In 1972, Green and Lyman5 reported that diversion of pancreatic juice from the duodenum or intraduodenal infusion of soybean trypsin inhibitor resulted in an increase in pancreatic secretion of proteins. The increase was abolished by the return of pancreatic juice or trypsin. It was proposed that pancreatic proteases play a negative feedback regulatory role on pancreatic exocrine secretion. Subsequent studies have indicated that such feedback regulatory mechanism is operative in several species, including the rat, human, dog, pig, and guinea pig.35 In rats, pigs, and humans, luminally administered proteases were shown to suppress PES both in the fasting state and the intestinal phase; whereas in dogs and guinea pigs, PES was suppressed only in the intestinal phase stimulated by emulsified oleic acid or sodium oleate or a meal (in dogs). In fasting rats, diversion of pancreatic juice from the duodenum or intraduodenal infusion of a trypsin inhibitor results in a significant increase in pancreatic secretion of protein and bicarbonate that was accompanied by elevation of both CCK and secretin in circulation. The increased pancreatic secretion was attributable to the increased release of CCK and secretin as it was abolished either by administration of a CCK receptor antagonist, an anti-CCK serum, or an anti-secretin serum. Diversion of pancreatic juice in dogs also increased plasma neurotensin level, which was suppressed by intraduodenal infusion of lipase. Moreover, diversion-evoked increase in PES was reduced by immunoneutralization of circulating neurotensin. Similarly, plasma PYY concentration in rats increased after pancreatic juice diversion. Immunon-eutralization of circulating PYY in rats resulted in augmentation of PES during pancreatic juice diversion. Thus, the feedback regulatory mechanism appears to involve the release of neurotensin in dogs and PYY in rats as well. Subsequent studies have demonstrated that the effect of pancreatic protease was mediated through degradation of a CCK-releasing peptide activity secreted from the intestinal mucosa. Similarly a secretin-releasing peptide (SRP) activity was shown to mediate the release of secretin in response to duodenal acidification. It is now clear that intestinal acid perfusate of both rats and dogs contain the SRP activity. On the other hand, the inhibitory effect of lipase on neurotensin release is yet to be explained.
A CCK-releasing peptide, termed monitor peptide, was isolated from rat pancreatic juice.36 Intraduodenal administration of monitor peptide in fasting rats with bile and pancreatic juice diversion resulted in a significant increase in pancreatic enzyme secretion and elevation of plasma CCK concentration. The peptide also stimulated the release of CCK from mucosal cells isolated from rat duodenum. The discovery of monitor peptide activity suggested that a positive feedback regulation of CCK release by pancreatic juice exists. Similarly, SRP activity was found in canine pancreatic juice. During the past decade, two CCK-RPs have been purified. Spannagel et al.37 have purified a luminal CCK-releasing factor (LCRF) from rat intestinal secretion. LCRF is a peptide of 8136.5 Da, whose N-terminal 41 residues have been determined. Intraduodenal administration of LCRF stimulated pancreatic fluid and protein secretion that was inhibited by the CCK-A antagonist, MK-329 (Figure 6.7).37 In addition, when a partially purified LCRF isolated from rat intestinal secretion was administered intraduodenally, pancreatic secretions of protein in recipient rats were elevated. The CCK-RP activity of the partially purified LCRF was
NaCI LCRF LCRF + MK329 *p < 0.05 vs. NaCI or MK329; **p < 0.05 vs. NaCI
Figure 6.7 Effect of intraduodenal infusion of LCRF on pancreatic secretion and plasma CCK levels in conscious rats. Intraduodenal infusion of LCRF stimulated pancreatic secretion of fluid and protein. The effects of LCRF were abolished by the CCK-A receptor antagonist, MK329 indicating mediation through the release of CCK that was demonstrated by LCRF-stimulated increase in plasma CCK level over the saline control (inset). The results strongly suggest that LCRF is a luminal CCK releasing factor. Source: Data from Spannagel et al.37 Used with permission.
abolished when it was percolated through an affinity column made of an anti-LCRF1-6 serum, but not when that was made of a normal rabbit serum. Synthetic fragments of LCRF, LCRF1-41, LCRF1-35, and LCRF11-25 but not LCRF1-6 were also bioactive. Interestingly, intravenous administration of LCRF1-35 also stimulated CCK release and pancreatic secretion. These results indicate that LCRF is an active form of CCK-RP in rat intestinal secretion. On the other hand, Herzig et al.38 have isolated a peptide of 86 amino acid residues with CCK-RP activity from the extracts of porcine small intestine. The amino acid sequence of this peptide was identical to diazepam-binding inhibitor (DBI1-86) previously purified by Mutt and coworkers.39 Intraduodenal administration of a fragment of DBI1-86, DBI33-50, in anesthetized and atropinized rats resulted in a dose-dependent increase in pancreatic protein secretion and elevation of plasma CCK concentration, although the fragment was less potent than DBI1-86. DBI was also shown to stimulate the release of CCK from mucosal I cell (CCK cell)-enriched preparation isolated from rat upper small intestine. Intraduodenal administration of an anti-DBI33-50 serum suppressed pancreatic protein secretion and plasma CCK level in response to bile-pancreatic juice diversion as well as intraduodenal infusion of a peptone solution (Figure 6.8).40 This observation suggests that DBI is also released into the intestinal lumen and contribute to the CCK-RP activity.
Two SRPs have been purified from canine pancreatic juice.41 Mass spectral analysis indicated that they were both 14 kDa polypeptides.
0 Preimmune rabbit serum ■ Anti-DBI33-50serum
0 Preimmune rabbit serum ■ Anti-DBI33-50serum
5 h after BPJ diversion 5% peptone
5 h after BPJ diversion 5% peptone
Fasting Peptone Peptone
Figure 6.8 Effect of anti-DBI33_50 antiserum on pancreatic secretion and plasma CCK concentration in response to duodenal infusion of peptone. Intraduodenal infusion of anti-DBI33_50 together with peptone suppressed peptone-stimulated protein output (left panel) and increase of plasma CCK concentration (right panel). The results indicated that a DBI33_50-like peptide mediates the stimulatory effect of peptone on pancreatic protein secretion and CCK release, thereby supporting the contention that DBI is a luminal CCK-releasing factor. Source: Data from Li et al.40 Used with permission.
N-terminal amino acid sequence analysis indicated they were identical or highly homologous to canine pancreatic PLA2. Both of these peptides stimulated the release of secretin from rat secretin-containing cells and murine neuroendocrine cell line, STC-1. Porcine pancreatic PLA2 also occur in multiple molecular forms of 14 kDa and each was shown to stimulate secretin release from secretin-producing cells. Intravenous administration in anesthetized rats of a specific anti-PLA2 serum produced against purified porcine pancreatic PLA2 resulted in suppression of PES and the release of secretin in response to duodenal acidification. Moreover, duodenal acidification increased PLA2-like immunoreactivity in the luminal perfusate. Preincubating the concentrate of acid perfusate (CAP) with anti-PLA2 antiserum followed by removal of the high molecular weight antibody-antigen complex by ultrafiltration diminished the SRP activity of CAP; whereas normal rabbit serum-treated CAP retained the SRP activity (Figure 6.9).42 These observations indicate that PLA2 is a luminal SRP (LSRP) that participate regulation of secretin release and PES.
The release and action of LSRP are also neural regulated. Thus, SRP activity in CAP prepared from vagotomized or propanolol (an adrenergic antagonist)-treated donor rats was significantly reduced as compared with the corresponding control CAPs. In addition, the stimulation of PES and
Figure 6.9 Effect of NRS or anti-PLA2 serum on secretin-releasing peptide activity of a concentrate of duodenal acid perfusate (CAP) in recipient rats. Preincubation of the CAP preparation was preincubated with anti-PLA2 serum, but not with NRS inhibited the SRP activity of CAP. Source: Data from Li et al.42 Used with permission.
secretin release by CAP was diminished by pretreatment of the recipient rats with tetrodotoxin, perivagal capsaicin, or vagotomy.26 Moreover, treatment of donor rats with methionine-enkephalin, which is known to inhibit PES and secretin release, also reduced the SRP activity of CAP. These observations suggest that the release and action of LSRP in response to duodenal acidification is neural mediated and that Met-ENK may be an inhibitory mediator of SRP release. Similarly, the release of CCK-RP is also neural regulated. The release and action of CCK-RP are inhibited by SS. The 5-HT3 receptor antagonist, ISC 205-930, ketanserin (5-HT2 receptor antagonist), a substance P antagonist, CP 96,345, tetrodotoxin, atropine, hexamethonium, and mucosal lidocaine inhibited the release of CCK-RP activity by intraduodenally administered peptone solution. Based on the observation, it was proposed that peptone in the intestinal lumen activates the enterochromaffin cells to release 5-HT, which in turn activate sub-stance-P-containing submucosal sensory neurons.43 The signal was then transmitted through the interneurons in the myenteric plexus to relay stimulatory signal to the submucosal secretomotor cholinergic neurons to release acetylcholine that acts on the CCK-RP containing cells in the mucosal epithelium to release CCK-RP.
In summary, PES is regulated by neurohormonal regulatory mechanism, involving integrated actions of hormones, neuropeptides, neurotransmit-ters, and hormone-releasing peptides. Although the roles of several key elements are now known, the mechanisms and pathways of their regulatory processes remain to be elucidated.
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