Neurogenic components of trypsin- and thrombin-induced inflammation in rat skin, in vivo.
Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10(-8)-10(-4) M) and thrombin (10(-6), 10(-5.5) and 10(-5) M) provoked PE and local VD in a dose-dependent manner. Trypsin (10(-4) M)-induced PE was inhibited by 87.2 +/- 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 +/- 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). By contrast, CGRP(8-37) did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10(-6) M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.
Obreja
Otilia
O
Department of Anaesthesiology and Intensive Care, Faculty of Clinical Medicine Mannheim, University of Medicine Heidelberg, Mannheim, Germany.
Rukwied
Roman
R
Steinhoff
Martin
M
Schmelz
Martin
M
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044462:Receptors, Proteinase-Activated / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000503:physiopathology*; D013917:Thrombin / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011812:Quinuclidines; D044462:Receptors, Proteinase-Activated; C058636:calcitonin gene-related peptide (8-37); C085215:SR 140333; D014357:Trypsin; D013917:Thrombin; D015740:Calcitonin Gene-Related Peptide