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      Colocalization of A 2a but not A 1 adenosine receptors with GABA‐ergic neurons in cardiopulmonary chemoreflex network in the caudal nucleus of the solitary tract

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          Abstract

          Adenosine operating in the nucleus of the solitary tract (NTS) may inhibit or facilitate neurotransmitter release from nerve terminals and directly inhibit or facilitate central neurons via A 1 and A 2a pre‐ and postsynaptic receptors, respectively. However, adenosine A 2a receptors, may also activate GABA‐ergic neurons/terminals which in turn inhibit glutamatergic transmission in the NTS network. Our previous studies showed that adenosine operating via both A 1 (inhibitor) and A 2a (activator) receptors powerfully inhibits the cardiopulmonary chemoreflex ( CCR) at the level of the caudal NTS. A 1 receptors most likely inhibit glutamate release in the CCR network, whereas A 2a receptors facilitate NTS GABA‐ergic mechanisms which in turn inhibit CCR glutamatergic transmission. Therefore, we hypothesized that A 2a receptors are located on NTS GABA‐ergic neurons/terminals whereas A 1 receptors may be located on NTS glutamatergic neurons/terminals. We investigated this hypothesis using double immunofluorescent staining for A 2a or A 1 adenosine receptors and GABA synthesizing enzyme, GAD67, in 30  μm thick, floating, medullary rat sections. We found that A 2a adenosine receptors are localized within the GABA‐ergic cells in the caudal NTS, whereas A 1 adenosine receptors are absent from these neurons. Instead, A 1 receptors were located on non‐ GABA‐ergic (likely glutamatergic) neurons/terminals in the caudal NTS. These data support our functional findings and the hypothesis that adenosine A 2a, but not A 1 receptors are located on GABA‐ergic neurons.

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          The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart.

          The concept of depressor reflexes originating in the heart was introduced by von Bezold in 1867 and was later revived by Jarisch. The Bezold-Jarisch reflex originates in cardiac sensory receptors with nonmyelinated vagal afferent pathways. The left ventricle, particularly the inferoposterior wall, is a principal location for these sensory receptors. Stimulation of these inhibitory cardiac receptors by stretch, chemical substances or drugs increases parasympathetic activity and inhibits sympathetic activity. These effects promote reflex bradycardia, vasodilation and hypotension (Bezold-Jarisch reflex) and also modulate renin release and vasopressin secretion. Conversely, decreases in the activity of these inhibitory sensory receptors reflexly increase sympathetic activity, vascular resistance, plasma renin activity and vasopressin. Long regarded as pharmacologic curiosities, it is now clear that reflexes originating in these inhibitory cardiac sensory receptors are important to the pathophysiology of many cardiovascular disorders. This paper reviews the role of inhibitory cardiac sensory receptors in several clinical states including 1) bradycardia, hypotension and gastrointestinal disorders with inferoposterior myocardial ischemia and infarction, 2) bradycardia and hypotension during coronary arteriography, 3) exertional syncope in aortic stenosis, 4) vasovagal syncope, 5) neurohumoral excitation in chronic heart failure, and 6) the therapeutic effects of digitalis.
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            Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum.

            Activation of adenosine A2A receptors (A2AR) has been shown to antagonize the function of D2 dopaminergic regulation of striatal gamma-aminobutyric acid (GABA)-ergic output and, thus, locomotor activity. Adenosine A2A receptor immunoreactivity (A2A-LI) has been localized to rat striatum by light microscopy by using a previously characterized human A2AR monoclonal antibody. In this study, we evaluated the localization of A2A-LI and its colocalization with GABA immunoreactivity (GABA-LI) in dorsolateral rat striatum by immunoelectron microscopy to further characterize the potential mechanism of purinergic control of striatal output. Ultrastructural analysis demonstrated A2A-LI associated with the plasma membrane and cytoplasmic membranous structures of striatal neurons. A2A-LI was prevalent in dendrites and dendritic spines ( approximately 70% of total A2A-profiles counted) and less prevalent in axons and axon terminals (23%), soma (3%), and glia (3%). Cellular elements exhibiting both A2A-LI and GABA-LI comprised 23% of the total profiles counted; colabeling was most common in dendrites. A2A-LI was observed primarily at asymmetric synapses (n = 70) (both pre- and postsynaptically but predominantly in the postsynaptic element) and less frequently at symmetric synapses (n = 17). Of the 714 A2A-immunoreactive profiles examined, 37% were apposed to GABA-labeled profiles. The most common appositions were A2A-labeled dendrites apposed to GABA-immunoreactive dendrites (n = 132), axon terminals (n = 28), and somata (n = 22) and A2A-labeled axons apposed to GABA-labeled dendrites (n = 58), axon terminals (n = 14), and somata (n = 9). Our findings suggest that adenosine may play an important role in modulating excitatory input to striatal neurons and that A2AR may modulate GABAergic signaling at several cellular sites within the rat striatum. Copyright 2001 Wiley-Liss, Inc.
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              Inhibition of NMDA receptor-mediated currents in isolated rat hippocampal neurones by adenosine A1 receptor activation.

              The effect of the stable adenosine analogue, 2-chloro-adenosine (CADO), on the currents elicited by iontophoretic application of N-methyl-D-aspartate (NMDA) to pyramidal cells acutely dissociated from the CA1 area of the rat hippocampus was studied using the patch-clamp technique in the whole-cell configuration. CADO (3-300 nM) reversibly inhibited NMDA receptor-mediated currents (maximal effect: 54.2 +/- 6.6% decrease, EC50 = 10.3 nM). This effect was prevented by the adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (50 nM). CADO (100 nM inhibited the conductance induced by iontophoretic application of NMDA, without changing its reversal potential, in both the absence and the presence of Mg2+ (30 microM). Adenosine may contribute to the regulation of the NMDA receptor function, particularly under conditions, like hypoxia and ischaemia, leading to excessive NMDA receptor activation.
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                Author and article information

                Contributors
                zminic@med.wayne.edu
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                22 November 2018
                November 2018
                : 6
                : 22 ( doiID: 10.1002/phy2.2018.6.issue-22 )
                : e13913
                Affiliations
                [ 1 ] Department of Physiology Wayne State University School of Medicine Detroit Michigan
                [ 2 ] Department of Anatomy and Cell Biology Wayne State University School of Medicine Detroit Michigan
                [ 3 ] Department of Emergency Medicine Wayne State University School of Medicine Detroit Michigan
                [ 4 ] Cardiovascular Research Institute Wayne State University School of Medicine Detroit Michigan
                Author notes
                [*] [* ] Correspondence

                Zeljka Minic, Department of Emergency Medicine, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201.

                Tel: (313)577‐8648

                Fax: (313)933‐7703

                E‐mail: zminic@ 123456med.wayne.edu

                Author information
                http://orcid.org/0000-0002-8427-9605
                Article
                PHY213913
                10.14814/phy2.13913
                6250926
                30467998
                12f568cc-6a43-482d-98da-b24bbacf9623
                © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 August 2018
                : 24 September 2018
                : 12 October 2018
                Page count
                Figures: 3, Tables: 0, Pages: 7, Words: 4857
                Funding
                Funded by: National Institute of Health
                Award ID: HL‐67814
                Categories
                Original Research
                Original Research
                Custom metadata
                2.0
                phy213913
                November 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:23.11.2018

                adenosine receptors,cardiopulmonary chemoreflex,nts
                adenosine receptors, cardiopulmonary chemoreflex, nts

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