NK-1 receptor desensitization and neutral endopeptidase terminate SP-induced pancreatic plasma extravasation

Substance P (SP) induces plasma extravasation and neutrophil infiltration b y activating the neurokinin-1 receptor (NK1-R). We characterized the mechan isms regulating this response in the rat pancreas. Anesthetized rats were c ontinuously infused with SP, and plasma extravasation was quantified using Evans blue (EB) dye. Continuous infusion of SP (8 nmol . kg(-1) . h(-1)) re sulted in a threshold increase in EB at 15 min, a peak effect at 30 min (15 0% increase), and a return to baseline by 60 min. The NK1-R antagonist CP-9 6,345 blocked SP-induced plasma extravasation. After 60 min, the NK1-R was desensitized to agonist challenge. Resensitization was first detected at 20 min and increased until full recovery was seen at 30 min. Inhibition of th e cell-surface protease neutral endopeptidase (NEP) by phosphoramidon poten tiated the effect of exogenous SP; therefore endogenous NEP attenuates SP-i nduced plasma extravasation. Thus the continuous infusion of SP stimulates plasma extravasation in the rat pancreas via activation of the NK1-R, and t hese effects are terminated by both desensitization of the NK1-R and the ce ll-surface protease NEP.