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

Petra Hartmann, Renáta Varga, Zsuzsanna Zobolyák, Júlia Héger, Blanka Csosz, István Németh, Zsolt Rázga, C. Vízler, Dénes Garab, P. Sántha, G. Jancsó, M. Borós, Andrea Szabó

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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 CGRP8-37 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 ischaemiareperfusion- 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 CGRP8-37 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 antiinflammatory 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.

Original languageEnglish
Pages (from-to)179-189
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume383
Issue number2
DOIs
Publication statusPublished - Feb 2011

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Ischemic Preconditioning
Anti-Inflammatory Agents
Extremities
Ischemia
Reperfusion
Calcitonin Gene-Related Peptide Receptors
Calcitonin Gene-Related Peptide
Leukocytes
Tissue Adhesions
Tourniquets
Periosteum
Unmyelinated Nerve Fibers
Venules
Capsaicin
Fluorescence Microscopy
Sprague Dawley Rats
Immunohistochemistry

Keywords

  • CGRP
  • ICAM-1
  • Intravital fluorescence microscopy
  • Microcirculation
  • Preconditioning
  • Resiniferatoxin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats. / Hartmann, Petra; Varga, Renáta; Zobolyák, Zsuzsanna; Héger, Júlia; Csosz, Blanka; Németh, István; Rázga, Zsolt; Vízler, C.; Garab, Dénes; Sántha, P.; Jancsó, G.; Borós, M.; Szabó, Andrea.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 383, No. 2, 02.2011, p. 179-189.

Research output: Contribution to journalArticle

Hartmann, Petra ; Varga, Renáta ; Zobolyák, Zsuzsanna ; Héger, Júlia ; Csosz, Blanka ; Németh, István ; Rázga, Zsolt ; Vízler, C. ; Garab, Dénes ; Sántha, P. ; Jancsó, G. ; Borós, M. ; Szabó, Andrea. / Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2011 ; Vol. 383, No. 2. pp. 179-189.
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AU - Németh, István

AU - Rázga, Zsolt

AU - Vízler, C.

AU - Garab, Dénes

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AU - Szabó, Andrea

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