Pituitary adenylate cyclase activating-peptide and its receptor antagonists in development of acute pancreatitis in rats.
OBJECTIVE
Pituitary adenylate cyclase activating-peptide (PACAP) is a late member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family of brain-gut peptides. It is unknown whether PACAP takes part in the development of acute pancreatitis and whether PACAP or its antagonists can be used to suppress the progression of acute pancreatitis. We investigated the actions of PACAP and its receptor antagonists in acute pancreatitis on rats.


METHODS
Acute pancreatitis was induced in rats with caerulein or 3.5% sodium taurocholate. The rats were continuously infused with 5-30 microg/kg PACAP via jugular vein within the first 90 min, while 10-100 microg/kg PACAP6-27 and (4-Cl-D-Phe6, Leu17) VIP (PACAP receptor antagonists) were intravenously infused for 1 h. Biochemical and histopathological assessments were made at 4 h after infusion. Pancreatic and duodenal PACAP concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Chinese ink-perfused pancreas was fixed, sectioned and cleared for counting the functional capillary density.


RESULTS
PACAP augmented caerulein-induced pancreatitis and failed to ameliorate sodium taurocholate-induced pancreatitis. ELISA revealed that relative concentrations of PACAP in pancreas and duodenum were significantly increased in both sodium taurocholate- and caerulein-induced pancreatitis compared with those in normal controls. Unexpectedly, PACAP6-27 and (4-Cl-D-Phe6, Leu17) VIP could induce mild acute pancreatitis and aggravate caerulein-induced pancreatitis with characteristic manifestations of acute hemorrhagic/necrotizing pancreatitis. Functional capillary density of pancreas was interpreted in the context of pancreatic edema, and calibrated functional capillary density (calibrated FCD), which combined measurement of functional capillary density with dry weight/wet weight ratio, was introduced. Hyperemia or congestion, rather than ischemia, characterized pancreatic microcirculatory changes in acute pancreatitis.


CONCLUSIONS
PACAP may take part in the pathogenesis of acute pancreatitis in rats. The two PACAP receptor antagonsits might act as partial agonists. Calibrated functional capillary density can reflect pancreatic microcirculatory changes in acute pancreatitis.
Chen
You-Dai
YD
Instistute of Digestive Surgery/ Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
Zhou
Zong-Guang
ZG
Wang
Zhao
Z
Gao
Hong-Kai
HK
Yan
Wen-Wei
WW
Wang
Cun
C
Zhao
Gao-Ping
GP
Peng
Xiao-Hui
XH
D000208:Acute Disease; D000818:Animals; D002196:Capillaries; D002108:Ceruletide; D002756:Cholagogues and Choleretics; D004195:Disease Models, Animal; D004386:Duodenum / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D013656:Taurocholic Acid; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000494:pharmacology
C495403:Adcyap1 protein, rat; D002756:Cholagogues and Choleretics; D006727:Hormone Antagonists; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C106317:pituitary adenylate-cyclase-activating peptide (6-27); C048507:vasoactive intestinal peptide, 4-chloro-Phe(6)-Leu(17)-; D014660:Vasoactive Intestinal Peptide; D013656:Taurocholic Acid; D002108:Ceruletide