effect of antihypertensive drugs on endothelium-dependent vasodilation in the peripheral conduit arteries of patients with essential hypertension, in a prospective, randomized, parallel group study, endothelial function was assessed in 168 hypertensive patients before and after 6-month treatment with randomly assigned nifedipine GITS (30 to 60 mg, n=28), amlodipine (5 to 10 mg, n=28), atenolol (50 to 100 mg, n=29), nebivolol (5 to 10 mg, n=28), telmisartan (80 to 160 mg, n=29), and perindopril (2 to 4 mg, n=28). If necessary, hydrochlorothiazide (25 mg) was added to each compound. We evaluated brachial artery flow-mediated, endothelium-dependent dilation (high-resolution ultrasound) compared with endothelium-independent response to glyceryl trinitrate (25 μg/s). Brachial artery diameter was measured by automatic computerized analysis. Forty healthy subjects were evaluated as a control group. Oxidative stress production was evaluated by measuring plasma malondialdehyde and plasma lipoperoxides; plasma antioxidant capacity was assessed as ferric-reducing antioxidant power. Hypertensive patients showed a significantly (
P
<0.01) lower flow-mediated dilation (5.2±1.9%) as compared with healthy control subjects (7.1±2.6%). Response to glyceryl trinitrate was similar in control subjects and patients. At baseline, blood pressure, diameter, flow-mediated dilation, and response to glyceryl trinitrate were similar in the different treatment groups. All treatments similarly reduced blood pressure, but only perindopril increased flow mediated dilation (from 5.1±2 to 6.4±2.4%;
P
<0.01) without modifying the response to glyceryl trinitrate. Perindopril but also telmisartan nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity. In patients with essential hypertension, ACE inhibitors appear to be the only compounds able to improve conduit artery endothelium-dependent vasodilation.
Pressor Effect of Water Drinking in Tetraplegic Patients May Be a Spinal Reflex
Authors: Tank Jens , Schroeder Christoph , Stoffels Mandy , Diedrich André , Sharma Arya M. , Luft Friedrich C. , Jordan Jens
Published: April 2003

Water drinking elicits a profound sympathetically mediated pressor response in patients with autonomic failure. To further elucidate the mechanism of the response, we assessed the acute effect of drinking water on supine blood pressure and heart rate in 13 tetraplegic patients (12 men, 1 woman; 39±4 years of age; body mass index, 25±1 kg/m
2
) with complete spinal cord injury (C2 to C7). Heart rate and finger blood pressure were recorded continuously. Brachial blood pressure was measured every 5 minutes. Baroreflex sensitivity was assessed by the sequence method. Stroke volume was calculated by use of transthoracic bioimpedance. Patients were placed in the supine position with the upper body elevated by 15°. After 30 minutes, supine patients ingested 500 mL of water and the following 60 minutes were monitored. Finger blood pressure at baseline was 123±8/65±4 mm Hg. Water drinking elicited a pressor response that was apparent within 5 minutes and reached a maximum of 138±8/73±4 mm Hg after 35 to 40 minutes (
P
<0.05). Heart rate decreased from 64±2 bpm at baseline to 60±2 bpm (
P
<0.001). The mean area under the curve for brachial systolic blood pressure changes differed significantly from zero (364±151 mm Hg/min). Total peripheral resistance increased by 15±4% (
P
<0.05). Baroreflex sensitivity increased from 18±5 ms/mm Hg at baseline to 23±6 ms/mm Hg at 35 minutes after water drinking (
P
<0.01). Water drinking elicits a pressor response even if the direct connection between brain stem cardiovascular centers and spinal sympathetic neurons is interrupted. This observation might suggest that water drinking activates postganglionic sympathetic neurons either directly or through a spinal reflex mechanism.
Decreases in ANP Secretion by Lysophosphatidylcholine Through Protein Kinase C
Authors: Han Jeong Hee , Cao Chunhua , Kim Sung Zoo , Cho Kyung Woo , Kim Suhn Hee
Published: April 2003

Lysophosphatidylcholine (LPC) is an endogenous phospholipid released from the cell membrane during ischemia, and it has potent, local effects on cardiac tissues. LPC has been implicated in arrhythmogenesis during ischemia by increasing intracellular Ca
2+
. However, it is not known whether LPC influences atrial release of atrial natriuretic peptide (ANP). The aim of this study was to investigate the effect of LPC on ANP secretion from isolated, perfused, beating rat atria. LPC (10 and 30 μmol/L) caused decreases in ANP secretion in a dose-dependent manner, with slight increases in intra-atrial pressure and extracellular fluid (ECF) translocation. Therefore, the ANP secretion in terms of ECF translocation was markedly decreased by LPC. The order of the suppressive effect of ANP release was stearoyl-LPC>LPC>myristoyl-LPC=lauroyl-LPC. Staurosporine and wortmannin significantly attenuated suppression of the ANP release and an increase in intra-atrial pressure by LPC. High extracellular Mg
2+
also attenuated the LPC-induced suppression of ANP release. However, other protein kinase C inhibitors such as chelerythrine, GF 109203X, and tamoxifen citrate did not affect LPC-induced suppression of ANP release. In single atrial myocytes, LPC caused increases in intracellular Ca
2+
in a dose-dependent manner. The order of an increase in intracellular Ca
2+
by LPC was stearoyl-LPC>LPC>myristoyl-LPC=lauroyl-LPC. An increase in intracellular Ca
2+
by LPC was attenuated by staurosporine. These results suggest that LPC-induced suppression of ANP release through protein kinase C/Ca
2+
and phosphoinositol-3-kinase might in part play an important role in the development of hypertension.
Heritability of Blood Pressure and Hemodynamics in African- and European-American Youth
Authors: Snieder Harold , Harshfield Gregory A. , Treiber Frank A.
Published: April 2003

Hypertension prevalence is much higher in African-Americans (AAs) than in European-Americans (EAs). It is unknown whether this difference is related to potential ethnic differences in the relative contribution of genes and environment to population variation in blood pressure and underlying hemodynamics. We studied 308 EA and 226 AA twin pairs, including monozygotic and dizygotic twins, of the same as well as the opposite sex (mean±SD age, 14.7±3.1 years). Supine resting systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, and heart rate (HR) were measured by a Dinamap instrument and hemodynamics (stroke volume, cardiac index, and total peripheral resistance [TPR] index) by impedance cardiography. Ethnic and sex effects on genetic and environmental contributions to resting blood pressure and hemodynamics were estimated by genetic model fitting. For most measures, the best-fitting model showed no differences in heritability between AAs and EAs or between males and females, with heritabilities of 0.50 for cardiac index, of 0.64 for HR, and of SBP, pulse pressure, and stroke volume in between. Heritability of DBP was 0.45 in EAs and 0.58 in AAs with no effect of sex. For TPR index in EAs, 46% of the variance could be attributed to familial effects, but no significant distinction could be made between shared environmental and genetic factors. Heritability of TPR index in AAs was 0.51. Adjustment for obesity yielded virtually identical heritabilities. In summary, relative influences of genetic and environmental factors on blood pressure and hemodynamics in AA and EA youth are similar and independent of (genes for) obesity.
Recreational Physical Activity During Pregnancy and Risk of Preeclampsia
Authors: Sorensen Tanya K. , Williams Michelle A. , Lee I-Min , Dashow Edward E. , Thompson Mary Lou , Luthy David A.
Published: April 2003

The potential benefits and risks of physical activity before and during pregnancy are not well studied. We studied the relation between recreational physical activity and the risk of preeclampsia in a case-control study of 201 preeclamptic and 383 normotensive pregnant women. Participants provided information about the type, intensity, frequency, and duration of physical activity performed during the first 20 weeks of pregnancy and during the year before pregnancy. Women who engaged in any regular physical activity during early pregnancy, compared with inactive women, experienced a 35% reduced risk of preeclampsia (odds ratio, 0.65; 95% confidence interval [CI], 0.43 to 0.99). Compared with inactive women, those engaged in light or moderate activities (ie, activities with metabolic-equivalent scores <6) experienced a 24% reduced risk of preeclampsia (95% CI, 0.48 to 1.20). The corresponding reduction for women participating in vigorous activities (metabolic equivalent scores ≥6) was 54% (95% CI, 0.27 to 0.79). Brisk walking (average walking pace ≥3 mi/h), when compared with no walking at all, was associated with a 30% to 33% reduction in preeclampsia risk. Stair climbing was inversely associated with the risk of preeclampsia (
P
for trend=0.039). Recreational physical activity performed during the year before pregnancy was associated with similar reductions in preeclampsia risk. These data suggest that regular physical activity, particularly when performed during the year before pregnancy and during early pregnancy, is associated with a reduced risk of preeclampsia.
Tumor Necrosis Factor-α Induces Early-Onset Endothelial Adhesivity by Protein Kinase Cζ–Dependent Activation of Intercellular Adhesion Molecule-1
Authors: Javaid Kamran , Rahman Arshad , Anwar Khandaker N. , Frey Randall S. , Minshall Richard D. , Malik Asrar B.
Published: April 2003

We tested the hypothesis that TNF-α induces early-onset endothelial adhesivity toward PMN by activating the constitutive endothelial cell surface ICAM-1, the β
2
-integrin (CD11/CD18) counter-receptor. Stimulation of human pulmonary artery endothelial cells with TNF-α resulted in phosphorylation of ICAM-1 within 1 minute, a response that was sustained up to 15 minutes after TNF-α challenge. We observed that TNF-α induced 10-fold increase in PMN adhesion to endothelial cells in an ICAM-1–dependent manner and that this response paralleled the rapid time course of ICAM-1 phosphorylation. We also observed that the early-onset TNF-α–induced endothelial adhesivity was protein synthesis–independent and associated with cell surface ICAM-1 clustering. Pretreatment of cells with the pan-PKC inhibitor, chelerythrine, prevented the activation of endothelial adhesivity. As PKCζ, an atypical PKC isoform abundantly expressed in endothelial cells, is implicated in signaling TNF-α–induced ICAM-1 gene transcription, we determined the possibility that PKCζ was involved in mediating endothelial adhesivity through ICAM-1 expression. We observed that TNF-α stimulation of endothelial cells induced PKCζ activation and its association with ICAM-1. Inhibition of PKCζ by pharmacological and genetic approaches prevented the TNF-α–induced phosphorylation and the clustering of the cell surface ICAM-1 as well as activation of endothelial adhesivity. Thus, TNF-α induces early-onset, protein synthesis–independent expression of endothelial adhesivity by PKCζ-dependent phosphorylation of cell surface ICAM-1 that precedes the de novo ICAM-1 synthesis. The rapid ICAM-1 expression represents a novel mechanism for promoting the stable adhesion of PMN to endothelial cells that is needed to facilitate the early-onset transendothelial migration of PMN.
Sympathetic Nerve Sprouting, Electrical Remodeling, and Increased Vulnerability to Ventricular Fibrillation in Hypercholesterolemic Rabbits
Authors: Liu Yen-Bin , Wu Chau-Chung , Lu Long-Sheng , Su Ming-Jai , Lin Chii-Wann , Lin Shien-Fong , Chen Lan S. , Fishbein Michael C. , Chen Peng-Sheng , Lee Yuan-Teh
Published: April 2003

Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097±288 mg/dL in HC group and 59±9 mg/dL in S group for protocol 1 and were 1889±577 mg/dL in HC group and 50±21 mg/dL in S group for protocol 2. Density of growth-associated protein 43– (GAP43) and tyrosine hydroxylase– (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (
I
Ca
) density (14.0±3.1 versus 9.1±3.4 pA/pF;
P
<0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (
R
2
=0.94;
P
<0.001) and TH (
R
2
=0.91;
P
<0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased
I
Ca
. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.
FIZZ1/RELMα, a Novel Hypoxia-Induced Mitogenic Factor in Lung With Vasoconstrictive and Angiogenic Properties
Authors: Teng Xingwu , Li Dechun , Champion Hunter C. , Johns Roger A.
Published: April 2003

In a mouse chronic hypoxia model of pulmonary hypertension, we discovered a novel hypoxia-inducible gene in lung, FIZZ1/RELMα, first through a cDNA array analysis and then confirmed by RT-PCR. Western blot and immunohistochemistry revealed that its expression was induced by hypoxia only in lung. The hypoxia-upregulated gene expression was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes.
3
H-thymidine incorporation demonstrated that the recombinant protein stimulated rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently ranging from 3.3×10
−9
to 3.3×10
−8
mol/L. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 μmol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II.
AIF-1 Is an Actin-Polymerizing and Rac1-Activating Protein That Promotes Vascular Smooth Muscle Cell Migration
Authors: Autieri Michael V. , Kelemen Sheri E. , Wendt Karl W.
Published: April 2003

Development of vascular restenosis is a multifaceted process characterized by migration and proliferation of vascular smooth muscle cells (VSMCs), resulting in loss of lumen diameter. Characterization of proteins that mediate this process is essential in our understanding of the pathogenesis of arterial injury. Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding protein that is expressed in VSMCs by allograft and balloon angioplasty injury. AIF-1 is not present in cultured human VSMCs but is induced by cytokines, and overexpression of AIF-1 results in increased VSMC growth and cell-cycle gene expression. To characterize AIF-1 modulatory effects in primary human VSMCs, AIF-1–interacting proteins were identified by an AIF-1/glutathione S transferase fusion protein affinity assay. MALDI-TOF mass spectrophotometric amino analysis identified actin as an AIF-1 interacting protein. This interaction was verified by coimmunoprecipitation. This is a functional interaction, because AIF-1 binds to and polymerizes F-actin in vitro. In unstimulated VSMCs, AIF-1 colocalizes with F-actin but translocates to lamellipodia on stimulation with platelet-derived growth factor. VSMCs stably transduced with AIF-1 retrovirus migrate 2.6-fold more rapidly (85.1±2.9 versus 225.5±16.6;
P
<0.001) in response to platelet-derived growth factor versus control cells. AIF-1 colocalizes with Rac1, and AIF-1–transduced VSMCs show a constitutive and enhanced activation of Rac1, providing a mechanism for the increased migration. These data indicate that AIF-1 binds and polymerizes F actin and also regulates Rac1 activity and VSMC migration. Considering the AIF-1 expression pattern in injured arteries, this suggests that AIF-1 may be involved in the cytoskeletal signaling network leading to vascular remodeling.
Evaluating the Genetic Component of Ischemic Stroke Subtypes
Authors: Jerrard-Dunne Paula , Cloud Geoffrey , Hassan Ahamad , Markus Hugh S.
Published: April 2003

Background and Purpose—

Twin and family history studies support a role for genetic factors in stroke risk. Because the etiology of ischemic stroke is heterogeneous, genetic factors may vary by etiologic subtype. We determined the familial aggregation of stroke risk in different stroke phenotypes and used the results to model estimated sample size requirements for case-control studies.

Methods—

One thousand consecutive white subjects with ischemic stroke and 800 white controls matched for age and sex were recruited. A first-degree family history of stroke and myocardial infarction was obtained by structured interview. Stroke subtype was determined with the use of modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.

Results—

A family history of stroke at ≤65 years was a significant risk factor for large-vessel disease (odds ratio [OR], 2.24; 95% CI, 1.49 to 3.36;
P
<0.001) and for small-vessel disease (OR, 1.93; 95% CI, 1.25 to 2.97;
P
=0.003). When only cases aged ≤65 years were considered, these ORs increased to 2.93 (95% CI, 1.68 to 5.13) (
P
<0.001) and 3.15 (95% CI, 1.81 to 5.50) (
P
<0.001), respectively. No significant associations were seen for cardioembolic stroke or stroke of undetermined etiology.

Conclusions—

A family history of vascular disease is an independent risk factor for both large-vessel atherosclerosis and small-vessel disease, especially in cases presenting before age 65 years. The estimated sample sizes for case-control studies illustrate how candidate gene studies for ischemic stroke might be made more effective by focusing on these specific phenotypes, in which the genetic component of the disease appears to be strongest.
Cognitive Impairment Is Related to Cerebral Lactate in Patients With Carotid Artery Occlusion and Ipsilateral Transient Ischemic Attacks
Authors: Bakker Floor C. , Klijn Catharina J.M. , Jennekens-Schinkel Aagje , van der Tweel Ingeborg , van der Grond Jeroen , van Huffelen Alexander C. , Tulleken Cornelis A.F. , Kappelle L. Jaap
Published: April 2003

Background and Purpose—

Patients with carotid artery occlusion (CAO) and ipsilateral transient ischemic attack (TIA) can have lasting cognitive impairment, despite the recovery of focal neurological deficits. We sought to assess whether cognitive impairment in these patients is associated with hemodynamic compromise and/or impaired cerebral metabolism.

Methods—

In 39 consecutive patients with a TIA associated with an angiographically proven occlusion of the carotid artery, we examined (1) cognitive functioning, (2) cerebrovascular reserve capacity of the middle cerebral artery ipsilateral to the CAO as measured by transcranial Doppler ultrasound, and (3) metabolic ratios as measured by
1
H-MR spectroscopy in the centrum semiovale ipsilateral to the symptomatic CAO. Findings were compared with those in healthy control subjects.

Results—

As a group, patients were cognitively impaired. Mean CO
2
reactivity and the mean ratio of
N
-acetyl aspartate to creatine were decreased. In approximately one third of patients, lactate was present in noninfarcted regions. The presence of lactate proved to be a stronger correlate of cognitive impairment than MRI-detected lesions (β=0.41 versus β=0.15). Cognitive impairment did not correlate with CO
2
reactivity or the ratio of
N
-acetyl aspartate to creatine.

Conclusions—

This exploratory study in patients with CAO and ipsilateral TIA showed that
1
H-MR spectroscopy–detected lactate in noninfarcted regions is a better indicator of cognitive impairment than MRI-detected lesions. Cognitive impairment did not correlate with CO
2
reactivity.
ATP-Sensitive Potassium Channels in the Cerebral Circulation
Authors: Rosenblum William I.
Published: April 2003

Background—

In brain blood vessels, electrophysiological studies proving the existence of ATP-sensitive potassium channels (K
ATP
) are scarce. However, numerous pharmacological studies establish the importance of K
ATP
channels in these blood vessels. This review emphasizes the data supporting the importance of vascular K
ATP
in the responses of brain blood vessels.

Summary of Review—

Electrophysiological data show the existence of K
ATP
in smooth muscle and endothelium of brain vessels. A much larger number of studies in virtually all experimental species have shown that classic openers of K
ATP
dilate brain arteries and arterioles. This response can by blocked by glibenclamide, a selective inhibitor of K
ATP
opening. Several physiological or pathophysiological responses are also blocked by glibenclamide. K
ATP
contains a multiplicity of potential sites of interaction with drugs of diverse, sometimes unrelated, structures. Drugs with imidazole or guanidinium groups are particularly likely to have effects on K
ATP
. This complicates interpretation of the actions of such drugs when used as supposedly selective pharmacological probes for other putative targets. A pH-sensitive site on the internal surface of cloned channels may explain the glibenclamide-inhibitable dilation produced by intracellular acidosis and perhaps by CO
2
. In some situations K
ATP
appears to be involved in either the synthesis/release or action of endothelium-derived mediators of cerebrovascular tone. The importance of K
ATP
may be dependent on the portion of the cerebrovascular tree being studied and on diverse experimental conditions, age, species, and the presence of disease.

Conclusions—

K
ATP
have been shown to mediate a wide range of cerebrovascular response in physiologic or pathologic circumstances in a variety of experimental conditions. Their relevance to cerebrovascular responses in humans remains to be explored.
Appropriating Liberation
Authors: Kew Barry
Published: April 2003

Media and nonhuman animal liberation is an under-researched area in the United Kingdom. If the most appropriate metaphor describing the media/social movement relationship is "dance," then largely the media and animal liberation are dancing in the dark of neglect. Drawing upon different approaches to media and offering some notes toward animal liberation media studies, this article explores how, by engaging with the "established terms of the problematic at play," animal liberationists and their claims are appropriated by speciesist ideology through exclusion and confusing and redefining maneuvers. A contextual analysis of its typical texts raises questions of the public interest role, due impartiality of media and, implicitly, of movement strategy.
Marxism and the Moral Status of Animals
Authors: Benton Ted
Published: April 2003

Perlo's engagement with the complex and ambiguous relationship between Marxism (and, more broadly, the socialist traditions) and the moral status of animals is very much to be welcomed. This sort of engagement is valuable for three main reasons. First, the more narrowly focused social movement activity—whether committed to animal rights, social justice in the workplace, or advancement for women—is liable to cut itself off from critical insights created in the context of other movements. I became aware of this, particularly during the 1980s in relation to radical green politics, as both deepening and widening the already existing socialist case against neo-liberal capitalism, just as the women's liberation movement had done a decade or more earlier. Second, this sort of analysis is valuable because without it "single-issue" movements run a serious risk of advancing the claims of their own preferred social group at the cost of (usually unknowingly and unintentionally) deepening the oppression or exploitation of other groups. Third, where radical social movements campaign for changes that conflict with the interests of wealthy and powerful interests, and are committed to democratic values, they need to be able to bring public opinion with them. Single-issue movements rarely can do this on their own: Broad-based coalitions are needed. Moreover, the sources of radical thought and the range of justified grievances are now so diverse that the notion of a single, unified political party as the centralized vehicle of change is no longer viable (if it ever was). So, the broadly based coalition has to be diverse and difference-respecting. But can it be this while still maintaining enough unity of purpose and coordination of its actions to be effective?