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      Comparison of Adrenergic and Purinergic Receptor Contributions to Vasomotor Responses in Mesenteric Arteries of C57BL/6J Mice and Wistar Rats

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          Introduction: The sympathetic nervous system can modulate arteriolar tone through release of adenosine triphosphate and norepinephrine, which bind to purinergic and adrenergic receptors (ARs), respectively. The expression pattern of these receptors, as well as the composition of neurotransmitters released from perivascular nerves (PVNs), can vary both in organ systems within and across species, such as mice and rats. Objective: This study explores the function of α<sub>1A</sub> subtypes in mouse and rat third-order mesenteric arteries and investigates PVN-mediated vasoconstriction to identify which neurotransmitters are released from sympathetic PVNs. Methods: Third-order mesenteric arteries from male C57BL/6J mice and Wistar rats were isolated and mounted on a wire myograph for functional assessment. Arteries were exposed to phenylephrine (PE) and then incubated with either α<sub>1A</sub> antagonist RS100329 (RS) or α<sub>1D</sub> antagonist BMY7378, before reexposure to PE. Electrical field stimulation was performed by passing current through platinum electrodes positioned adjacent to arteries in the absence and presence of a nonspecific alpha AR blocker phentolamine and/or P2X<sub>1</sub>-specific purinergic receptor blocker NF449. Results: Inhibition of α<sub>1</sub> ARs by RS revealed that PE-induced vasoconstriction is primarily mediated through α<sub>1A</sub> and that the contribution of the α<sub>1A</sub> AR is greater in rats than in mice. In the mouse model, sympathetic nerve-mediated vasoconstriction is mediated by both ARs and purinergic receptors, whereas in rats, vasoconstriction appeared to only be mediated by ARs and a nonpurinergic neurotransmitter. Further, neither model demonstrated that α<sub>1D</sub> ARs play a significant role in PE-mediated vasoconstriction. Conclusions: The mesenteric arteries of male C57BL/6J mice and Wistar rats have subtle differences in the signaling mechanisms used to mediate vasoconstriction. As signaling pathways in humans under physiological and pathophysiological conditions become better defined, the current study may inform animal model selection for preclinical studies.

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          Is Open Access

          THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors

          The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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            Do some nerve cells release more than one transmitter?

            The concept that each nerve cell makes and releases only one nerve transmitter (widely known as Dale's Principle) has been re-examined. Experiments suggesting that some nerve cells store and release more than one transmitter have been reviewed. Developmental and evolutionary factors are considered. Conceptual and experimental difficulties in investigating this problem are discussed. It is suggested that the term 'transmitter' should be applied to any substance that is synthesised and stored in nerve cells, is released during nerve activity and whose interaction with specific receptors on the postsynaptic membrane leads to changes in postsynaptic activity. Expressed in this way, it seems likely that while many nerves do have only one transmitter, others in some species, during development or during hormone-dependent cycles, employ multiple transmitters.
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              Elevation of intracellular calcium in smooth muscle causes endothelial cell generation of NO in arterioles.

              It is well known that vascular smooth muscle tone can be modulated by signals arising in the endothelium (e.g., endothelium-derived relaxing factor, endothelium-derived hyperpolarizing factor, and prostaglandins). Here we show that during vasoconstriction a signal can originate in smooth muscle cells and act on the endothelium to cause synthesis of endothelium-derived relaxing factor. We studied responses to two vasoconstrictors (phenylephrine and KCl) that act by initiating a rise in smooth muscle cell intracellular Ca2+ concentration ([Ca2+]i) and exert little or no direct effect on the endothelium. Fluo-3 was used as a Ca2+ indicator in either smooth muscle or endothelial cells of arterioles from the hamster cheek pouch. Phenylephrine and KCl caused the expected rise in smooth muscle cell [Ca2+]i that was accompanied by an elevation in endothelial cell [Ca2+]i. The rise in endothelial cell [Ca2+]i was followed by increased synthesis of NO, as evidenced by an enhancement of the vasoconstriction induced by both agents after blockade of NO synthesis. The molecule involved in signal transmission from smooth muscle to endothelium is as yet unknown. However, given that myoendothelial cell junctions are frequent in these vessels, we hypothesize that the rise in smooth muscle cell Ca2+ generates a diffusion gradient that drives Ca2+ through myoendothelial cell junctions and into the endothelial cells, thereby initiating the synthesis of NO.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                January 2021
                11 December 2020
                : 58
                : 1
                : 1-15
                aDepartment of Medical Physiology, Texas A&M University Health Science Center, Bryan, Texas, USA
                bDepartment of Microbiology and Molecular Medicine University of Geneva, Geneva, Switzerland
                Author notes
                *Pooneh Bagher, Department of Medical Physiology, Texas A&amp;M University Health Science Center, Medical Research and Education, Building 2, 8447 Riverside Parkway, Bryan, TX 77807 (USA), bagher@tamu.edu
                511462 J Vasc Res 2021;58:1–15
                © 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: 15
                Research Article


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