title: Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats.
abstract: 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.
authors.affiliation: Institute of Surgical Research, University of Szeged, Pécsi utca 6, 6720, Szeged, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Hartmann
authors.forename: Renáta
authors.initials: R
authors.lastname: Varga
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Zobolyák
authors.forename: Júlia
authors.initials: J
authors.lastname: Héger
authors.forename: Blanka
authors.initials: B
authors.lastname: Csosz
authors.forename: István
authors.initials: I
authors.lastname: Németh
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Rázga
authors.forename: Csaba
authors.initials: C
authors.lastname: Vízler
authors.forename: Dénes
authors.initials: D
authors.lastname: Garab
authors.forename: Péter
authors.initials: P
authors.lastname: Sántha
authors.forename: Gábor
authors.initials: G
authors.lastname: Jancsó
authors.forename: Mihály
authors.initials: M
authors.lastname: Boros
authors.forename: Andrea
authors.initials: A
authors.lastname: Szabó
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000627:therapeutic use; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002448:Cell Adhesion / Q000187:drug effects; D004224:Diterpenes / Q000627:therapeutic use; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018715:Microscopy, Video; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000627:therapeutic use; D010521:Periosteum / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000819:agonists*; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D014699:Venules / Q000187:drug effects / Q000378:metabolism
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004224:Diterpenes; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D018799:Intercellular Adhesion Molecule-1; C024353:resiniferatoxin; D015740:Calcitonin Gene-Related Peptide