EFFECTS OF NICARDIPINE ON PANCREATIC EXOCRINE SECRETION IN THE DOG

1. The effects of nicardipine on the secretion of pancreatic juice were investigated in dog isolated, blood-perfused pancreas, and compared with those of papaverine, aminophylline and secretin. 2. Intra-arterial administration of nicardipine (1-10 μg) elicited a dose-dependent increase in pancreatic secretion. Papaverine (0.1-1 mg), aminophylline (0.3-3 mg) and secretin (0.03-0.1 units) also elicited increased secretion. The secretory activity of nicardipine (10μg) was approximately equal to that of 0.5 mg of papaverine, 1.5 mgof aminophylline and 0.03 units of secretin. 3. The concentration of bicarbonate in the pancreatic juice induced by nicardipine was increased, but the protein concentration was only increased slightly. These effects are analogous to those of secretin. 4. Nicardipine-induced secretion was not modified by pretreatment with relatively large doses of phentolamine, propranolol, atropine, guanethidine, haloperidol or metiamide. 5. Secretin-induced secretion was significantly potentiated by infusion of papaverine, but not by infusion of nicardipine or aminophylline. 6.These results suggest that nicardipine acts on the exocrine cells in the dog pancreas, at least in part, through the increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.     

Effects of ZSY-27, a synthesized phosphodiesterase inhibitor, on exocrine secretion and cyclic nucleotide concentration in the dog pancreas

1. Effects of intravenous injections of ZSY-27, a synthesized phosphodiesterase inhibitor, on pancreatic exocrine secretion and on pancreatic cyclic AMP and cyclic GMP concentrations of dogs were investigated. 2. ZSY-27 (0.3 and 1 mg/kg) increased cyclic AMP concentration dose-dependently, which preceded the increase in pancreatic secretion but did not affect cyclic GMP concentration. 3. These results suggest that ZSY-27 causes exocrine secretion from the dog pancreas mediated through an increase in intracellular cyclic AMP concentration.     

EFFECTS OF 2-NICOTINAMIDOETHYL NITRATE (SG-75) ON PANCREATIC SECRETION IN THE ISOLATED, BLOOD-PERFUSED PANCREAS OF THE DOG

1. The effects of 2-nicotinamidoethyl nitrate (SG-75) on the secretion of pancreatic juice were compared with those of acetylcholine, secretin and pancreozymin in the isolated, blood-perfused dog pancreas. 2. Intra-arterial administration of SG-75 (0.3-3 mg) elicited a dose-dependent increase in pancreatic secretion. Acetylcholine (10-100 micrograms), secretin (0.03-0.3 units) and in pancreozymin (0.1-1.0 units) also elicited increased secretion. 3. Secretory responses to acetylcholine were inhibited by treatment with atropine, while SG-75-, secretin-, and pancreozymin-induced secretions were not modified. 4. Bicarbonate concentrations in pancreatic juice induced by SG-75 and secretin were increased in a dose-dependent manner. However, there were slight changes with acetylcholine or pancreozymin. 5. Amylase activity in pancreatic juice was increased by SG-75, acetylcholine and pancreozymin, but was decreased by secretin. 6. These results suggest that SG-75 stimulates pancreatic secretion by acting both on the acinar and ductular cells of the dog pancreas.     

EFFECTS OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IV INHIBITOR, Ro20,1724, ON PANCREATIC EXOCRINE SECRETION IN DOG

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretin and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1–30 nmol/kg), IBMX (3–30 nmol/kg), secretin (0.01–0.1 pmol/kg) or CCK-8 (0.1–1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 μmol/ kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.     

Effects of the cyclic nucleotide phosphodiesterase inhibitors, rolipram, 3-isobutyl-1-methylxanthine, amrinone and zaprinast, on pancreatic exocrine secretion in dogs.

The effects of the cyclic phosphodiesterase (PDE) inhibitors, rolipram, 3-isobutyl-1-methylxanthine (IBMX), amrinone and zaprinast on pancreatic exocrine secretion were investigated in anesthetized dogs. Rolipram (1-30 nmol), IBMX (44-440 nmol) or zaprinast (1-10 mumol) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but amrinone (up to 53 mumol) did not. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by rolipram and IBMX, but neither was affected by zaprinast. Rolipram elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with rolipram were additive. Rolipram and IBMX, but not zaprinast, increased cyclic AMP concentration but did not affect cyclic GMP concentration. These results suggest that rolipram, IBMX and zaprinast have direct secretory properties on pancreatic exocrine glands of the dog, which may be mediated through the increase of intracellular cyclic AMP concentration, by inhibiting PDE activity. Furthermore, the pancreatic PDE enzyme in the dog pancreas may be mainly a type IV.     

EFFECT OF DEPLETION OF SERUM CALCIUM BY EGTA ON CANINE PANCREATIC SECRETION INDUCED BY DOPAMINE AND BY SECRETIN

SUMMARY 1. Pancreatic secretion has been monitored in the isolated, blood-perfused canine pancreas, and the effects of depletion of serum calcium by infusion of EGTA on the increases in secretion produced by intra-arterial injections of dopamine and secretin have been investigated.
2. Under resting conditions in preparations in dogs fasted for 24 h, the mean rate of pancreatic secretion was 16.4 μ1/min (s. e. m. = 2, n = 12). The mean concentrations of protein, bicarbonate and chloride in the pancreatic juice were 53.8 mg/ml (s. e. m. = 4.5), 18.0 mmol/1 (s. e. m. = 1.1) and 122.5 mmol/1 (s. e. m. = 7.5), respectively. Infusion of EGTA had no effect on resting secretion.
3. Secretion elicited by dopamine or secretin was diminished about 50% during the intra-arterial infusion of EGTA (10⁻² mM/ml) in the perfusing blood. The protein concentration in the secretion was diminished to a similar extent. The concentrations of bicarbonate and chloride in the pancreatic juice was not modified by EGTA infusion.
4. Concomitant infusion of an equimolar concentration of CaCl₂ solution abolished the inhibitory effects of EGTA infusion on the secretory responses to dopamine or secretin.
5. The results suggest that dopamine and secretin influence the exocrine secretions of the pancreas by actions on both acinar and ductular cells. Acinar cell secretion is more susceptible to depletion of serum calcium levels than is secretion from ductular cells.     

EFFECTS OF GLUCAGON ON PANCREATIC SECRETION IN THE DOG

1. The effects of glucagon on the secretion of pancreatic juice were investigated using blood-perfused canine pancreas preparations. 2. Intravenous administration of glucagon (3–30 μg/kg) to the donor dog elicited a dose-dependent increase in pancreatic secretion. Intra-arterial administration of glucagon (10–100 μg) into the perfused pancreas also elicited increased secretion. 3. There were slight increases in amylase concentration of the pancreatic juice with the largest doses of glucagon given by either route. 4. Glucagon-induced secretion was not modified by treatment with phentolamine, propranolol, atropine, guanethidine, tetrodotoxin, haloperidol, prostaglandin F2a or calcitonin. 5. The results suggest that glucagon acts directly on the exocrine cells of the canine pancreas.     

EFFECTS OF BROMOCRIPTINE ON PANCREATIC SECRETION IN THE ISOLATED, BLOOD-PERFUSED PANCREAS OF THE DOG

1. Effects of bromocriptine on the secretion of pancreatic juice were investigated with dog isolated, blood-perfused pancreas. 2. Bromocriptine (1–10 mg) caused dose-dependent increases in the secretion of pancreatic juice. However, bromocriptine did not affect the perfusion blood flow rate. The secretory response to bromocriptine was inhibited by pretreatment with a dopamine antagonist, sulpiride, but not by phentolamine, propranolol, atropine, metiamide, indomethacin or tetrodotoxin. 3. Bromocriptine caused a dopamine-like secretion of the pancreatic juice containing a high concentration of bicarbonate but had little effect on protein output. 4. These results suggest that bromocriptine increases pancreatic secretion stimulating directly on pancreatic dopamine receptors.     

Effects of DN-9693, a synthesized phosphodiesterase inhibitor, on pancreatic exocrine secretion in dogs

The effects of DN-9693, a synthesized phosphodiesterase inhibitor, on the secretion of pancreatic juice were investigated in preparations of the isolated and blood-perfused dog pancreas. DN-9693 injected intraarterially caused a dose-dependent increase in the secretion of pancreatic juice and decrease in the perfusion pressure. The threshold doses to increase the pancreatic secretion and to decrease the perfusion pressure were about 100 micrograms and 1 microgram, to decrease the perfusion pressure were about 100 micrograms and 1 micrograms, respectively. Thus, the secretory response was less effective than the vascular response. The secretory activity of DN-9693 (0.3 mg) was approximately equal to that of 0.03 mg of 3-isobutyl-1-methylxanthine, 0.5 mg of papaverine, 5 mg of theophylline, 0.08 0.5 mg of papaverine, 5 mg of theophylline, 0.08 units of secretin and 0.2 units of cholecystokinin. The concentration of bicarbonate in the pancreatic juice induced by DN-9693 was increased, but protein concentration was not. DN-9693-induced pancreatic secretion was not modified by pretreatments with phentolamine, propranolol, atropine, sulpiride and cimetidine. Secretin-induced pancreatic secretion was significantly potentiated by infusion of DN-9693 (10 micrograms/min), but cholecystokinin-induced one was not. From these results, it is concluded that DN-9693 may produce an increase in pancreatic secretion by acting directly on the pancreatic exocrine gland of the dog, which might be mediated through an increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.     

Effect of dopamine on pancreatic secretion in the dog

1. Effects of L-dopa and dopamine on the secretion of pancreatic juice were investigated in preparations of the isolated blood-perfused canine pancreas.2. Dopamine (1-10 mug) given intra-arterially caused a profuse flow of juice.3. The secretory activity of dopamine (3 mug) was approximately equal to that of secretin (0.1 unit).4. L-Dopa (10-100 mug) given by a single intra-arterial injection was ineffective, but infusion at 100 mug/min for 10 min caused a marked increase of secretion after a delay of a few minutes.5. Intravenous administration of either L-dopa (3 mg/kg) or dopamine (10-100 mug/kg) elicited a marked increase of pancreatic secretion, but was definitely less effective than intra-arterial injection.6. Dopamine-induced secretion was not modified by atropine, phentolamine, propranolol, guanethidine or tetrodotoxin.7. It is concluded that dopamine acts directly on the exocrine cells in the pancreas.     

EFFECTS OF SUBSTANCE P ON PANCREATIC EXOCRINE SECRETION STIMULATED BY SECRETIN, DOPAMINE AND CHOLECYSTOKININ IN DOGS

The effect of substance P (SP) on pancreatic exocrine responses to exogenous cholecystokinin, secretin, and dopamine, were studied in the isolated and blood-perfused pancreas of dogs. Intra-arterial injection of SP had a significant biphasic effect on pancreatic secretion: an initial transient inhibition, followed by an increase in the secretion stimulated by the infusion of cholecystokinin. However, SP caused only an inhibition of secretion stimulated by the infusion of secretin and dopamine. SP increased protein concentration but not bicarbonate concentration in juice stimulated by cholecystokinin, but SP did not affect significantly either protein or bicarbonate concentrations in juice stimulated by secretin and dopamine. These results suggest that SP has greater effects on the pancreatic secretion stimulated by cholecystokinin than that stimulated by secretin and dopamine.     

EFFECT OF SECRETAGOCUES ON PANCREATIC EXOCRINE SECRETION IN THE MONKEY AND THE DOG

The effects of secretin, cholecystokinin, dopamine, histamine and acetylcholine on the secretion of pancreatic juice were investigated in the monkey and the dog. In the resting state, bicarbonate concentration and the volume of pancreatic juice in the monkey were greater than those in the dog. However, the protein concentration of pancreatic juice in the monkey was less than that in the dog. Intravenous administration of secretin, cholecystokinin, histamine and acetylcholine caused a dose dependent increase in pancreatic secretion in both species. The responses in the monkey were greater than those in the dog. Dopamine caused pancreatic secretion only in the dog. The increase in bicarbonate concentrations of pancreatic juice induced by secretin and histamine in the monkey were greater than that in the dog. Increase in protein concentrations of the juice induced by cholecystokinin and acetylcholine in the monkey were less than that in the dog. However, pancreatic juice pH in both species was the same and was not affected by the secretagogues in the resting state or during the stimulation by secretogogues. From these results, it is concluded that there is a species difference in the secretory actions of the secretagogues in the monkey and the dog.     

DIRECT AND INDIRECT STIMULATION OF PANCREATIC EXOCRINE SECRETION BY NEUROTENSIN IN ANAESTHETIZED DOGS

1. The effects of neurotensin on pancreatic exocrine secretion were investigated both in the intact whole pancreas and in the isolated, blood-perfused pancreas ex vivo in anaesthetized dogs. 2. Intravenous (i.v.) injections of neurotensin (0.01-1 nmol/kg) elicited dose-dependent increases in the secretory rate of pancreatic juice without changes in plasma levels of cholecystokinin (CCK). The concentration of bicarbonate in the pancreatic juice induced by neurotensin was increased, but the protein concentration was scarcely changed. 3. The neurotensin-induced secretion was inhibited by SCH23390, a dopamine D-1 antagonist, but not by domperidone, phentolamine, propranolol, atropine, cimetidine, or L-364,718, a CCK antagonist. 4. Intra-arterial (i.a.) injections of neurotensin (0.1-3 nmol/kg) also elicited dose-dependent increases in the secretory rate of pancreatic juice flow, but did not change bicarbonate or protein concentration. The secretory activities were less effective and 1 nmol/kg of neurotensin i.a. was approximately equal to that of 0.03 nmol/kg of neurotensin i.v. 5. These results suggest that neurotensin mainly stimulates pancreatic secretion by acting indirectly. Neurotensin-induced secretion is, at least in part, mediated by endogenously released dopamine which activates dopamine D-1 receptors on the pancreas. In addition to its indirect action, neurotensin has a weak direct action to stimulate pancreatic secretion.     

Effects of synthesized phosphodiesterase inhibitors, DM 9278 and HWA 285, on pancreatic exocrine secretion of the dog

The effects of synthesized phosphodiesterase inhibitors, DM 9278 and HWA 285, on pancreatic exocrine secretion were investigated in isolated and blood-perfused canine pancreas. Close-arterial injections of DM 9278 (10-300 micrograms) and HWA 285 (300-3000 micrograms) caused dose-dependent increases in the flow rate of pancreatic juice and perfusion blood flow. Bicarbonate concentration in the pancreatic juice stimulated by DM 9278 (300 micrograms) or HWA 285 (3000 micrograms) was significantly higher than that in the resting pancreatic juice, although neither of the compounds affected protein concentrations in the pancreatic juice. In the secretory volume, 100 micrograms of DM 9278 corresponded roughly to 1000 micrograms of HWA 285, 0.1 units of secretin or 0.3 units of pancreozymin. These secretory and vascular effects were not modified by pretreatment with atropine or sulpiride. This study suggests that both DM 9278 and HWA 285 act directly on ductular cells of the pancreas and induce secretion of water and electrolytes.     

Effects of dopamine on exocrine secretion and cyclic nucleotide concentration in the dog pancreas

The effects of intravenous injection of dopamine on pancreatic exocrine secretion and on pancreatic cyclic AMP and cyclic GMP concentrations of mongrel dogs were compared with the effects of secretin and pancreozymin. Dopamine (1--10 micrograms/kg), secretin (0.03--0.3 units/kg) and pancreozymin (0.1--1 units/kg) increased exocrine secretion dose dependently, Sulpiride (0.3--1 mg/kg) and yohimbine (0.3--1 mg/kg), D2-receptor antagonists, inhibited the dopamine-induced exocrine secretion dose-dependently but did not inhibit the secretin- or pancreozymin-induced secretion. Secretin (0.3 units/kg) increased cyclic AMp concentration by about 50% but did not affect cyclic GMP concentration. Pancreozymin (1 unit/kg) slightly increased cyclic AMp concentration but markedly increased cyclic GMP concentration by about 50%. However, dopamine (10 micrograms/kg) increased neither cyclic AMP nor cyclic GMP concentration. These results suggest that dopamine causes exocrine secretion from the dog pancreas through D2-receptors which are not linked to adenylate cyclase.     

EFFECTS OF CALCITONIN ON THE SECRETION OF PANCREATIC JUICE INDUCED BY DOPAMINE, SECRETIN AND PANCREOZYMIN

1. Effects of calcitonin on dopamine-, secretin- and pancreozymin-induced pancreatic secretion were investigated in the isolated blood-perfused canine pancreas. 2. The volume of pancreatic secretion induced by pancreozymin given intra-arterially (i.a.) was decreased by an i.a. infusion of 1 u/min of calcitonin, but that induced by dopamine or secretin given i.a. was not affected by calcitonin treatment. 3. Amylase concentration in pancreatic juice either in spontaneous secretion in the resting state or in that of stimulated secretion by pancreozymin was decreased approximately 30% by calcitonin treatment, but amylase concentration in pancreatic juice induced by dopamine or secretin was not affected by calcitonin treatment. 4. Calcitonin had no effect on bicarbonate concentration in pancreatic juice stimulated by these secretagogues. 5. Calcium concentration in pancreatic juice in the resting state was reduced about 36% by calcitonin treatment. Calcitonin caused a decrease in a calcium concentration in the pancreozymin-induced secretion, but did not cause any change in the dopamine- or secretin-induced one. 6. These results suggest that calcitonin may affect the secretory mechanism of the acinar cells but not that of the ductular cells, and that the acinar cells are active even in the resting state.     

EFFECTS OF THREE PURINE-RELATED COMPOUNDS ON PANCREATIC EXOCRINE SECRETION IN THE DOG

The effects of adenosine, adenosine 5'-triphosphate (ATP) and inosine on pancreatic exocrine secretion were investigated in the vascularly isolated and self-haemoperfused dog pancreas. Drugs were injected close-arterially (i.a.) in a single bolus. These three purine-related compounds per se did not affect resting rate of pancreatic secretion and the concentrations of protein and bicarbonate in the resting juice. Graded doses of adenosine (0.1-1.0 mg, i.a.) and ATP (0.1-1.0 mg i.a.) administered 1 min prior to secretin (0.025 clinical units, i.a.) increased a secretin-stimulated secretory volume dose-dependently, and the effects of adenosine and ATP were reversed by pretreatments with theophylline (0.3 mg, i.a.). Inosine (1.0 mg, i.a.) affected neither secretin- nor dopamine-stimulated (3 micrograms, i.a.) pancreatic secretion. Adenosine and ATP did not affect dopamine-stimulated pancreatic secretion. These results suggest that adenosine and ATP (or terminal phosphate hydrolyzed derivatives) enhance secretin-stimulated pancreatic exocrine secretion through 'P1' purine receptors in the exocrine cells, without conversion to inosine.     

EFFECTS OF VERAPAMIL ON PANCREATIC EXOCRINE SECRETION INDUCED BY DOPAMINE, SECRETIN AND PANCREOZYMIN IN THE DOG

1. The effects of verapamil on dopamine-, secretin- and pancreozymin-induced pancreatic secretion were investigated in the isolated, blood-perfused canine pancreas in vivo. 2. The volume of pancreatic secretion either in the resting state or induced by pancreozymin given intra-arterially (i.a.) was decreased by an infusion of 5 μg/min of verapamil; that induced by dopamine or secretin i.a. was also decreased but the changes were not statistically significant. 3. Protein concentration in pancreatic juice either in the resting state or in that of stimulated secretion by pancreozymin was decreased significantly, but protein concentration induced by dopamine or secretin was not affected, by verapamil treatment. 4. Verapamil had no effect on bicarbonate concentration in pancreatic juice secreted either in the resting state or when stimulated by these secretagogues. 5 These results suggest that verapamil, at least in part, may affect the secretory mechanisms of acinar cells but not that of the ductular cells.     

Cholecystokinin acts as an essential factor in the exacerbation of pancreatic bile duct ligation-induced rat pancreatitis model under non-fasting condition

We examined the influence of 2 gut hormones involved in the enhancement of pancreatic exocrine secretion, secretin and cholecystokinin (CCK), in the exacerbation of pancreatitis. We also examined the role of the vagal system, which was considered to be a transmission route for these hormones. Our model of pancreatitis in the rat was prepared by pancreatic bile duct ligation (PBDL), which simultaneously ligated the pancreatic duct and the common bile duct. Serum amylase activity and histopathological changes in the pancreas were used as indices of pancreatitis. We also measured the volume of pancreatic juice, as well as the amylase activity and protein level of the pancreatic juice, as indices of increased pancreatic exocrine secretion. Two gut hormones were given 6 times at 1-h intervals. Administration of secretin (1-3 microg/kg, s.c.) did not influence serum amylase activity in rats with PBDL-induced pancreatitis. However, food stimulation and administration of CCK-8 (1 microg/kg, s.c.) increased serum amylase activity and promoted vacuolation of the pancreatic acinar cells in rats with PBDL-induced pancreatitis. Administration of atropine (3 mg/kg, s.c.) or a CCK1-receptor antagonist, Z-203 (0.1 mg/kg, i.v.), inhibited food-stimulated or CCK-8-induced (1 microg/kg, s.c.) enhancement of pancreatic exocrine secretion and exacerbation after the development of PBDL-induced pancreatitis. These results suggest that not secretin, which regulates the volume of pancreatic juice, but CCK, which regulates the secretion of pancreatic enzymes via the vagal system, plays an essential role in food-stimulated exacerbation after the development of pancreatitis.     

Effects of furosemide on biliary secretion, pancreatic blood flow, and pancreatic exocrine secretion

The effects of furosemide on biliary secretion and on pancreatic hemodynamics and exocrine function were studied by quantitative flowmetry and timed collections of biliary and pancreatic exocrine secretion in the anesthetized dog. Biliary flow and the output of its components (Na+, K+, Ca, Mg, 3-OH bile salts, and bilirubin) increased significantly following a furosemide injection of 0.6 mg/kg and rose progressively to 75-150 per cent above basal levels as the furosemide dose was increased to 9.6 mg/kg. Pretreatment with secretin had no influence on furosemide-induced biliary secretion. Furosemide doses of 4.8 and 9.6 mg/kg increased blood flow in the superior pancreaticoduodenal arterial bed by 30-60 per cent but did not alter flow in the inferior pancreaticoduodenal arterial bed or the pancreatic branch of the splenic artery. However, small increases were seen in flow in the latter two arterial beds after furosemide when secretin administration preceded furosemide. Basal pancreatic secretion was not affected by furosemide, but pretreatment with a submaximal sustaining infusion of secretin uncovered a furosemide action to increase pancreatic exocrine flow and the outputs of Na+, K+, Ca, Mg, and enzymes by 25-35 per cent. These data extend previous studies of the gastrointestinal vasodilator effects of furosemide to the pancreatic circulation and previous data demonstrating furosemide-induced ionic transport in nonrenal systems to biliary, pancreatic acinar, and ductular transport in both organs. Whether the augmentation of pancreatic blood flow is secondary to enhanced ion transport in the exocrine pancreas or to an effect on ionic cotransport in vascular smooth muscle is unknown.