Characterization of neurogenic inflammation in the airways of two highly inbred rat strains.
Tachykinins released from sensory airway nerves have been shown to increase vascular permeability and plasma-protein extravasation (PPE) in rodent airways. We previously demonstrated that in Fisher (F344) rats, tachykinins cause bronchoconstriction mainly by indirect mechanisms involving the activation of NK1 receptor and mast cells, whereas in the less responsive BDE rats tachykinins have a direct NK2 receptor-mediated effect on bronchial smooth muscle. Using Evans blue dye as an intravascular marker, we demonstrated that F344 rats are hyperresponsive for the PPE induced by substance P (SP) and capsaicin. The NK1 receptor antagonist RP 67,580 reduced the neurogenic PPE in both strains, whereas the NK2 receptor antagonist SR 48,968 had no effect, indicating that only NK1 receptors are involved in the PPE. Pretreatment with the 5-HT antagonist methysergide decreased the neurogenic PPE in F344 rats but not in BDE rats. In F344 rats depleted of mast-cell mediators with compound 48/80, the SP-induced PPE was significantly reduced. Pretreatment with the H1 antagonist mepyramine and the H2 antagonist cimetidine caused a similar reduction in SP-induced PPE in main bronchi of both strains. Pretreatment with atropine, indomethacin, or the leukotriene antagonist ICI 198,615 did not affect the SP-induced PPE. In conclusion, neurogenic PPE in rat airways involves the activation of NK1 receptors. In F344 but not in BDE rats, an additional indirect mechanism involving 5-HT release and mast-cell activation participates in the neurogenic PPE.
Department of Respiratory Diseases, University of Ghent, Belgium.
P R
PR
Germonpré
G F
GF
Joos
E
E
Everaert
J C
JC
Kips
R A
RA
Pauwels
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000098:blood supply* / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin; D002927:Cimetidine / Q000494:pharmacology; D004396:Coloring Agents; D004305:Dose-Response Relationship, Drug; D005070:Evans Blue; D006633:Histamine Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D054833:Isoindoles; D008784:Methysergide / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013373:Substance P; D014132:Trachea / Q000098:blood supply* / Q000187:drug effects
D001549:Benzamides; D004396:Coloring Agents; D006633:Histamine Antagonists; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D012702:Serotonin Antagonists; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D012701:Serotonin; D013373:Substance P; D005070:Evans Blue; C073839:SR 48968; D002927:Cimetidine; D011738:Pyrilamine; D002211:Capsaicin; D008784:Methysergide