bluuebunny/crossref_metadata_2025 huggingface dataset:
Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity
Authors: Watanabe Susumu , Kang Duk-Hee , Feng Lili , Nakagawa Takahiko , Kanellis John , Lan Hui , Mazzali Marilda , Johnson Richard J.
Published: September 2002

Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.
Perindopril Effect on Uncoupling Protein and Energy Metabolism in Failing Rat Hearts
Authors: Murakami Kazushi , Mizushige Katsufumi , Noma Takahisa , Tsuji Teppei , Kimura Shoji , Kohno Masakazu
Published: September 2002

Uncoupling proteins, inner mitochondrial membrane proton transporters, are important for regulating myocardial energy efficiency. We investigated the effects of the ACE inhibitor perindopril on cardiac performance, myocardial energy efficiency, and uncoupling protein expression in an aortic regurgitation rat model. Twenty male Sprague-Dawley rats, in which aortic regurgitation was produced, were divided into untreated and perindopril-treated (5 mg · kg
−1
· d
−1
) rats. The treatments were initiated 3 days after operation. Ten control rats were sham-operated. Measurements of blood pressure and echocardiography were repeated before and 100 days after operation (endpoint). Left ventricular uncoupling protein-2 expression, creatine phosphate, and adenosine triphosphate were measured at endpoint. In perindopril-treated rats, systolic and diastolic blood pressure decreased after treatment (92±4/65±2 mm Hg). At endpoint, left ventricular end-diastolic dimension in untreated (10.7±0.2 mm) and treated rats (9.2±0.2 mm) was increased, and fractional shortening was reduced in untreated rats (28±1%) but did not change in treated rats (36±2%). Uncoupling protein-2 mRNA expression increased in untreated rats (3.7-fold) and was suppressed by perindopril (1.5-fold). The creatine phosphate was reduced in untreated rats (10.6±0.7 μmol/g) but not in treated rats (15.9±2.0 μmol/g). In the chronic stage of aortic regurgitation, perindopril improved cardiac performance and myocardial energy efficiency, in which the suppression of uncoupling protein-2 may play an important role.
Role of AT
2
Receptors in the Cardioprotective Effect of AT
1
Antagonists in Mice
Authors: Xu Jiang , Carretero Oscar A. , Liu Yun-He , Shesely Edward G. , Yang Fang , Kapke Alissa , Yang Xiao-Ping
Published: September 2002

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT
1
and AT
2
. Most of the known biological actions of Ang II are mediated by AT
1
receptors; however, the role of AT
2
receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT
1
receptor antagonists (AT
1
-ant) after myocardial infarction (MI) are partially mediated by activation of AT
2
receptors; thus in AT
2
receptor gene knockout mice (AT
2
−/Y), the effect of AT
1
-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT
2
−/Y and their wild-type littermates (AT
2
+/Y) were started on vehicle, AT
1
-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT
2
+/Y and AT
2
−/Y. AT
1
-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT
2
+/Y, and these effects were significantly diminished in AT
2
−/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT
2
during AT
1
blockade plays an important role in the therapeutic effect of AT
1
-ant and (2) the AT
2
receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.
Essential Hypertension and β
2
-Adrenergic Receptor Gene
Authors: Tomaszewski Maciej , Brain Nick J.R. , Charchar Fadi J. , Wang William Y.S. , Lacka Beata , Padmanabahn Sandosh , Clark James S. , Anderson Niall H. , Edwards Helen V. , Zukowska-Szczechowska Ewa , Grzeszczak Wladyslaw , Dominiczak Anna F.
Published: September 2002

A region on human chromosome 5 (5q31.1-qter) contains several genes that encode important blood pressure regulators and thus is a good candidate for analysis of linkage and association with hypertension. We recruited 638 individuals from 212 Polish pedigrees with clustering of essential hypertension. These subjects were genotyped for 11 microsatellite markers that span this region to test for linkage to essential hypertension and systolic and diastolic blood pressures. The segment of this region of ≈7 cM delineated by D5S1480 and D5S500 markers was linked to blood pressures in multipoint analysis. In 2-point analysis, D5S1480—the marker in close proximity to β
2
-adrenergic receptor gene—reached the maximal linkage to essential hypertension and adjusted systolic and diastolic blood pressures, implicating this gene as a positional candidate for further association studies. Arg16Gly, Gln27Glu, and Thr164Ile—3 functional single nucleotide polymorphisms within the β
2
-adrenergic receptor gene—were tested for association with essential hypertension. None of these polymorphisms showed a significant association with essential hypertension, separately or in the haplotype analysis. This study provided evidence of linkage of 5q31.1-5qter region to essential hypertension in the European population. Moreover, it implicated the chromosomal segment in close proximity to D5S1480 and D5S500. The detailed analysis of 3 single nucleotide polymorphisms does not support the role of the β
2
-adrenergic receptor gene as a major causative gene for the detected linkage.
Kidney Specificity of Rat Chromosome 1 Blood Pressure Quantitative Trait Locus Region
Authors: Clemitson Jenny-Rebecca , Pratt Julian R. , Frantz Simon , Sacks Steven , Samani Nilesh J.
Published: September 2002

Rat chromosome 1 has a region containing loci that influence blood pressure. In the present study, we investigated whether these loci mediate their effect via the kidney. Taking advantage of the histocompatability between a congenic strain (WKY.SHR-
Sa
, which contains the relevant chromosomal region from the spontaneously hypertensive rat) and its parental strain, the Wistar-Kyoto rat (WKY), we compared the effect of transplanting a kidney at 5 to 6 weeks of age from either congenic rats or WKY into bilaterally nephrectomized WKY. WKY.SHR-
Sa
animals and WKY with intact kidneys and with unilateral nephrectomy were studied as controls. Blood pressure was measured at 12, 16, 20, and 25 weeks of age. At all time points, blood pressure was significantly higher (by between 8 to 22 mm Hg,
P
<0.001) in 2-kidney WKY.SHR-
Sa
animals compared with WKY. This genotype-related difference was maintained in unilaterally nephrectomized rats. Most importantly, WKY that received transplants from WKY.SHR-
Sa
rats had significantly higher blood pressure (
P
<0.001 at all time points) compared with those that received transplants from other WKY. At any age, this difference was between 70% to 100% of the difference observed between the 1-kidney groups. There was no difference in plasma urea or creatinine between groups or evidence of chronic rejection in the cross-transplant group. The findings indicate that the major proportion of the blood pressure effect of loci on rat chromosome 1 is mediated through the kidney, and provide a rational basis for investigating genes located in the relevant chromosomal region and expressed in the kidney as likely candidates.
P450-Dependent Arachidonic Acid Metabolism and Angiotensin II–Induced Renal Damage
Authors: Kaergel Eva , Muller Dominik N. , Honeck Horst , Theuer Juergen , Shagdarsuren Erdenechimeg , Mullally Alexander , Luft Friedrich C. , Schunck Wolf-Hagen
Published: September 2002

Transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR) develop hypertension, inflammation, and renal failure. We tested the hypothesis that these pathological features are associated with changes in renal P450-dependent arachidonic acid (AA) metabolism. Samples were prepared from 5- and 7-week-old dTGR and from normotensive Sprague-Dawley (SD) rats, ie, before and after the dTGR developed severe hypertension and albuminuria. At both stages, dTGR showed significantly lower renal microsomal AA epoxygenase and hydroxylase activities that reached 63% and 76% of the control values at week 7. Furthermore, the protein levels of several potential AA epoxygenases (CYP2C11, CYP2C23, and CYP2J) were significantly reduced. Immunoinhibition studies identified CYP2C23 as the major AA epoxygenase, both in dTGR and SD rats. Immunohistochemistry showed that CYP2C23 was localized in cortical and outer medullary tubules that progressively lost this enzyme from week 5 to week 7 in dTGR. CYP2C11 expression occurred only in the outer medullary tubules and was markedly reduced in dTGR compared with age-matched SD rats. These findings indicate site-specific decreases in the availability of AA epoxygenase products in the kidney of dTGR. In contrast to renal microsomes, liver microsomes of dTGR and SD rats showed no change in the expression and activity of AA epoxygenases and hydroxylases. We conclude that hypertension and end-organ damage in dTGR is associated with kidney-specific downregulation of P450-dependent AA metabolism. Because the products of AA epoxygenation have anti-inflammatory properties, this alteration may contribute to uncontrolled renal inflammation, which is a major cause of renal damage in dTGR.
Augmented Upregulation by c-
fos
of Angiotensin Subtype 1 Receptor in Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats
Authors: Chan Julie Y.H. , Wang Ling-Lin , Lee Hsien-Yang , Chan Samuel H.H.
Published: September 2002

Our laboratory demonstrated previously that spontaneously hypertensive rats (SHR) exhibited an elevated basal Fos expression in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, and that Fos protein is required for the re-expression of angiotensin subtype 1 receptor (AT1R) mRNA in the NTS after baroreceptor activation. The present study evaluated the hypothesis that this re-expression of AT1R is augmented in SHR and is promoted by the heightened Fos expression. Reverse transcription–polymerase chain reaction analysis revealed that baroreceptor activation via sustained increase in systemic arterial pressure resulted in a discernible reduction in the expression of AT1R mRNA at the dorsomedial medulla of SHR and normotensive Wistar-Kyoto rats. However, SHR manifested an appreciably larger magnitude of decline, followed by a faster time course of re-expression in AT1R mRNA. Parallel findings were obtained from the pressor response induced by microinjection unilaterally of angiotensin II (40 pmol) into the NTS. Whereas the re-expression of AT1R at both transcriptional and functional expression levels after baroreceptor activation was discernibly blunted by prior bilateral application into the NTS of an antisense c-
fos
oligonucleotide (50 pmol), the suppression in SHR was again significantly more intense. Control pretreatment with the corresponding sense or scrambled c-
fos
oligonucleotide was ineffective. We conclude that the heightened Fos expression in SHR is causatively related to the augmented re-expression of AT1R in the NTS at both transcriptional and functional levels.
Mitogenic Activity of Oxidized Lipoprotein (a) on Human Vascular Smooth Muscle Cells
Authors: Komai Norio , Morishita Ryuichi , Yamada Shingo , Oishi Mitsuru , Iguchi Sota , Aoki Motokuni , Sasaki Minako , Sakurabayashi Ikunosuke , Higaki Jitsuo , Ogihara Toshio
Published: September 2002

Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (
P
<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.
Noninvasive Study of Endothelial Function in White Coat Hypertension
Authors: Gómez-Cerezo Jorge , Ríos Blanco Juan José , Suárez García Inés , Moreno Anaya Pilar , García Raya Pilar , Vázquez-Muñoz Enrique , Barbado Hernández Francisco Javier
Published: September 2002

Several studies have demonstrated that endothelial dysfunction is present in patients with essential hypertension. However, the presence of endothelial dysfunction in patients with white coat hypertension has not been studied. We evaluated the variation in the diameter of the brachial artery produced by flow-mediated dilation after a mechanical stimulus in patients with recently diagnosed mild to moderate sustained essential hypertension compared with patients with white coat hypertension. A total of 29 patients fulfilled inclusion criteria; 15 healthy volunteers were also included. After 24-hour ambulatory blood pressure monitoring, 15 patients were classified with sustained essential hypertension; 14 patients with white coat hypertension. Vascular ultrasound scans were performed according to the method described by Celermajer et al, with modification for noninvasive determination of endothelial dysfunction. Basal brachial artery diameter did not differ significantly among the 3 groups. Changes in arterial diameter 60 seconds after cuff deflation were higher in the control group compared with both hypertensive groups, but no significant differences were found between the sustained essential hypertension group and the white coat hypertension group. Flow-mediated dilation was similar in white coat hypertensives and sustained essential hypertensives. The presence of endothelial dysfunction in subjects with white coat hypertension suggests that it should not be considered a harmless trait and that white coat hypertension has common features with sustained essential hypertension.
Vascular Inflammation Is Negatively Autoregulated by Interaction Between CCAAT/Enhancer-Binding Protein-δ and Peroxisome Proliferator-Activated Receptor-γ
Authors: Takata Yasunori , Kitami Yutaka , Yang Zhao-Hui , Nakamura Michitsugu , Okura Takafumi , Hiwada Kunio
Published: September 2002

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-γ is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-γ gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-δ plays a pivotal role in transactivation of PPAR-γ gene. It has been well known that the interaction between C/EBPs and PPAR-γ plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-γ and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-δ expression induced by inflammation positively regulated transcription and protein expression of PPAR-γ in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-γ ligands troglitazone, pioglitazone, and 15-deoxy-Δ
12,14
-prostaglandin J
2
inhibited IL-1β-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-γ ligands inhibited IL-1β-induced transactivation of IL-6 gene via suppression of not only nuclear factor-κB but also C/EBP-DNA binding. Moreover, PPAR-γ ligands suppressed protein expression and transcription of C/EBP-δ through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-δ is negatively autoregulated via transactivation of PPAR-γ. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.
Luminal Ca
2+
Controls Termination and Refractory Behavior of Ca
2+
-Induced Ca
2+
Release in Cardiac Myocytes
Authors: Terentyev Dmitry , Viatchenko-Karpinski Serge , Valdivia Héctor H. , Escobar Ariel L. , Györke Sandor
Published: September 2002

Despite extensive research, the mechanisms responsible for the graded nature and early termination of Ca
2+
-induced Ca
2+
release (CICR) from the sarcoplasmic reticulum (SR) in cardiac muscle remain poorly understood. Suggested mechanisms include cytosolic Ca
2+
-dependent inactivation/adaptation and luminal Ca
2+
-dependent deactivtion of the SR Ca
2+
release channels/ryanodine receptors (RyRs). To explore the importance of cytosolic versus luminal Ca
2+
regulatory mechanisms in controlling CICR, we assessed the impact of intra-SR Ca
2+
buffering on global and local Ca
2+
release properties of patch-clamped or permeabilized rat ventricular myocytes. Exogenous, low-affinity Ca
2+
buffers (5 to 20 mmol/L ADA, citrate or maleate) were introduced into the SR by exposing the cells to “internal” solutions containing the buffers. Enhanced Ca
2+
buffering in the SR was confirmed by an increase in the total SR Ca
2+
content, as revealed by application of caffeine. At the whole-cell level, intra-SR [Ca
2+
] buffering dramatically increased the magnitude of Ca
2+
transients induced by
I
Ca
and deranged the smoothly graded
I
Ca
-SR Ca
2+
release relationship. The amplitude and time-to-peak of local Ca
2+
release events, Ca
2+
sparks, as well as the duration of local Ca
2+
release fluxes underlying sparks were increased up to 2- to 3-fold. The exogenous Ca
2+
buffers in the SR also reduced the frequency of repetitive activity observed at individual release sites in the presence of the RyR activator Imperatoxin A. We conclude that regulation of RyR openings by local intra-SR [Ca
2+
] is responsible for termination of CICR and for the subsequent restitution behavior of Ca
2+
release sites in cardiac muscle.
Gα
q
and Gβγ Regulate PAR-1 Signaling of Thrombin-Induced NF-κB Activation and ICAM-1 Transcription in Endothelial Cells
Authors: Rahman Arshad , True Andrea L. , Anwar Khandaker N. , Ye Richard D. , Voyno-Yasenetskaya Tatyana A. , Malik Asrar B.
Published: September 2002

As thrombin binding to the G protein–coupled proteinase activated receptor-1 (PAR-1) induces endothelial adhesivity to leukocytes through NF-κB activation and intercellular adhesion molecule-1 (ICAM-1) expression, we determined the signaling pathways mediating the response. Studies showed that the heterotrimeric G proteins, Gα
q
, and the Gβγ dimer were key determinants of the PAR-1 agonist peptide (TFLLRNPNDK)-induced NF-κB activation and ICAM-1 expression in endothelial cells. Cotransfection of RGS3T, a regulator of G-protein signaling that inhibits Gα
q
, or α-transducin (Gα
t
), a scavenger of the Gβγ, markedly decreased NF-κB activity induced by PAR-1 activation. We determined the downstream signaling targets activated by Gα
q
and Gβγ that mediate NF-κB activation. Expression of the kinase-defective protein kinase C (PKC)-δ mutant inhibited NF-κB activation induced by the constitutively active Gα
q
mutant, but had no effect on NF-κB activity induced by Gβ
1
γ
2
. In related experiments, NF-κB as well as ICAM-1 promoter activation induced by Gβ
1
γ
2
were inhibited by the expression of the dominant-negative mutant of 85-kDa regulatory subunit of PI 3-kinase; however, the expression of this mutant had no effect on the response induced by activated Gα
q
. Cotransfection of the catalytically inactive Akt mutant inhibited the NF-κB activation induced by the constitutively active PI 3-kinase mutant as well as that by the activated forms of Gα
q
and PKC-δ. These results support a model in which ligation of PAR-1 induces NF-κB activation and ICAM-1 transcription by the engagement of parallel Gαq/PKC-δ and Gβγ/PI3-kinase pathways that converge at Akt.
Nitric Oxide–Induced Motility in Aortic Smooth Muscle Cells
Authors: Chang Yingzi , Ceacareanu Bogdan , Dixit Madhulika , Sreejayan Nair , Hassid Aviv
Published: September 2002

We have previously reported that SHP-2 upregulation is necessary for NO-stimulated motility in differentiated rat aortic smooth muscle cells. We now test the hypothesis that upregulation of SHP-2 is necessary and sufficient to stimulate cell motility. Overexpression of SHP-2 via recombinant adenoviral vector stimulated motility to the same extent as NO, whereas the expression of C463S-SHP-2, the dominant-negative SHP-2 allele, blocked the motogenic effect of NO. On the basis of previous studies, we next tested the hypothesis that NO decreases RhoA activity and that this event is necessary and sufficient to explain NO-induced motogenesis. We found that NO decreased RhoA activity in a concentration-dependent manner. Moreover, a dominant-negative SHP-2 allele, DSH2, blocked the NO-induced inhibition of RhoA activity, indicating that upregulation of SHP-2 is necessary for this event. Expression of G14V-RhoA, the constitutively active RhoA allele, decreased cell motility and blocked the motogenic effect of NO, whereas the expression of T19N-RhoA, the dominant-negative RhoA allele, increased cell motility to an extent similar to that induced by NO. Dominant-negative RhoA reversed the effect of dominant-negative SHP-2, indicating that RhoA functions downstream from SHP-2. To investigate events downstream from RhoA, we treated cells with fasudil, a selective Rho kinase inhibitor, and found that it increased cell motility. These results indicate that upregulation of SHP-2, leading to downregulation of RhoA, which is followed by decreased Rho kinase activity, is a sequence of events necessary and sufficient to explain NO-induced cell motility in differentiated aortic smooth muscle cells. The results may be of relevance to in vivo events such as neointimal formation, angiogenesis, and vasculogenesis.
Is the Hypercoagulable State in Atrial Fibrillation Mediated by Vascular Endothelial Growth Factor?
Authors: Chung Natali A.Y. , Belgore Funmi , Li-Saw-Hee Foo Leong , Conway Dwayne S.G. , Blann Andrew D. , Lip Gregory Y.H.
Published: September 2002

Background and Purpose—

Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state.

Methods—

We studied 25 patients with AF (20 men; mean±SD age, 62±13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60±9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60±12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay.

Results—

VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (
P
<0.001,
P
=0.022, and
P
=0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman’s
r
=0.65,
P
<0.001) and sFlt (
r
=0.54,
P
=0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (
r
=0.39,
P
=0.02). There were no significant correlations among the healthy control subjects.

Conclusions—

Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.
Treatment of Basilar Artery Embolism With a Mechanical Extraction Device
Authors: Mayer Thomas E. , Hamann Gerhard F. , Brueckmann Hartmut J.
Published: September 2002

Background and Purpose—

The success of local fibrinolysis in vertebrobasilar thromboembolism depends on the volume and composition of the clot. Since thrombolysis can also be time consuming and cause bleeding, we investigated the feasibility of a mechanical clot retraction device based on a nitinol basket advanced through a microcatheter.

Methods—

Five patients with acute embolism of the basilar artery who presented with progressive stroke and impaired consciousness were included in a multicenter study (Neuronet Evaluation in Embolic Stroke Disease [NEED]). In 3 patients flow reversal was induced with the use of silicone balloons or coaxial catheters. Three patients required additional fibrinolysis.

Results—

The device failed to retrieve the clots in our first 2 patients with distal basilar artery embolism. After successful recanalization by local fibrinolysis, both patients survived, 1 disabled and 1 with little residual impairment. In the next 3 patients the anterograde flow in the basilar artery was reversed during the short retraction period by temporarily blocking the vertebral or subclavian arteries. Two of these patients were completely recanalized by solely mechanical means; the third patient needed additional fibrinolysis before also being recanalized. All 3 patients survived: 1 remained disabled, 1 had almost a full recovery, and 1 became asymptomatic the day after the procedure.

Conclusions—

Mechanical thrombus extraction seems to be a feasible method for preventing infarction by rapid, complete, and safe recanalization of the basilar artery. We recommend the use of flow control to support retrieval of the thrombus (which the proximal flow would otherwise keep in place like a cork) and to protect the distal vessels from embolization by fragments.
CT and Diffusion-Weighted MR Imaging in Randomized Order
Authors: Fiebach J.B. , Schellinger P.D. , Jansen O. , Meyer M. , Wilde P. , Bender J. , Schramm P. , Jüttler E. , Oehler J. , Hartmann M. , Hähnel S. , Knauth M. , Hacke W. , Sartor K.
Published: September 2002

Background and Purpose—

Diffusion-weighted MRI (DWI) has become a commonly used imaging modality in stroke centers. The value of this method as a routine procedure is still being discussed. In previous studies, CT was always performed before DWI. Therefore, infarct progression could be a reason for the better result in DWI.

Methods—

All hyperacute (<6 hours) stroke patients admitted to our emergency department with a National Institutes of Health Stroke Scale (NIHSS) score >3 were prospectively randomized for the order in which CT and MRI were performed. Five stroke experts and 4 residents blinded to clinical data judged stroke signs and lesion size on the images. To determine the interrater variability, we calculated κ values for both rating groups.

Results—

A total of 50 patients with ischemic stroke and 4 patients with transient symptoms of acute stroke (median NIHSS score, 11; range, 3 to 27) were analyzed. Of the 50 patients, 55% were examined with DWI first. The mean delay from symptom onset until CT was 180 minutes; that from symptom onset until DWI was 189 minutes. The mean delay between DWI and CT was 30 minutes. The sensitivity of infarct detection by the experts was significantly better when based on DWI (CT/DWI, 61/91%). Accuracy was 91% when based on DWI (CT, 61%). Interrater variability of lesion detection was also significantly better for DWI (CT/DWI, κ=0.51/0.84). The assessment of lesion extent was less homogeneous on CT (CT/DWI, κ=0.38/0.62). The differences between the 2 modalities were stronger in the residents’ ratings (CT/DWI: sensitivity, 46/81%; κ=0.38/0.76).

Conclusions—

CT and DWI performed with the same delay after onset of ischemic stroke resulted in significant differences in diagnostic accuracy. DWI gives good interrater homogeneity and has a substantially better sensitivity and accuracy than CT even if the raters have limited experience.
Air Pollution
Authors: Hong Yun-Chul , Lee Jong-Tae , Kim Ho , Kwon Ho-Jang
Published: September 2002

Background and Purpose—

Air pollution is known to be associated with cardiovascular disease, but little is known about the occurrence of stroke in relation to air pollution. We investigated the association between acute stroke mortality and air pollution over a 7-year period (January 1991 through December 1997) in Seoul, Korea.

Methods—

A generalized additive model was used to regress daily stroke death counts for each air pollutant, controlling for time trends, day of the week, and meteorological influences such as temperature, relative humidity, and atmospheric pressure. Ischemic and hemorrhagic stroke deaths were examined separately.

Results—

The effects of air pollutants on ischemic stroke mortality were statistically significant, whereas this was not the case for hemorrhagic stroke mortality. We observed estimated relative risks of 1.03 (95% CI, 1.00 to 1.06) and 1.04 (95% CI, 1.01 to 1.08) for ischemic stroke mortality for each interquartile range increase in total suspended particulates and sulfur dioxide concentrations on the same day. We also found significantly increased relative risks of 1.04 (95% CI, 1.01 to 1.07) for nitrogen dioxide with a 1-day lag, of 1.06 (95% CI, 1.02 to 1.09) for carbon monoxide with a 1-day lag, and of 1.06 (95% CI, 1.02 to 1.10) for ozone with a 3-day lag for each interquartile range increase.

Conclusions—

These findings indicate that air pollutants are significantly associated with ischemic stroke mortality, which suggests an acute pathogenetic process in the cerebrovascular system induced by air pollution.
Gene Transfer of Inducible Nitric Oxide Synthase Impairs Relaxation in Human and Rabbit Cerebral Arteries
Authors: Gunnett C.A. , Lund D.D. , Howard M.A. , Chu Y. , Faraci F.M. , Heistad D.D.
Published: September 2002

Background and Purpose—

These studies evaluated whether gene transfer of inducible nitric oxide synthase (iNOS) is a sufficient stimulus to produce vascular dysfunction in cerebral arteries.

Methods—

Intracranial (pial) arteries were dissected from human brain tissue obtained during elective surgery. Isolated human arteries were incubated in vitro with adenovirus containing iNOS (AdiNOS) or a nonexpressive transgene (control, AdBglII) (500 μL, 3×10
9
plaque-forming units per milliliter), and vascular function was examined 24 hours later. In anesthetized rabbits, AdiNOS or AdBglII (300 μL 1×10
10
) was injected into the cisterna magna. Three days later, the basilar artery was removed, and reactivity was examined ex vivo.

Results—

In submaximally precontracted vessels, we observed impairment of NO-dependent relaxation in human cerebral arteries after gene transfer of iNOS. Maximum relaxation to bradykinin (1 μmol/L, an endothelium-dependent agonist) was 77±11% (mean±SE) after AdBglII and 31±22% (
P
<0.05) after AdiNOS. After AdiNOS, responses to nitroprusside (an endothelium-independent NO donor) also were impaired. Responses to both nitroprusside and bradykinin were improved by aminoguanidine (300 μmol/L), an inhibitor of iNOS. AdiNOS produced no change in vasoconstrictor responses to U46619. In basilar arteries from rabbits examined in vitro after gene transfer in vivo, responses to histamine, serotonin, and nitroprusside all were similar after AdiNOS or AdBglII. In contrast, relaxation to acetylcholine was significantly depressed after AdiNOS. Maximum relaxation to acetylcholine (10 μmol/L) was 90±3% after AdBglII and 68±5% (
P
<0.05) after AdiNOS. Relaxation of arteries after AdiNOS was improved by aminoguanidine.

Conclusions—

These studies suggest that expression of iNOS may impair NO-dependent relaxation in both human and rabbit cerebral arteries.
Mesencephalic and Associated Posterior Circulation Infarcts
Authors: Kumral Emre , Bayulkem Gamze , Akyol Ali , Yunten Nilgün , Sirin Hadiye , Sagduyu Ayse
Published: September 2002

Background and Purpose—

The purposes of this study were to evaluate and review the risk factors and clinical features of patients with posterior circulation stroke involving mesencephalon and neighboring structures and to describe the clinical syndromes according to the mesencephalic arterial territory involved.

Methods—

We studied all patients with acute posterior circulation stroke involving mesencephalon who were admitted consecutively to our stroke unit over a 6-year period. We selected these patients (3%) from 1296 patients with posterior circulation infarct. Neurological and radiological investigations, including MRI and angiography, were performed in all cases. We classified patients into 4 groups on the basis of MRI findings: (1) isolated mesencephalic infarcts (9 patients); (2) distal territory infarcts (19 patients), including mesencephalon, thalamus, medial temporal and occipital lobes, and cerebellum; (3) middle territory infarcts (12 patients), including the pons and anterior inferior cerebellar artery territory; and (4) proximal territory infarcts (1 patient), including the medulla and posterior inferior cerebellar artery territory.

Results—

Middle mesencephalon involvement was the most common in all groups, and the anteromedial territory was frequently affected, depending on the direct perforators of basilar artery. In patients with isolated mesencephalic infarct, the clinical picture was dominated by nuclear or fascicular third-nerve palsy and contralateral motor deficits. The distal territory involvement was the most common and associated with consciousness disturbances, gait ataxia, ocular motor disturbances, and visual field deficits. The neurological picture of middle territory infarcts was dominated by consciousness disturbances with dysarthria, horizontal ocular motor disorders, and hemiparesis. Proximal territory involvement was rare and associated with acute unsteadiness, vertigo, dysphagia, dysphonia, tetra-ataxia, and motor weakness. The most common cause of stroke was large-artery disease in 16 patients (39%), cardioembolism in 8 (20%), and small-artery disease with lacunar mesencephalic infarct in 10 (24%). Bilateral mesencephalic infarcts were not uncommon (27%), mainly in patients with multiple and extended infarcts in the posterior circulation, and were associated with poor outcome compared with unilateral infarct.

Conclusions—

Our study highlights the topographic and clinical heterogeneity of the acute posterior circulation infarcts involving mesencephalon. The variety of the underlying potential causes of stroke requires detailed investigations of the extra and intracranial arteries and the heart.
Altered Endothelial Ca
2+
Regulation After Ischemia/Reperfusion Produces Potentiated Endothelium-Derived Hyperpolarizing Factor–Mediated Dilations
Authors: Marrelli Sean P.
Published: September 2002

Background and Purpose—

Endothelium-derived hyperpolarizing factor (EDHF)–mediated dilations are potentiated after several pathologies, including ischemia/reperfusion (I/R). However, no study to date has addressed the mechanism by which this potentiation occurs. This study tested the hypothesis that potentiated EDHF-mediated dilations are due to altered endothelial Ca
2+
handling after I/R.

Methods—

Rat middle cerebral arteries (MCAs) were isolated after 2 hours of MCA occlusion and 24 hours of reperfusion (or sham surgery). This model has been previously demonstrated to produce potentiated EDHF-mediated dilations. MCAs were studied in a pressurized/perfused vessel chamber equipped for the simultaneous measurement of endothelial Ca
2+
(with fura 2) and artery diameter. Measures were made after luminal administration of UTP (P2Y
2
purinoceptor agonist), 2 MeS-ATP (P2Y
1
purinoceptor agonist), and Br-A23187 (receptor-independent Ca
2+
ionophore) for sham and I/R MCAs.

Results—

I/R resulted in significantly potentiated UTP-mediated dilations (through a P2Y
2
purinoceptor) and endothelial Ca
2+
responses in the presence of
N
G
-nitro-
l
-arginine methyl ester (L-NAME) and indomethacin. Endothelial Ca
2+
and diameter responses were also significantly potentiated with 2 MeS-ATP (through a P2Y
1
purinoceptor) when L-NAME and indomethacin were absent. Br-A23187, a receptor-independent Ca
2+
ionophore, produced significantly potentiated endothelial Ca
2+
responses after I/R in the presence of L-NAME/indomethacin. Evaluation of artery diameter as a function of endothelial Ca
2+
demonstrated no differences between sham and I/R groups.

Conclusions—

These findings demonstrate that I/R results in augmented endothelial Ca
2+
responses that appear to be downstream of the receptor level. Moreover, these data suggest that this augmented Ca
2+
response contributes to the potentiated EDHF-mediated dilations after I/R.
Hypoxic Depolarization of Cerebellar Granule Neurons by Specific Inhibition of TASK-1
Authors: Plant Leigh D. , Kemp Paul J. , Peers Chris , Henderson Zaineb , Pearson Hugh A.
Published: September 2002

Background and Purpose—

The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K
+
leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K
+
current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.

Methods—

Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.

Results—

Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2±2.6 mV (n=5;
P
<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1–selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.

Conclusions—

Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.
Cerebral Ischemia Upregulates Vascular Endothelin ET
B
Receptors in Rat
Authors: Stenman Emelie , Malmsjö Malin , Uddman Erik , Gidö Gunilla , Wieloch Tadeuz , Edvinsson Lars
Published: September 2002

Background and Purpose—

Elevated levels of endothelin-1 (ET-1) have been reported in cerebral ischemia. A role for ET may prove more important if the vascular receptors were changed. We addressed whether there is any change in ET receptor expression in cerebral ischemia.

Methods—

The right middle cerebral artery (MCA) was occluded in male Wistar rats for 2 hours with the intraluminal filament method. The basilar artery and both MCAs were removed after 46 hours of recirculation. The contractile responses to ET-1, a combined ET
A
and ET
B
receptor agonist, and sarafotoxin 6c (S6c), a selective ET
B
receptor agonist, were examined in vitro, and ET receptor mRNA was quantified by real-time polymerase chain reaction.

Results—

S6c, which had no contractile effect per se on fresh or sham-operated rat cerebral arteries, induced a marked contraction in the occluded MCA (E
max
[maximum contraction, calculated as percentage of the contractile capacity of 63.5 mmol/L K
+
]=68±68%;
P
<0.0001), while there was no difference in the responses to ET-1 after cerebral ischemia. Real-time polymerase chain reaction revealed a significant upregulation of both the ET
A
and ET
B
receptors (both
P
<0.05) in the occluded MCA compared with the nonoccluded MCA from the same rats.

Conclusions—

Focal cerebral ischemia in rat induces increased transcription of both ET
A
and ET
B
receptors, which results in the appearance of a contractile response to the ET
B
receptor agonist S6c. These results suggest a role for ET receptors in the pathogenesis of a vascular component after cerebral ischemia.
Incidence of Dementia After Ischemic Stroke
Authors: Desmond David W. , Moroney Joan T. , Sano Mary , Stern Yaakov
Published: September 2002

Background and Purpose—

A number of cross-sectional epidemiological studies have reported that one fourth of elderly patients meet criteria for dementia 3 months after ischemic stroke, but few longitudinal studies of the incidence of dementia after stroke have been performed. We conducted the present study to investigate the incidence and clinical predictors of dementia after ischemic stroke.

Methods—

We administered neurological, neuropsychological, and functional assessments annually to 334 ischemic stroke patients (age, 70.4±7.5 years) and 241 stroke-free control subjects (age, 70.6±6.5 years), all of whom were nondemented in baseline examinations. We diagnosed incident dementia using modified
Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition
criteria requiring deficits in memory and ≥2 additional cognitive domains, as well as functional impairment.

Results—

The crude incidence rate of dementia was 8.49 cases per 100 person-years in the stroke cohort and 1.37 cases per 100 person-years in the control cohort. A Cox proportional-hazards analysis found that the relative risk (RR) of incident dementia associated with stroke was 3.83 (95% CI, 2.14 to 6.84), adjusting for demographic variables and baseline Mini-Mental State Examination score. Within the stroke cohort, intercurrent medical illnesses associated with cerebral hypoxia or ischemia were independently related to incident dementia (RR, 4.40; 95% CI, 2.20 to 8.85), adjusting for recurrent stroke, demographic variables, and baseline Mini-Mental State Examination score.

Conclusions—

The risk of incident dementia is high among patients with ischemic stroke, particularly in association with intercurrent medical illnesses that might cause cerebral hypoxia or ischemia, suggesting that cerebral hypoperfusion may serve as a basis for some cases of dementia after stroke.
Microplasmin: A Novel Thrombolytic That Improves Behavioral Outcome After Embolic Strokes in Rabbits
Authors: Lapchak Paul A. , Araujo Dalia M. , Pakola Steve , Song Donghuan , Wei Jiandong , Zivin Justin A.
Published: September 2002

Background and Purpose—

It has been proposed that the novel thrombolytic microplasmin may be useful in the treatment of ischemic stroke. In the present study the effects and safety profile of microplasmin were evaluated in 2 rabbit embolic stroke models that have been used successfully to develop tissue plasminogen activator (tPA) as the only Food and Drug Administration-approved treatment for stroke. The rabbit small clot embolic stroke model (RSCEM) and rabbit large clot embolic stroke model (RLCEM) were used to determine the potential neuroprotective properties and safety profile of microplasmin, respectively, after an embolic stroke.

Methods—

Rabbits were embolized by injecting small blood clots (RSCEM) or large blood clots (RLCEM) into the cerebral circulation. For the RSCEM, 126 rabbits were included, with behavioral analysis conducted 24 hours later, allowing for determination of the effective stroke dose (ES
50
) or clot amount (milligrams) that produces severe neurological deficits in 50% of rabbits. For RLCEM safety study analysis, 47 rabbits were included, with postmortem analyses consisting of assessment of hemorrhage and infarct rate and size. In test animals microplasmin was infused intravenously 60 minutes after embolization, whereas control rabbits were given infusions of the saline/Plasma-Lyte vehicle with all assessments performed in a blinded fashion.

Results—

In the RSCEM, a drug is considered neuroprotective if it significantly increases the ES
50
compared with the vehicle-treated control group. The ES
50
of the vehicle-treated control group 24 hours after embolization was 1.36±0.42 mg (n=38). Microplasmin, infused starting 60 minutes after embolization, increased the ES
50
to 2.32±0.57 (n=21), 1.89±0.48 (n=21), 2.81±0.55 (n=22), and 1.89±0.28 mg (n=24) for the 1-, 2-, 4-, and 8-mg/kg doses, respectively. There was a statistically significant behavioral improvement in the 4-mg/kg dose arm (
P
=0.040). The microplasmin dose of microplasmin that was statistically significant (4 mg/kg) was subsequently determined to be safe in the RLCEM because it did not increase the incidence of hemorrhages (56%) compared with vehicle-treated rabbits (63%), nor did it significantly alter hemorrhage volume, infarct rate, or infarct volume.

Conclusions—

The present study shows that microplasmin improves behavioral rating scores in the RSCEM when administered 60 minutes after embolization, at a dose that does not increase hemorrhages in the RLCEM. This is in contrast to tPA, which significantly enhances the hemorrhage rate in the RLCEM.