Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats

We have shown that ischaemic preconditioning ameliorates both the local periosteal and the systemic leukocyte activation evoked by limb ischaemia–reperfusion. We hypothesized that the activation of chemosensitive afferent nerves by transient ischaemia contributes to the protective mechanisms of isch...

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Published in:Naunyn-Schmiedeberg's archives of pharmacology 2011-02, Vol.383 (2), p.179-189
Main Authors: Hartmann, Petra, Varga, Renáta, Zobolyák, Zsuzsanna, Héger, Júlia, Csősz, Blanka, Németh, István, Rázga, Zsolt, Vízler, Csaba, Garab, Dénes, Sántha, Péter, Jancsó, Gábor, Boros, Mihály, Szabó, Andrea
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Calcitonin Gene-Related Peptide - therapeutic use
Cell Adhesion - drug effects
Diterpenes - therapeutic use
Hindlimb - blood supply
Humans
Intercellular Adhesion Molecule-1 - metabolism
Ischemic Preconditioning - methods
Leukocyte Rolling - drug effects
Leukocytes - cytology
Leukocytes - drug effects
Male
Microcirculation - drug effects
Microscopy, Video
Nerve Fibers - drug effects
Nerve Fibers - metabolism
Neurons, Afferent - drug effects
Neurons, Afferent - metabolism
Neurosciences
Original Article
Peptide Fragments - therapeutic use
Periosteum - blood supply
Periosteum - immunology
Periosteum - metabolism
Pharmacology/Toxicology
Rats
Rats, Sprague-Dawley
Receptors, Calcitonin Gene-Related Peptide - agonists
Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors
Reperfusion Injury - blood
Reperfusion Injury - immunology
Reperfusion Injury - metabolism
Reperfusion Injury - prevention & control
Sensory Receptor Cells - drug effects
Sensory Receptor Cells - metabolism
Venules - drug effects
Venules - metabolism
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Summary:We have shown that ischaemic preconditioning ameliorates both the local periosteal and the systemic leukocyte activation evoked by limb ischaemia–reperfusion. We hypothesized that the activation of chemosensitive afferent nerves by transient ischaemia contributes to the protective mechanisms of ischaemic preconditioning via a calcitonin gene-related peptide (CGRP)-dependent mechanism. In Sprague–Dawley rats, 60-min complete limb ischaemia was followed by 180 min of reperfusion. In further experiments, the CGRP analogue hCGRP (0.3 μg kg −1 ) or ischaemic preconditioning (2 × 10-min ischaemia/10-min reperfusion) was applied prior to the ischaemia–reperfusion insult. Ischaemic preconditioning was performed in three subgroups in which animals received the CGRP receptor antagonist CGRP 8–37 (30 μg kg −1  h −1 ), the chemosensitive afferent nerve inactivator resiniferatoxin (3 × 15 μg kg −1 , sc), or vehicle. The effects of CGRP 8-37 and resiniferatoxin on ischaemia–reperfusion without ischaemic preconditioning were also evaluated. In the tibial periosteum of rats, intravital fluorescence microscopy and immunohistochemistry revealed significant attenuations of ischaemia-reperfusion-induced post-ischaemic leukocyte–endothelial interactions (rolling and adherence in the postcapillary venules) and tissue intracellular adhesion molecule expression following ischaemic preconditioning or hCGRP administration. Administration of CGRP 8-37 or pretreatment of animals with resiniferatoxin reversed the anti-inflammatory effects of limb ischaemic preconditioning, but failed to affect the microcirculatory consequences of ischaemia–reperfusion without ischaemic preconditioning. The results suggest that activation of the chemo- (capsaicin-) sensitive afferent nerves is involved in the mechanisms of microcirculatory anti-inflammatory protection provided by limb ischaemic preconditioning. Controlled activation of chemosensitive C-fibres or the CGRP receptors by the induction of ischaemic preconditioning or other means may furnish therapeutic benefit by ameliorating the periosteal microcirculatory consequences of tourniquet ischaemia.
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-010-0588-4