resiniferatoxin and Reperfusion-Injury

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.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cell Adhesion; Diterpenes; Hindlimb; Humans; Intercellular Adhesion Molecule-1; Ischemic Preconditioning; Leukocyte Rolling; Leukocytes; Male; Microcirculation; Microscopy, Video; Nerve Fibers; Neurons, Afferent; Peptide Fragments; Periosteum; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin Gene-Related Peptide; Reperfusion Injury; Sensory Receptor Cells; Venules

We evaluated the effect of capsaicin, one of the transient receptor potential vanilloid receptor 1 (TRPV1) agonists, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated ARF rats markedly decreased at 24 hours after reperfusion. Treatment with capsaicin (3, 10, and 30 mg/kg, orally) 30 minutes before ischemia dose-dependently attenuated ischemia/reperfusion-induced renal dysfunction. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, renal superoxide production, and renal tumor necrosis factor (TNF)-alpha mRNA expression were augmented, but these alterations were attenuated by the treatment with capsaicin. On the other hand, ischemia/reperfusion-enhanced renal interleukin (IL)-10 mRNA expression and plasma concentrations of IL-10 were augmented by treatment with capsaicin in ARF rats. In addition, resiniferatoxin (20 microg/kg, subcutaneous), a more selective and potent TRPV1 agonist, showed a renoprotective effect on ischemia/reperfusion-induced renal injury, in a qualitatively similar way to cases seen with capsaicin. These results demonstrate that TRPV1 agonists prevent ischemia/reperfusion-induced renal dysfunction. These renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1.

Topics: Acute Kidney Injury; Animals; Capsaicin; Diterpenes; Interleukin-10; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Reperfusion Injury; TRPV Cation Channels; Tumor Necrosis Factor-alpha