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Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice.

Abstract
Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of fluid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the neurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil infiltration, a process termed neurogenic inflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of specific NK1-R agonists/antagonists in rats and NK1-R(+/+)/(-/-) mice. The effects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were characterized. In rats, both SP and the NK1-R selective agonist [Sar(9) Met(O(2))(11)]SP stimulated pancreatic plasma extravasation, and this response was blocked by the NK1-R antagonist CP 96,345. Selective agonists of the NK-2 or NK-3 receptors had no effect. In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. These responses were blocked by the NK1-R antagonist CP 96,345. In wildtype mice, SP induced plasma extravasation while SP had no effect in NK1-R knockout mice. In NK1-R knockout mice, the effects of cerulein on pancreatic plasma extravasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75%, as compared to wildtype animals. Neurogenic mechanisms of inflammation are important in the development of inflammatory oedema in acute interstitial pancreatitis.
AuthorsE F Grady, S K Yoshimi, J Maa, D Valeroso, R K Vartanian, S Rahim, E H Kim, C Gerard, N Gerard, N W Bunnett, K S Kirkwood
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 130 Issue 3 Pg. 505-12 (Jun 2000) ISSN: 0007-1188 [Print] England
PMID10821777 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Gastrointestinal Agents
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Substance P
  • Ceruletide
  • Peroxidase
  • Amylases
Topics
  • Acute Disease
  • Amylases (blood)
  • Animals
  • Blood Pressure (drug effects)
  • Ceruletide
  • Edema (pathology, physiopathology)
  • Gastrointestinal Agents
  • Inflammation (pathology, physiopathology)
  • Male
  • Mice
  • Neurokinin-1 Receptor Antagonists
  • Pancreatitis (chemically induced, pathology, physiopathology)
  • Peroxidase (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-1 (drug effects)
  • Substance P (physiology)

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