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


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.


CONCLUSIONS
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.
Neuroscience, Physiology and Pharmacology,  University College London, Gower Street, London WC1E 6BT,  UK.
Svetlana
S
Mastitskaya
Nephtali
N
Marina
Andrey
A
Gourine
Michael P
MP
Gilbey
K Michael
KM
Spyer
Anja G
AG
Teschemacher
Sergey
S
Kasparov
Stefan
S
Trapp
Gareth L
GL
Ackland
Alexander V
AV
Gourine
D000200:Action Potentials; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003250:Constriction; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D006321:Heart / Q000294:innervation*; D006614:Hindlimb; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000098:blood supply*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009434:Neural Pathways / Q000503:physiopathology; D009479:Neuropeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
C096426:AstA-R1 protein, Drosophila; D029721:Drosophila Proteins; D018727:Muscarinic Antagonists; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011993:Recombinant Fusion Proteins; C076523:allatostatin; D001285:Atropine; D012243:Rhodopsin