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Introduction: In acute pancreatitis, nonesterified fatty acids (NEFA) might be released by lipase and cause tissue necrosis by their detergent properties, but this has not been established in vivo., Aims: To measure the release of NEFA in the blood stream, pancreatic tissue, and peritoneal cavity during taurocholate-induced acute necrotizing pancreatitis in rats., Methodology: Ascites and blood were repeatedly sampled; after 24 hours, pancreatic lesions were scored, and NEFA were measured in the pancreas. The effects of a specific lipase inhibitor (Tetrahydrolipstatin [THL]) were also studied., Results: A slight transient increase (22%) of NEFA concentration was observed in systemic circulation but did not parallel the time course of lipase activity, arguing against an intravascular production of NEFA by circulating lipase. Pancreatic NEFA did not differ between rats with pancreatitis and control rats. NEFA in ascites increased to threefold the basal value immediately after taurocholate and decreased rapidly thereafter, whereas lipase increased later in ascites and remained elevated during the 24-hour duration of the experiment. Lipase inhibition by THL neither modified the early increase of NEFA in ascites, nor altered the macroscopic, enzymatic, and histologic evolution of pancreatitis., Conclusion: This in vivo study does not confirm the hypothetical role of NEFA produced by pancreatic lipase in the necrotic process and its systemic complications, up to now mainly suggested on the basis of ex vivo experiments.

Glicentin (GLIC), oxyntomodulin (OXM), and peptide YY (PYY) released in blood by ileocolonic L-cells after meals may inhibit pancreatic secretion. Whereas OXM interacts with glucagon and tGLP-1 receptors, OXM 19-37, a biologically active fragment, does not. The purpose of this study was to measure the effect of OXM, OXM 19-37, GLIC, tGLP-1, and PYY on pancreatic secretion stimulated by 2 deoxyglucose (2DG), electrical stimulation of the vagus nerves (VES), acetylcholine and cholecystokinin octapeptide (CCK8) in anesthetized rats. The effect of OXM was also studied in dispersed pancreatic acini. Plasma oxyntomodulin-like immunoreactivity (OLI) was measured by radioimmunoassay after the exogenous infusion of OXM and after an intraduodenal meal. OXM 19-37, infused at doses mimicking postprandial plasma levels of OLI, decreased pancreatic secretion stimulated by 2DG, VES, or CCK8. Similar effects were found with OXM and GLIC. OXM 19-37 did not change the pancreatic stimulation induced by acetylcholine in vivo, or CCK-induced amylase release in isolated acini. Vagotomy completely suppressed the inhibitory effect of OXM 19-37 on CCK8-stimulated pancreatic secretion. PYY inhibited the effect of 2DG, but not that of CCK8, whereas tGLP-1, even in pharmacologic doses, had no effect on stimulated pancreatic secretion. OXM, OXM 19-37, but not tGLP-1, inhibit pancreatic secretion at physiologic doses, through a vagal neural indirect mechanism, different from that used by PYY, and probably through a GLIC-related peptide-specific receptor.

The effect of endogenous catecholamines on pancreatic secretion was analyzed with nisoxetine, a specific norepinephrine uptake blocker, and specific adrenoceptor antagonists in anesthetized acute fistula rats. Nisoxetine was administered alone or with alpha-1 (prazosin), alpha-2 (idazoxan or yohimbine), or beta (propranolol) adrenoceptor antagonists. Pancreatic secretion was measured in basal conditions or after stimulation by 2-deoxy-D-glucose (2DG), electrical vagal stimulation, or acetylcholine. (a) Basal. Nisoxetine alone had no effect. Associated with idazoxan or yohimbine, nisoxetine produced a dose-related stimulation (p < 0.01) of water and electrolyte without changing protein output. Addition of propranolol abolished this stimulation. (b) 2DG. Nisoxetine inhibited 2DG-induced secretion (p < 0.01). Idazoxan or yohimbine suppressed the nisoxetine inhibition of water and electrolyte output (p < 0.01) but had no effect on protein output, which was restored only by adding a mixture of idazoxan, prazosin, and propranolol. (c) Electrical stimulation. Nisoxetine did not modify water and electrolyte but inhibited protein response by 75%. Adding idazoxan to nisoxetine significantly increased (p < 0.01) water and bicarbonate response and partly restored protein response. Water and bicarbonate response was restored by propranolol, whereas protein response was only restored by adding a mixture of idazoxan, prazosin, and propranolol. (d) Nisoxetine did not modify pancreatic response to acetylcholine. In conclusion, endogenous norepinephrine affects the response to vagally mediated effects through several subtypes of adrenoceptors, without changing basal or acetylcholine stimulated secretion.

Lipid peroxidation, which may be involved in the pathogenesis of acute pancreatitis, is usually assessed in vitro or indirectly using antioxidants or free radical scavengers. We assessed lipid peroxidation in an in vivo model by measuring ethane exhalation in two models of acute pancreatitis. Edematous acute pancreatitis was induced by a supramaximal intraperitoneal injection of cerulein. Necrotizing acute pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreaticobiliary duct. Rats were placed in closed chambers and ethane exhalation was measured in aliquots. Ethane exhalation was significantly increased (p < 0.002) in cerulein (n = 12)- but not in taurocholate (n = 6)-induced pancreatitis compared to controls (n = 12 and 6, respectively). Our results suggest that free radicals may play a role in the pathogenesis of edematous pancreatitis but do not play an important role in the progression to necrotizing pancreatitis.

The endocrine peptide YY (PYY) inhibits pancreatic secretion in animals and in man through indirect pathways. Neuropeptide Y (NPY), whose chemical structure is very close, displays similar effects. Recently, sigma ligands were shown to produce in vivo several neural pharmacologic effects that seemed indistinguishable from those of NPY. This might occur by interaction with the same (or closely related) receptors or by activation of a common final pathway. The purpose of the present work was to test whether PYY, NPY, and sigma agonists also display closely related activities on pancreatic secretion. The sigma ligands (+)-N-allyl normetazocine (d-NANM) and di(ortho-tolyl) guanidine (DTG) were used. Pancreatic secretion was stimulated by the centrally acting agent 2-deoxyglucose (2DG) in anesthetized rats. The rats were also administered either an infusion of peptide (PYY: 25-250 pmol/kg/h, NPY: 75-750 pmol/kg/h), continued for 2 h, or a bolus injection of d-NANM (3 mg/kg) or DTG (1 mg/kg). In antagonist experiments, the dopamine and sigma antagonist haloperidol (1 mg/kg, i.v.), the adrenoceptor antagonists idazoxan (0.3 mg/kg, s.c.), prazosin (0.5 mg/kg, s.c.), propranolol (1 mg/kg, s.c.) and the opiate receptor antagonist naloxone (1 mg/kg, s.c.) were injected, 5 min before the peptide infusion had begun. Neither PYY nor NPY changed basal pancreatic secretion. PYY and NPY produced a dose-related inhibition of 2DG-stimulated pancreatic secretion. The observed inhibition after 250 pmol/kg/h of PYY was volume, 78% (p < 0.01); bicarbonate, 84% (p < 0.01); protein, 78% (p < 0.01); whereas the physiologically relevant dose of 25 pmol/kg/h induced approximately 30% inhibition of these variables.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this work was to study whether stimulation or destruction of sensory afferents can modulate pancreatic secretion. The neurotoxin capsaicin is specific for a subpopulation of small diameter primary afferent neurons. Small doses of capsaicin were administered to anesthetized rats as intraduodenal or intragastric bolus injections to stimulate digestive sensory fibers, and pancreatic secretory response was measured. In addition, several high-dose subcutaneous capsaicin injections were administered 10 days before the experiments began, in order to inactivate sensory fibers. Basal and 2-deoxy-D-glucose (2DG)-stimulated pancreatic secretion was then measured. Intraduodenal capsaicin (96-3,050 micrograms/kg) induced a progressive (peak response 40-60 min after the injection), dose-related and long-lasting (> 180 min) increase in pancreatic output of sodium, bicarbonate, and total protein. The maximal response was obtained with 964 micrograms/kg capsaicin; it amounted to about 15% of the maximal response to exogenous cholecystokinin octapeptide (CCK8). The response was not decreased by atropine, hexamethonium, vagotomy, a mixture of adrenoceptor antagonists (prazosin + idazoxan + propranolol), or by the CCKB receptor antagonist L365,260. In contrast, the CCKA receptor antagonist L364,718 reduced by 30-40% the sodium and bicarbonate response and reduced by 90% the protein response induced by capsaicin, but not the response induced by methacholine or 2DG. However, intraluminal capsaicin did not release CCK in a preparation of isolated perfused duodeno-jejunum. Intragastric capsaicin did not significantly change pancreatic secretion. Capsaicin pretreatment had no effect on basal and 2DG-stimulated secretion, but abolished the response to intraduodenal capsaicin. In conclusion, intraduodenal capsaicin can stimulate external pancreatic secretion in anesthetized rats through capsaicin-sensitive sensory neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of this study was to analyze the mechanism of the neurotensin effect on external pancreatic secretion in the rat. The pancreatic dose-response curve to 40-min venous infusions of neurotensin 1-13 (0.1-10 micrograms/kg-h = 0.06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 micrograms/kg-h and reached approximately 30% of the maximal response to cholecystokinin (CCK). The ED50 was 0.27 micrograms/kg-h (= 0.16 nmol/kg-h) for bicarbonate and 0.45 micrograms/kg-h (= 0.27 nmol/kg-h) for protein output. Pancreatic secretion in response to each neurotensin dose increased steadily during the infusion and peaked 20-40 min after the end of infusion. Atropine and hexamethonium suppressed the stimulatory effect of neurotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCKA receptor antagonist L364718 decreased by 80% sodium and bicarbonate response (p < 0.01) and suppressed protein response (p < 0.01) to neurotensin. Methadone reduced the response to neurotensin by 85%, vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha 1-, alpha 2-, and beta-adrenoreceptors or of CCKB receptors did not change the neurotensin effect. We conclude that the mechanism of neurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCKA receptors, and, in part, capsaicin-sensitive sensory fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E2 (PGE2) has been reported to exert some centrally mediated effects on intestinal motility and secretion and on gastric secretion, but it is not known whether such central effects exist on pancreatic secretion. The central and peripheral effects of PGE2 and enprostil, a long-acting, potent PGE2 analogue, were studied in conscious and anesthetized rats fitted with pancreatic fistulae. In chronically implanted, conscious rats, PGE2 inhibited the secretion of fluid, bicarbonate, and total protein in the pancreatic juice, both after i.v. or intracerebroventricular (icv) injections. The maximal inhibition was similar after both injection procedures (about 45% for fluid and bicarbonate and 60% for protein), but the potency of PGE2 was three to 10 times greater by the icv than the i.v. route. Enprostil also inhibited pancreatic secretion in a dose-related way. The maximal inhibition was larger than after PGE2 injection (about 70% for fluid and bicarbonate and 90% for protein). The potency of enprostil was five to 10 times lower by the icv than by the i.v. route. The diversion of gastric secretion suppressed the effect of icv PGE2 on fluid and bicarbonate output but not on protein and did not change the effect of enprostil on all the variables of pancreatic secretion. Adrenergic antagonists did not suppress the effect of icv PGE2 or enprostil on pancreatic secretion. In anesthetized rats, i.v. PGE2 inhibited hormone-stimulated protein secretion but did not change fluid and bicarbonate output, while i.v. enprostil inhibited cholecystokinin-stimulated fluid, bicarbonate, and protein output in the pancreatic juice.(ABSTRACT TRUNCATED AT 250 WORDS)