Cerium-based histochemical demonstration of oxidative stress in taurocholate-induced acute pancreatitis in rats. A confocal laser scanning microscopic study.

Direct in vivo histological detection of oxygen-derived free radicals (OFRs) in inflammatory conditions is not fully resolved. We report an application of cerium histochemistry (in which capture of OFRs by Ce atoms results in laser-reflectant cerium-perhydroxide precipitates) combined with reflectance confocal laser scanning microscopy (CLSM) to demonstrate the evolution of oxidative stress in taurocholate-induced acute pancreatitis (AP) in rats. Animals were perfused with CeCl(3) in vivo and cryostat sections of pancreata were studied by CLSM. Vascular endothelium was immunolabeled for PECAM-1. OFR production by isolated polymorphonuclear leukocytes (PMNs) incubated in vitro with CeCl(3) was quantified by image analysis. In the pancreas, strong OFR-derived cerium reflectance signals were seen in acinar cells at 1-2 hr, capillaries and small venules were frequently engorged by cerium precipitates, and adherent PMNs presented weak intracellular reflectance signals. At 8-24 hr, acinar cell OFR production decreased, whereas adherent/transmigrated PMNs displayed abundant intra- and pericellular reflectance. PECAM-1 expression was unchanged. PMNs from ascites or blood showed significant (p<0.01) time-dependent OFR production, plateauing from 2 hr. The modified cerium capture/CLSM method allows the co-demonstration of in vivo oxidative stress and cellular structures labeled with fluorescent markers. In vivo oxidative stress was shown histologically for the first time in experimental AP.

Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion.

Control of pepsin secretion by regulatory peptides in the rat stomach: comparison with acid secretion.

Previous studies of the control of pepsin secretion by neurohumoral agents showed some discrepancies between in vitro (isolated cells) and in vivo experiments. In the present work, the effects on pepsin secretion of CCK, pentagastrin, secretin, VIP, neurotensin, histamine, and methacholine were reinvestigated in conscious gastric fistula rats, in comparison to acid secretion. ED50's and doses inducing maximal responses were measured to directly compare the potency and efficacy of these substances. Methacholine was the most efficient (maximal response = 4.5 x basal level, ED50 = 1.3 mumol/kg.h) and CCK the most potent (ED50 = 1.9 nmol/kg.h) stimulant, whereas secretin was a potent (ED50 regulators of pepsin secretion in the rat. Pentagastrin and histamine did not stimulate pepsin output, as found by others with isolated chief cells in vitro. Neurotensin and large doses of VIP marginally inhibited pepsin secretion.

Effect of rGRF on exocrine pancreatic secretion of the rat in vivo.

Human and rat GRFs have been reported to stimulate cAMP production and amylase release by guinea pig acinar cells in vitro, with different potencies. Previous reports indicated that hGRF had no effect on pancreatic secretion of the rat in vivo. In the present experiments, dose-response studies were made with rGRF, VIP and secretin on the pancreatic secretion of anaesthetized rats. All three peptides stimulated pancreatic secretion. rGRF induced a slight water and electrolyte secretion, with an efficacy about ten times smaller than secretin, and a potency about thirty times smaller. rGRF stimulated total protein output with the same efficacy as secretin and VIP, and with the same potency as VIP, that is about 100 times smaller than secretin. rGRF increased the concentration of total protein, but not that of bicarbonate in pancreatic juice. Maximal doses of VIP and rGRF did not show any additive effect. It is concluded that large doses of rGRF are able to stimulate the rat acinar cells in vivo, presumably through an interaction with VIP receptors.

Neural mechanism of the antisecretory effect of peptide YY in the rat colon in vivo.

The purpose of this work was to determine the mechanism of the antisecretory effect of peptide YY in the rat colon and whether this effect is physiological. In this prospect, doses of exogenous peptide YY producing physiological and supraphysiological plasma levels were intravenously infused in rats provided with colonic and jejunal ligated loops in vivo, under secretory stimulation by vasoactive intestinal peptide. Peptide YY decreased the secretory effect of VIP in a dose-related fashion. The effect of peptide YY was blocked or strongly decreased by tetrodotoxin, hexamethonium, idazoxan, haloperidol, and the sigma antagonist BMY 14, 802 in both the colon and jejunum. We conclude that peptide YY decreases water and electrolyte secretion in the colonic mucosa by a complex neural mechanism involving at least two neurons connected through a nicotinic synapse, alpha-2 adrenoceptors and sigma receptors, and that this effect can occur with physiological doses of peptide YY.

Inhibitory effects of peptide YY on basal and VIP-stimulated short-circuit current in the rat jejunum: influence of technical conditions on observed results.

The interaction of PYY and VIP was studied in stripped and intact rat jejunum preparations mounted in Ussing chambers. PYY decreased basal Isc in intact as well as in stripped jejunum. Stripping was necessary to evidence a stimulation of basal Isc by VIP. When PYY and VIP were administered at the same time in the serosal bath, their effects seemed additive; VIP stimulation took over when VIP was present in ten times larger amounts than PYY, while PYY inhibition predominated at isomolar concentrations (10(-7) M) of both peptides. However, when PYY was administered three to six minutes before isomolar amounts of VIP, the VIP stimulation developed without being notably hampered. At this time, however, the amount of radioimmunoassayable PYY in the serosal compartment represented still 60% of the added amount. In conclusion, the experimental conditions can significantly change the results: stripping the longitudinal muscle/myenteric plexus impairs the effect of PYY and VIP in a different fashion, while the timing and order of administration of the peptides may change the apparent interaction between VIP stimulation and PYY inhibition.

Antisecretory effect of peptide YY through neural receptors in the rat jejunum in vitro.

Basal short circuit current (Isc) was measured in stripped rat jejunum after addition of neural antagonists and of peptide YY (PYY). Basal Isc was slightly (by 10-21%) but significantly inhibited by tetrodotoxin, hexamethonium, idazoxan, and the sigma antagonist BMY 14,802. PYY (10(-7) M) reduced basal Isc by approximately 54%. This inhibition was unchanged by hexamethonium but reduced by 44-68% in the presence of tetrodotoxin, idazoxan, haloperidol, BMY 14,802, and atropine. The Y2 agonist pYY(3-36) was more potent than the Y1 agonist (Leu31,Pro34)PYY. In conclusion, PYY reduces basal Isc in rat jejunum in part through a neural mechanism involving muscarinic receptors, alpha2 adrenoceptors, and sigma receptors and, in part, through a direct effect on enterocytes. The PYY effect seems mainly carried out through Y2-receptor activation.

Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat.

The effect of caseinomacropeptide (CMP) (the [106-169] fragment of kappa-casein produced during digestion of milk protein), was studied in anesthetized rats using bile diversion for a pure pancreatic juice collection system. Intraduodenal administration of CMP induced a dose-related specific stimulation of pancreatic secretion which was nearly abolished by devazepide, atropine, hexamethonium, vagotomy or perivagal capsaicin pretreatment. Moreover, CMP did not inhibit in vitro trypsin activity. These results demonstrate that CMP is more likely to stimulate pancreatic secretion specifically through cholecystokinin release and activation of a vago-vagal cholinergic reflex loop than by inhibition of luminal trypsin, in anesthetized rats.

Several receptors mediate the antisecretory effect of peptide YY, neuropeptide Y, and pancreatic polypeptide on VIP-induced fluid secretion in the rat jejunum in vivo.

Several Y receptor subtypes have been cloned and/or pharmacologically characterized that mediate the effects of the regulatory peptides peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). These peptides possess antisecretory properties on the intestine. This effect can be blocked in vivo by neural antagonists, suggesting the intervention of neural receptors, although epithelial PYY-preferring receptors have been evidenced on jejunal crypt cells. The purpose of the present experiments was to compare the antisecretory properties in vivo of a series of PYY and NPY derivatives with various affinities for different Y receptor subtypes, in order to determine which subtypes were involved. A model of VIP-stimulated secretion by rat jejunal loops was used. The results were compared with the binding affinities for PYY-preferring receptors determined on rat jejunal crypt cell membranes. Full-length PYY(1-36) was about three times more potent than NPY(1-36), and 10 times more potent than PP in the low dose range. PP, however, had a low efficacy limited to about 50% inhibition of VIP effect. Both Y1 agonists ([Leu31, Pro34]PYY and [Leu31,Pro34]NPY), and Y2 agonists [C-terminal fragments ranging from PYY (3-36) and NPY(3-36) to PYY(22-36) to NPY(22-36)] displayed potent antisecretory properties. PYY derivatives and fragments were always more potent than their respective NPY counterparts. In contrast, Y1 derivatives and PP had very low affinity for the epithelial PYY receptor as measured in vitro by radioreceptor assay. These data suggest that the antisecretory effect of PYY/NPY/PP peptides in vivo involves the effects of several receptors: a Y2-like, PYY-preferring receptor identical to the epithelial receptor, a Y1-like receptor, and a third receptor with high affinity for PP.

Mechanism of neurotensin stimulation of external pancreatic secretion in the rat.

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)

Differential effects of peptide YY, neuropeptide Y, and sigma ligands on neurally stimulated external pancreatic secretion in the rat.

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)

Etorphine inhibition of pancreatic exocrine secretion in rats: comparison with methadone.

The effects of etorphine, a potent opiate agonist without preferential affinity for mu, delta or kappa receptors, on exocrine pancreatic secretion were studied in rats fitted with chronic or acute pancreatic fistulas and compared to those of methadone, a well-documented mu agonist. In conscious rats etorphine (3 micrograms/kg s.c.) inhibited basal pancreatic secretion by about 50% for volume and bicarbonate output and by 70% for protein output. Pancreatic secretion returned to its basal level within 2 h. Methadone (5 mg/kg s.c.) was about equipotent but the inhibition lasted longer. The effects of both etorphine and methadone were completely antagonized by naloxone (1 mg/kg s.c.) and to a lesser extent by diprenorphine (10 microgram/kg s.c.). Yohimbine did not suppress the inhibitory effect of etorphine on protein output but showed some antagonism against the effects of etorphine on water and bicarbonate output. In anaesthetized rats etorphine (3 micrograms/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose, a centrally acting vagal stimulatory agent, by 50-60% for volume and bicarbonate output and totally for protein output. The same dose of etorphine did not inhibit the pancreatic secretion evoked by vagal electrical stimulation, a peripheral stimulus. Methadone (5 mg/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose to the same extent, but for a longer time than etorphine, and at the same dose did not suppress the pancreatic pancreatic response to vagal electrical stimulation. The inhibitory effects of etorphine and methadone in anaesthetized rats were completely suppressed by naloxone (1 mg/kg s.c.) and only reduced by diprenorphine (10 micrograms/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

Methadone inhibition of vagally induced pancreatic and gastric secretions in rats: central and peripheral sites of action.

Pancreatic and gastric secretions after stimulation with acetylcholine, electrical vagal stimulation or 2-deoxyglucose injection were studied in anesthetized rats. The effects of methadone on these secretions were investigated. Maximal stimulation of pancreatic secretion by acetylcholine was not affected by methadone. Gastric acid stimulation by acetylcholine was only slightly decreased by methadone (30% or less). Electrical vagal stimulation of pancreatic and gastric secretions was progressively and dose-dependently decreased to a maximum of 50% by methadone. Maximal stimulation of pancreatic and gastric secretions by 2-deoxyglucose was completely suppressed by methadone with an ID50 of about 1 mg/kg and an ID100 of about 2.5 mg/kg for both secretions. It is concluded that methadone inhibits vagal stimulation of digestive secretions by acting both centrally and peripherally (probably by inhibiting the release of acetylcholine from vagal fibers). The central mechanism appears to be more important, since it occurs with lower doses and can produce complete suppression of secretion.

Effect of modafinil on pancreatic exocrine secretion in the rat. A comparison with methadone.

Modafinil is a recently developed drug which increases wakefulness in several animal species and in man, an effect involving, at least in part, central adrenoceptors. In the present experiments, the effect of modafinil was studied on a model of neurally stimulated secretion, pancreatic secretion induced by 2-deoxyglucose (2DG) in the rat, and compared with that of the mu-opiate methadone. Modafinil induced a dose-related inhibition of 2DG-stimulated pancreatic secretion, reaching more than 80% after 250 mg/kg i.p. The modafinil effect was suppressed by idazoxan or by large doses of prazosin but not by naloxone. In addition modafinil (250 mg/kg i.p.) did not change the pancreatic response to electrical vagal stimulation. Methadone also potently suppressed 2DG-stimulated pancreatic secretion, but in contrast to modafinil, the methadone effect was blocked by naloxone, but not by the adrenoceptor antagonists idazoxan, prazosin and propranolol. It is concluded that modafinil decreases centrally 2DG-stimulated pancreatic secretion through a pathway involving alpha 1- and alpha 2-adrenoceptors, without an interaction with opiate receptors.

Effects of buflomedil and its two derivatives, CRL40634 and CRL40598, on pancreatic exocrine secretion in the rat.

Buflomedil is a vasoactive drug used in the treatment of peripheral vascular disease, and seems to be an antagonist of both alpha 1- and alpha 2-vascular adrenoceptors. CRL40634 and CRL40598 are metabolites of buflomedil and also possess vasoactive properties. The purpose of this study was to investigate whether buflomedil, CRL40634 and CRL40598 have antagonist activity on the alpha 2-adrenoceptors involved in the inhibition of exocrine pancreatic secretion. In acute pancreatic fistula rats, buflomedil, CRL40634 and CRL40598 did not suppress the inhibitory effect of clonidine against 2-deoxy-glucose-induced pancreatic secretion. However, all three drugs inhibited 2-deoxy-glucose-induced pancreatic secretion, their order of potency being CRL40598 greater than CRL40634 greater than buflomedil.

Central and peripheral effects of prostaglandin E2 and enprostil on exocrine pancreatic secretion in rats.

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)

Effects of CRL 40827 and salbutamol on exocrine pancreatic secretion in rats.

The effects of the drug CRL 40827 and salbutamol, a structurally related compound, on exocrine pancreatic secretion in acutely fistulized anaesthetized rats and in chronically fistulized conscious rats were studied. CRL 40827 and salbutamol (0.05-0.45 mumol/kg per min, for 2 h) increased the basal secretion of fluid and bicarbonate in anaesthetized rats. The effect of CRL 40827 (15% of the maximal effect of secretin) was suppressed by propranolol (a non-specific beta-adrenoceptor antagonist), by ICI 118551 (a beta 2-antagonist) and by atenolol (a beta 1-antagonist). The effect of salbutamol (25% of the maximal effect of secretin) was suppressed by propranolol and ICI 118551 but was only slightly decreased by atenolol. The stimulant peak effects of CRL 40827 and salbutamol on volume and bicarbonate output were additive to those of 2-deoxy-glucose whereas the effect of 2-deoxy-glucose on protein output was not changed by either drug. CRL 40827 and salbutamol decreased the basal interdigestive protein output in a dose-related manner in conscious rats. CRL 40827 was 27 times less potent than salbutamol. The pancreatic outputs of fluid, bicarbonate and protein after an intragastric meal were decreased by both drugs. However, only salbutamol significantly decreased the cumulative effect of the meal on protein output compared to basal output. These results suggest that the stimulant effect of salbutamol on the pancreatic secretion of fluid and bicarbonate depends mainly on beta 2-adrenoceptors whereas that of CRL 40827 involves adrenoceptors of an as yet undefined subtype.

Neural modulation of the antisecretory effect of peptide YY in the rat jejunum.

The endocrine and neural peptide, peptide YY, inhibits intestinal secretion of water and electrolytes in several animal species and in man. Peptide YY receptors have been evidenced on isolated rat jejunal crypt cells, but neural receptors are also likely to participate in the antisecretory effect of peptide YY in vivo. The aim of the present study was to investigate the mechanisms of the peptide YY effect on vasoactive intestinal peptide (VIP)-stimulated jejunal net water flux in the rat. Antagonist experiments using several drugs affecting neurally mediated processes were done for the purpose. A small peptide YY dose (10 pmol/kg) inhibited significantly (P < 0.005) the jejunal net water flux produced by 30 microg/kg per h of VIP. The inhibitory effect of peptide YY was suppressed, or strongly and significantly reduced, by tetrodotoxin, hexamethonium, lidocaine, idazoxan and BMY14,802 (51-(4-fluorophenyl)-4-(-4-(5-fluoro-2pyrimidinyl)-1-piperazinyl)- 1-butanol), whereas devazepide and L-NAME (L-omega-N-arginine methyl ester) had no effect. These results suggest that peptide YY inhibits VIP-stimulated jejunal net water flux in vivo through a neural mechanism implicating the participation of nicotinic synapses, alpha2-adrenoceptors and sigma receptors.

Effect of sumatriptan on external pancreatic secretion and its interaction with endogenous norepinephrine in the rat.

We reported previously that blocking norepinephrine reuptake by nisoxetine could modulate external pancreatic secretion in the rat. We report in this study the interaction of serotonin (5-HT) with endogenous catecholamines by using sumatriptan, an agonist of 5-HT1 receptors, in combination with nisoxetine. Urethane-anesthetized male Wistar rats were fitted with an acute pancreatic fistula. Nisoxetine (0.3 mg/kg, i.v.) and sumatriptan (0.1-1 mg/kg, s.c.) were administered alone or in combination. Pancreatic secretion was measured under stimulation by 2-deoxy-D-glucose (2DG; 75 mg/kg, i.v.), by vagal electrical stimulation (4 V, 2 ms, 10 Hz), or by acetylcholine (60-1,800 microg/kg.h). (i) 2DG: Nisoxetine alone inhibited 2DG-induced pancreatic secretion (p < 0.01). Sumatriptan alone also produced a dose-related inhibition of 2DG-induced pancreatic secretion (p < 0.01). When sumatriptan and nisoxetine were combined, protein response to 2DG remained inhibited, whereas water and electrolyte secretion was restored. (ii) Vagal stimulation: Nisoxetine did not modify water and electrolyte output in response to vagal electrical stimulation (VES), whereas it inhibited protein response by 75%. Sumatriptan alone strongly inhibited pancreatic response to VES (p < 0.01). When nisoxetine and sumatriptan were combined, the protein response to VES remained inhibited, whereas water and electrolyte response to VES was restored. (iii) Acetylcholine: Nisoxetine and sumatriptan alone or combined did not modify pancreatic response to acetylcholine. These results indicate that noradrenergic and serotonergic agents can indirectly affect pancreatic secretion through a modulation of the vagal cholinergic pathway. Nisoxetine and sumatriptan interact negatively on hydroelectrolytic pancreatic secretion, whereas they inhibit the secretion of enzymes both alone and in combination.

Modulation of external pancreatic secretion by endogenous norepinephrine: study with a norepinephrine uptake blocker in the rat.

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.