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      Novel Expression of GABA A Receptors on Resistance Arteries That Modulate Myogenic Tone

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          Abstract

          The clinical administration of GABAergic medications leads to hypotension which has classically been attributed to the modulation of neuronal activity in the central and peripheral nervous systems. However, certain types of peripheral smooth muscle cells have been shown to express GABA<sub>A</sub> receptors, which modulate smooth muscle tone, by the activation of these chloride channels on smooth muscle cell plasma membranes. Limited prior studies demonstrate that non-human large-caliber capacitance blood vessels mounted on a wire myograph are responsive to GABA<sub>A</sub> ligands. We questioned whether GABA<sub>A</sub> receptors are expressed in human resistance arteries and whether they modulate myogenic tone. We demonstrate the novel expression of GABA<sub>A</sub> subunits on vascular smooth muscle from small-caliber human omental and mouse tail resistance arteries. We show that GABA<sub>A</sub> receptors modulate both plasma membrane potential and calcium responses in primary cultured cells from human resistance arteries. Lastly, we demonstrate functional physiologic modulation of myogenic tone via GABA<sub>A</sub> receptor activation in human and mouse arteries. Together, these studies demonstrate a previously unrecognized role for GABA<sub>A</sub> receptors in the modulation of myogenic tone in mouse and human resistance arteries.

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          Most cited references 34

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          Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000.

          Prior analyses of National Health and Nutrition Examination Survey (NHANES) data through 1991 have suggested that hypertension prevalence is declining, but more recent self-reported rates of hypertension suggest that the rate is increasing. To describe trends in the prevalence, awareness, treatment, and control of hypertension in the United States using NHANES data. Survey using a stratified multistage probability sample of the civilian noninstitutionalized population. The most recent NHANES survey, conducted in 1999-2000 (n = 5448), was compared with the 2 phases of NHANES III conducted in 1988-1991 (n = 9901) and 1991-1994 (n = 9717). Individuals aged 18 years or older were included in this analysis. Hypertension, defined as a measured blood pressure of 140/90 mm Hg or greater or reported use of antihypertensive medications. Hypertension awareness and treatment were assessed with standardized questions. Hypertension control was defined as treatment with antihypertensive medication and a measured blood pressure of less than 140/90 mm Hg. In 1999-2000, 28.7% of NHANES participants had hypertension, an increase of 3.7% (95% confidence interval [CI], 0%-8.3%) from 1988-1991. Hypertension prevalence was highest in non-Hispanic blacks (33.5%), increased with age (65.4% among those aged > or =60 years), and tended to be higher in women (30.1%). In a multiple regression analysis, increasing age, increasing body mass index, and non-Hispanic black race/ethnicity were independently associated with increased rates of hypertension. Overall, in 1999-2000, 68.9% were aware of their hypertension (nonsignificant decline of -0.3%; 95% CI, -4.2% to 3.6%), 58.4% were treated (increase of 6.0%; 95% CI, 1.2%-10.8%), and hypertension was controlled in 31.0% (increase of 6.4%; 95% CI, 1.6%-11.2%). Women, Mexican Americans, and those aged 60 years or older had significantly lower rates of control compared with men, younger individuals, and non-Hispanic whites. Contrary to earlier reports, hypertension prevalence is increasing in the United States. Hypertension control rates, although improving, continue to be low. Programs targeting hypertension prevention and treatment are of utmost importance.
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            Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012.

            The overall prevalence of hypertension has not changed appreciably since 2009-2010. The age-adjusted prevalence of hypertension among U.S. adults was 29.1% in 2011-2012. Among adults with hypertension in 2011-2012, 82.8% were aware of their hypertension, 75.7% were currently taking medication to lower their blood pressure, and 51.9% had their blood pressure controlled to less than 140/90 mm Hg. Men and women had similar prevalence and awareness of hypertension, but more women than men were treating their hypertension and had it under control. Young adults aged 18-39 continued to have lower awareness, treatment, and control of their hypertension compared with older adults. Hypertension prevalence was still highest among non-Hispanic black adults. However, awareness, treatment, and control of hypertension were similar among non-Hispanic black, non-Hispanic white, and Hispanic adults. Non-Hispanic Asian adults had a lower prevalence of awareness than the other race and Hispanic origin groups, and lower treatment than non-Hispanic white and non-Hispanic black adults. However, hypertension control was similar among non-Hispanic Asian adults and the other race and Hispanic origin groups. Hypertension is a common and manageable chronic condition. Based on recent national data from 2011-2012, treatment of hypertension exceeded the Healthy People 2020 target goal of 69.5%. However, the control of hypertension has neither met the goal of the Healthy People 2020 (61.2% by 2020) nor the Million Hearts Initiative (65% by 2017). These results provide evidence for continued efforts to improve the management of hypertension in order to attain these goals. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.
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              From ion currents to genomic analysis: recent advances in GABAA receptor research.

              The gamma-aminobutyric acid type A (GABAA) receptor represents an elementary switching mechanism integral to the functioning of the central nervous system and a locus for the action of many mood- and emotion-altering agents such as benzodiazepines, barbiturates, steroids, and alcohol. Anxiety, sleep disorders, and convulsive disorders have been effectively treated with therapeutic agents that enhance the action of GABA at the GABAA receptor or increase the concentration of GABA in nervous tissue. The GABAA receptor is a multimeric membrane-spanning ligand-gated ion channel that admits chloride upon binding of the neurotransmitter GABA and is modulated by many endogenous and therapeutically important agents. Since GABA is the major inhibitory neurotransmitter in the CNS, modulation of its response has profound implications for brain functioning. The GABAA receptor is virtually the only site of action for the centrally acting benzodiazepines, the most widely prescribed of the anti-anxiety medications. Increasing evidence points to an important role for GABA in epilepsy and various neuropsychiatric disorders. Recent advances in molecular biology and complementary information derived from pharmacology, biochemistry, electrophysiology, anatomy and cell biology, and behavior have led to a phenomenal growth in our understanding of the structure, function, regulation, and evolution of the GABAA receptor. Benzodiazepines, barbiturates, steroids, polyvalent cations, and ethanol act as positive or negative modulators of receptor function. The description of a receptor gene superfamily comprising the subunits of the GABAA, nicotinic acetylcholine, and glycine receptors has led to a new way of thinking about gene expression and receptor assembly in the nervous system. Seventeen genetically distinct subunit subtypes (alpha 1-alpha 6, beta 1-beta 4, gamma 1-gamma 4, delta, p1-p2) and alternatively spliced variants contribute to the molecular architecture of the GABAA receptor. Mysteriously, certain preferred combinations of subunits, most notably the alpha 1 beta 2 gamma 2 arrangement, are widely codistributed, while the expression of other subunits, such as beta 1 or alpha 6, is severely restricted to specific neurons in the hippocampal formation or cerebellar cortex. Nervous tissue has the capacity to exert control over receptor number, allosteric uncoupling, subunit mRNA levels, and posttranslational modifications through cellular signal transduction mechanisms under active investigation. The genomic organization of the GABAA receptor genes suggests that the present abundance of subtypes arose during evolution through the duplication and translocations of a primordial alpha-beta-gamma gene cluster. This review describes these varied aspects of GABAA receptor research with special emphasis on contemporary cellular and molecular discoveries.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2020
                May 2020
                25 February 2020
                : 57
                : 3
                : 113-125
                Affiliations
                aDepartment of Anesthesiology, Columbia University, New York, New York, USA
                bDepartment of Surgery, Columbia University, New York, New York, USA
                cDepartment of Anesthesiology and Perioperative Medicine, University of Alabama, Birmingham, Alabama, USA
                Author notes
                *Dr. Peter D. Yim, Department of Anesthesiology, 622 West 168th Street, P&amp;S Box 46, New York, NY 10032 (USA), pdy1@columbia.edu
                Article
                505456 J Vasc Res 2020;57:113–125
                10.1159/000505456
                32097943
                © 2020 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.

                Page count
                Figures: 5, Tables: 1, Pages: 13
                Categories
                Research Article

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