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      Cerebrovascular Reactivity to L-Arginine in Patients with Lacunar Infarctions

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          Abstract

          Background: It is well known that endothelial dysfunction plays an important role in the pathogenesis of many cardiovascular disorders. The aim of this study was to test the hypothesis that specific, marked endothelial dysfunction of cerebral arteries is present in patients with lacunar cerebral infarctions. Methods: Cerebrovascular reactivity to L-arginine, which reveals the function of the cerebral endothelium, was investigated in patients with lacunar infarctions (20 patients, 11 male and 9 female, aged 60.9 ± 7.3 years), 21 age- and gender-matched asymptomatic patients with similar cardiovascular risk factors (all patients had arterial hypertension) and 21 age- and gender-matched healthy controls. The mean arterial velocity (v<sub>m</sub>) in both middle cerebral arteries was measured by transcranial Doppler sonography during a 15-min baseline period, a 30-min intravenous infusion of L-arginine and a 15-min interval after L-arginine infusion. Arterial blood pressure, heart rate and CO<sub>2</sub> were measured continuously. Results: The measured v<sub>m</sub> increase during L-arginine infusion in the patients with lacunar infarctions (13.4 ± 9.1%) was significantly lower compared to the healthy controls (20.5 ± 9.9%) but similar to that obtained in the patients with cardiovascular risk factors (11.5 ± 8.9%). Conclusions: Our results showed that cerebrovascular reactivity to L-arginine, which demonstrates cerebral endothelial function, is significantly impaired in patients with cardiovascular risk factors. Importantly, we found that patients with lacunar infarctions do not show any additional impairment of cerebral endothelial function.

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          Vascular endothelial cells synthesize nitric oxide from L-arginine.

          Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue and for the inhibition of platelet aggregation and platelet adhesion attributed to endothelium-derived relaxing factor. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay, chemiluminescence or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
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            Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.

            Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension. To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography. The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03). Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.
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              Mannheim Intima-Media Thickness Consensus

              Intima-media thickness (IMT) is increasingly used in clinical trials as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. The necessity for unified criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is addressed in this consensus statement. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of ≧1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is recommended in all epidemiological and interventional trials dealing with vascular diseases to improve characterization of the population investigated. The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMT values in individual patients apart from few exceptions. Although IMT has been suggested to represent an important risk marker, it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of studies incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.
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                Author and article information

                Journal
                CED
                Cerebrovasc Dis
                10.1159/issn.1015-9770
                Cerebrovascular Diseases
                S. Karger AG
                1015-9770
                1421-9786
                2006
                February 2006
                24 February 2006
                : 21
                : 3
                : 180-186
                Affiliations
                Departments of a Neurology and b Internal Medicine, Ljubljana Medical Centre, Ljubljana, Slovenia
                Article
                90530 Cerebrovasc Dis 2006;21:180–186
                10.1159/000090530
                16388193
                5af7559a-86fc-454f-b922-66f20062a822
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 17 June 2005
                : 21 September 2005
                Page count
                Figures: 2, Tables: 2, References: 25, Pages: 7
                Categories
                Original Paper

                Geriatric medicine,Neurology,Cardiovascular Medicine,Neurosciences,Clinical Psychology & Psychiatry,Public health
                Endothelial dysfunction,Nitric oxide synthase,Lacunar infarction,Nitric oxide,Cerebrovascular reactivity to <italic>L-</italic>arginine

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