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      Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones

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          Abstract

          Aims

          Innate mechanisms of inter-organ protection underlie the phenomenon of remote ischaemic preconditioning (RPc) in which episode(s) of ischaemia and reperfusion in tissues remote from the heart reduce myocardial ischaemia/reperfusion injury. The uncertainty surrounding the mechanism(s) underlying RPc centres on whether humoral factor(s) produced during ischaemia/reperfusion of remote tissue and released into the systemic circulation mediate RPc, or whether a neural signal is required. While these two hypotheses may not be incompatible, one approach to clarify the potential role of a neural pathway requires targeted disruption or activation of discrete central nervous substrate(s).

          Methods and results

          Using a rat model of myocardial ischaemia/reperfusion injury in combination with viral gene transfer, pharmaco-, and optogenetics, we tested the hypothesis that RPc cardioprotection depends on the activity of vagal pre-ganglionic neurones and consequently an intact parasympathetic drive. For cell-specific silencing or activation, neurones of the brainstem dorsal motor nucleus of the vagus nerve (DVMN) were targeted using viral vectors to express a Drosophila allatostatin receptor (AlstR) or light-sensitive fast channelrhodopsin variant (ChIEF), respectively. RPc cardioprotection, elicited by ischaemia/reperfusion of the limbs, was abolished when DVMN neurones transduced to express AlstR were silenced by selective ligand allatostatin or in conditions of systemic muscarinic receptor blockade with atropine. In the absence of remote ischaemia/reperfusion, optogenetic activation of DVMN neurones transduced to express ChIEF reduced infarct size, mimicking the effect of RPc.

          Conclusion

          These data indicate a crucial dependence of RPc cardioprotection against ischaemia/reperfusion injury upon the activity of a distinct population of vagal pre-ganglionic neurones.

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          Most cited references30

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          Annual review prize lecture. Central nervous mechanisms contributing to cardiovascular control.

          M. Spyer (1994)
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            Reverse physiology in drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family.

            By using degenerate oligonucleotide primers deduced from the conserved regions of the mammalian somatostatin receptors, a novel G-protein-coupled receptor from Drosophila melanogaster has been isolated exhibiting structural similarities to mammalian somatostatin/galanin/opioid receptors. To identify the bioactive ligand, a 'reverse physiology' strategy was used whereby orphan Drosophila receptor-expressing frog oocytes were screened against potential ligands. Agonistic activity was electrophysiologically recorded as inward potassium currents mediated through co-expressed G-protein-gated inwardly rectifying potassium channels (GIRK). Using this approach a novel peptide was purified from Drosophila head extracts. Mass spectrometry revealed an octapeptide of 925 Da with a sequence Ser-Arg-Pro-Tyr-Ser-Phe-Gly-Leu-NH(2) reminiscent of insect allatostatin peptides known to control diverse functions such as juvenile hormone synthesis during metamorphosis or visceral muscle contractions. Picomolar concentrations of the synthesized octapeptide activated the cognate receptor response mediated through GIRK1, indicating that we have isolated the 394-amino-acid Drosophila allatostatin receptor which is coupled to the Gi/Go class of G proteins.
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              Essential role of Phox2b-expressing ventrolateral brainstem neurons in the chemosensory control of inspiration and expiration.

              Phox2b-expressing neurons of the retrotrapezoid nucleus (RTN), located in the ventrolateral brainstem, are sensitive to changes in PCO(2)/pH, have excitatory projections to the central respiratory rhythm/pattern generator, and their activation enhances central respiratory drive. Using in vivo (conscious and anesthetized rats) and in situ (arterially perfused rat brainstem-spinal cord preparations) models, we evaluated the functional significance of this neuronal population for both resting respiratory activity and the CO(2)-evoked respiratory responses by reversibly inhibiting these neurons using the insect peptide allatostatin following transduction with a lentiviral construct to express the G-protein-coupled Drosophila allatostatin receptor. Selective inhibition of the Phox2b-expressing neurons in the ventrolateral brainstem, including the RTN, using allatostatin was without effect on resting respiratory activity in conscious rats, but decreased the amplitude of the phrenic nerve discharge in anesthetized rats and the in situ rat preparations. Postinspiratory activity was also reduced in situ. In the absence or presence of the peripheral chemoreceptor input, inhibiting the Phox2b-expressing neurons during hypercapnia abolished the CO(2)-evoked abdominal expiratory activity in anesthetized rats and in situ preparations. Inspiratory responses evoked by rising levels of CO(2) in the breathing air were also reduced in anesthetized rats with denervated carotid bodies and conscious rats with peripheral chemoreceptors intact (by 28% and 60%, respectively). These data indicate a crucial dependence of central expiratory drive upon Phox2b-expressing neurons of the ventrolateral brainstem and support the hypothesis that these neurons contribute in a significant manner to CO(2)-evoked increases of inspiratory activity.
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                Author and article information

                Journal
                Cardiovasc Res
                Cardiovasc. Res
                cvrese
                cardiovascres
                Cardiovascular Research
                Oxford University Press
                0008-6363
                1755-3245
                1 September 2012
                27 June 2012
                27 June 2012
                : 95
                : 4
                : 487-494
                Affiliations
                [1 ]Neuroscience, Physiology and Pharmacology, simpleUniversity College London , Gower Street, London WC1E 6BT, UK
                [2 ]Department of Cardiology, simpleKarolinska Institutet, Karolinska University Hospital , Stockholm, Sweden
                [3 ]Department of Physiology and Pharmacology, simpleUniversity of Bristol , Bristol, UK
                [4 ]Department of Surgery and Cancer, simpleImperial College London , London, UK
                [5 ]Department of Medicine, simpleUniversity College London , London, UK
                Author notes
                [* ]Corresponding author. Tel: +44 20 7679 6480; fax: +44 20 7679 7298, Email: a.gourine@ 123456ucl.ac.uk
                Article
                cvs212
                10.1093/cvr/cvs212
                3422080
                22739118
                4b3c300e-cc15-4af6-b0c5-18694edd17f5
                Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: journals.permissions@oup.com.

                The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oup.com.

                History
                : 12 March 2012
                : 8 June 2012
                : 22 June 2012
                Page count
                Pages: 8
                Categories
                Original Articles
                Custom metadata
                Time for primary review: 28 days

                Cardiovascular Medicine
                preconditioning,ischaemia/reperfusion injury,vagus nerve,brain
                Cardiovascular Medicine
                preconditioning, ischaemia/reperfusion injury, vagus nerve, brain

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