vasoactive-intestinal-peptide--4-chloro-phe(6)-leu(17)- and Disease-Models--Animal

We tested the hypothesis that spontaneous release of vasoactive intestinal peptide (VIP) from enteric neurons maintains homeostasis in smooth muscle function in mild inflammatory insults and that infusion of exogenous VIP has therapeutic effects on colonic smooth muscle dysfunction in inflammation. In vitro experiments were performed on human colonic circular smooth muscle tissues and in vivo on rats. The incubation of human colonic circular smooth muscle strips with TNF-alpha suppressed their contractile response to ACh and the expression of the pore-forming alpha(1C) subunit of Ca(v)1.2 channels. VIP reversed both effects by blocking the translocation of NF-kappaB to the nucleus and its binding to the kappaB recognition sites on halpha(1C)1b promoter. The translocation of NF-kappaB was inhibited by blocking the degradation of IkappaBbeta. Induction of inflammation by a subthreshold dose of 17 mg/kg trinitrobenzene sulfonic acid (TNBS) in rats moderately decreased muscularis externa concentration of VIP, and it had little effect on the contractile response of circular smooth muscle strips to ACh. The blockade of VIP and pituitary adenylate cyclase-activating peptide receptors 1/2 during mild inflammatory insult significantly worsened the suppression of contractility and the inflammatory response. The induction of more severe inflammation by 68 mg/kg TNBS induced marked suppression of colonic circular muscle contractility and decrease in serum VIP. Exogenous infusion of VIP by an osmotic pump reversed these effects. We conclude that the spontaneous release of VIP from the enteric motor neurons maintains homeostasis in smooth muscle function in mild inflammation by blocking the activation of NF-kappaB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.

Topics: Acetylcholine; Active Transport, Cell Nucleus; Animals; Binding Sites; Calcium Channels, L-Type; Cells, Cultured; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Enteric Nervous System; Homeostasis; Hormone Antagonists; Humans; I-kappa B Proteins; In Vitro Techniques; Inflammation Mediators; Infusions, Subcutaneous; Muscle Contraction; Muscle, Smooth; Neuroimmunomodulation; NF-kappa B; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Time Factors; Transfection; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

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.. 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.. 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.. 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.

Topics: Acute Disease; Animals; Capillaries; Ceruletide; Cholagogues and Choleretics; Disease Models, Animal; Duodenum; Hormone Antagonists; Male; Nerve Growth Factors; Neuropeptides; Neurotransmitter Agents; Pancreas, Exocrine; Pancreatitis; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Taurocholic Acid; Vasoactive Intestinal Peptide