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      Impact of Short-Term Treatment with Telmisartan on Cerebral Arterial Remodeling in SHR

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          Abstract

          Background and Purpose

          Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR.

          Methods

          Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships.

          Results

          Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR.

          Conclusion

          In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values.

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          Most cited references20

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          Autoregulation of brain circulation in severe arterial hypertension.

          Cerebral blood flow was studied by the arteriovenous oxygen difference method in patients with severe hypertension and in normotensive controls. The blood pressure was lowered to study the lower limit of autoregulation (the pressure below which cerebral blood flow decreases) and the pressure limit of brain hypoxia. Both limits were shifted upwards in the hypertensive patients, probably as a consequence of hypertrophy of the arteriolar walls. These findings have practical implications for antihypertensive therapy.When the blood pressure was raised some patients showed an upper limit of autoregulation beyond which an increase of cerebral blood flow above the resting value was seen without clinical symptoms. No evidence of vasospasm was found in any patient at high blood pressure. These observations may be of importance for the understanding of the pathogenesis of hypertensive encephalopathy.
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            Remodeling of cerebral arterioles in chronic hypertension.

            Chronic hypertension impairs dilatation of cerebral arterioles. Impairment of dilatation generally has been attributed to hypertrophy of the vessel wall with encroachment on the vascular lumen. In this study, we tested the hypothesis that a reduction in external diameter may contribute to encroachment on the vascular lumen during chronic hypertension. We examined 10-12-month-old, anesthetized Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). External diameter, stress, and strain of pial arterioles were calculated from measurements of pial arteriolar pressure (servo null), diameter, and cross-sectional area of the arteriolar wall. During maximal dilatation produced with ethylenediaminetetraacetic acid, cross-sectional area of the arteriolar wall was greater in SHRSP than in WKY rats (2,038 +/- 57 vs. 1,456 +/- 61 micron 2, p less than 0.05). External, as well as internal, diameter was less in SHRSP than in WKY rats (101 +/- 3 and 88 +/- 3 micron in SHRSP vs. 111 +/- 3 and 102 +/- 3 micron in WKY rats for external and internal diameter, respectively, p less than 0.05). Reduction in external diameter accounted for 76% of encroachment on the lumen in SHRSP, and hypertrophy per se accounted for only 24%. Distensibility of deactivated pial arterioles was increased in SHRSP. These findings suggest that reduction in external diameter plays an important role in impairment of maximal dilatation of cerebral arterioles in SHRSP, and reduction in vascular diameter in SHRSP cannot be accounted for by altered distensibility. We propose that, during chronic hypertension, cerebral arterioles undergo structural remodeling that results in a smaller external diameter and encroachment on the vascular lumen.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Responses of cerebral arteries and arterioles to acute hypotension and hypertension.

              The responses of cerebral precapillary vessels to changes in arterial blood pressure were studied in anesthetized cats equipped with cranial windows for the direct observation of the pial microcirculation of the parietal cortex. Vessel responses were found to be size dependent. Between mean arterial pressures of 110 and 160 mmHg autoregulatory adjustments in caliber, e.g., constriction when the pressure rose and dilation when the pressure decreased, occurred only in vessels larger than 200 micron in diameter. Small arterioles, less than 100 micron in diameter, dilated only at pressures equal to or less than 90 mmHg; below 70 mmHg their dilation exceeded that of the larger vessels. When pressure rose to 170- 200 mmHg, small vessels dilated while the larger vessels remained constricted. At very high pressures (greater than 200 mmHg) forced dilation was frequently irreversible and was accompanied by loss of responsiveness to hypocapnia. Measurement of the pressure differences across various segments of the cerebral vascular bed showed that the larger surface cerebral vessels, extending from the circle of Willis to pial arteries 200 micron in diameter, were primarily responsible for the adjustments in flow over most of the pressure range.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 October 2014
                : 9
                : 10
                : e110766
                Affiliations
                [1]Université de Lorraine, CITHÉFOR “Drug targets, formulation and preclinical assessment,” EA3452, Faculté de Pharmacie, Nancy, France
                Charité Universitätsmedizin Berlin, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SF IL FD. Performed the experiments: SF FD. Analyzed the data: SF IL FD. Contributed reagents/materials/analysis tools: SF IL FD. Contributed to the writing of the manuscript: SF IL FD.

                [¤]

                Current address: CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands

                Article
                PONE-D-14-21615
                10.1371/journal.pone.0110766
                4198293
                37c59068-6b7b-43be-9028-6319ac4c3a1e
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 May 2014
                : 20 September 2014
                Page count
                Pages: 5
                Funding
                The work was funded by the French Ministry of Education, Research and Technology (Paris, France, EA3452), the Lorraine Regional Development Committee (Metz, France), the Regional Coordination and Research Council (Nancy, Metz, France), and the “Université de Lorraine” (Nancy, France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Cerebral Arteries
                Medicine and Health Sciences
                Cardiology
                Cardiovascular Pharmacology
                Pharmacology
                Vascular Medicine
                Blood Pressure
                Hypertension
                Primary Hypertension
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                Uncategorized
                Uncategorized

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