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Substance P Mediates Cerulein-Induced Pancreatic Microcirculatory Dysfunction in Mice

Objectives: The present study was conducted to examine the contribution of substance P to the pancreatic microcirculatory dysfunction during acute pancreatitis. Methods: Pancreatitis was elicited by up to 6 hourly injections of cerulein (50 &mgr;g/kg IP) in male C57Bl/6 mice. At 0, 1, 3, and 6 hours after cerulein treatment, the pancreatic microvasculature in anesthetized mice was studied using established high-resolution in vivo microscopic methods. Results: Treatment of mice with cerulein for 6 hours caused a 30% decrease in capillary perfusion and the diameter of the capillaries and an increase in microvascular permeability (20%) and interstitial space (30-fold). The administration of the substance P receptor antagonist (D-Arg1, D-Pro2, D-Trp7,9, Leu11) (2 mg/kg IP) minimized the pancreatic microcirculatory dysfunction 3 hours after cerulein treatment. The superfusion of substance P for 0.5 hours decreased the diameter (by 22%) and increased microvascular permeability (by 23%) along with interstitial space (22-fold increase). Blockade of substance P receptor attenuated substance P-induced pancreatic microcirculatory dysfunction. Conclusions: These results suggest that substance P mediates pancreatic microcirculatory dysfunction during the development of acute pancreatitis.