Effect of L-364,718 on GRP-stimulated pancreatic and gastric secretions and GI peptides in conscious dogs

The effect of L-364,718, a cholecystokinin (CCK) receptor antagonist, on exocrine pancreatic secretion, gastric secretion, and plasma levels of gastrointestinal (GI) peptides stimulated by gastrin-releasing peptide (GRP) was examined in five conscious dogs. Intravenous infusion of graded doses of synthetic porcine GRP (18, 36, and 178 pmol/kg/h) caused significant and dose-dependent increases in pancreatic and gastric juice secretion and in plasma levels of pancreatic polypeptide (PP), CCK, and gastrin. Intravenous injection of L-364,718 (20 nmol/kg) significantly inhibited GRP-stimulated pancreatic outputs of juice volume, protein, and amylase and plasma PP release. L-364,718, however, did not affect gastric juice volume and plasma levels of CCK and gastrin. The results suggest that endogenously released CCK is, at least in part, responsible for GRP-stimulated pancreatic protein and enzyme secretions and PP release in dogs. The results further suggest that GRP-stimulated pancreatic secretion might be, in part, a direct response of GRP to exocrine pancreas.     

Role of cholecystokinin, gastrin and gastrin-releasing peptide in the regulation of pancreatic secretion in cats.

This study performed on 6 conscious cats with chronic pancreatic fistulas was designed to determine the role of cholecystokinin (CCK), gastrin and gastrin-releasing peptide (GRP) in stimulation of pancreatic secretion in this species. Pancreatic response to GRP infused intravenously in graded doses appears to be mediated predominantly by CCK because a CCK receptor antagonist, L-364,718, abolished this response. Also, gastrin appears to mediate in part the secretory response to GRP because blockade of gastrin receptors by L-365,260, given at the dose that completely abolished the pancreatic response to exogenous gastrin, caused a significant reduction in the bombesin-induced pancreatic secretion. CCK and partly gastrin appear to mediate the postprandial pancreatic secretion in cats as the administration of L-364,718 and L-365,260 inhibited this secretion by over 90 and 30%, respectively. In contrast, GRP does not seem to contribute to food-induced pancreatic secretory stimulation, because the blockade of GRP receptors using novel bombesin/GRP antagonist (RC-3100) failed to affect this secretion. We conclude that CCK and partly gastrin, but not GRP, play an essential role in the postprandial pancreatic secretion.     

Effects of L-364,718 on pancreatic exocrine and endocrine secretion in the rat.

We examined the inhibitory effect of L-364,718, a nonpeptide cholecystokinin (CCK) antagonist, on CCK stimulation of pancreatic exocrine and endocrine secretion in both the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, L-364,718 inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of 125I-CCK-8 in a dose-dependent manner without appreciable effects on the basal amylase secretion. L-364,718 also inhibited amylase release in response to caerulein and gastrin I, but had no effect on amylase release stimulated by other secretagogues or by agents bypassing receptors. Similarly, binding of N-methylscopolamine to pancreatic acini was not inhibited by L-364,718. In the isolated perfused pancreata, L-364,718 inhibited CCK-8-stimulated pancreatic exocrine secretion and insulin release. The inhibitory effects of L-364,718 were more potent for insulin release than for exocrine secretion and persisted even after the removal of L-364,718 infusion. These results clearly demonstrate that L-364,718 is a specific, potent, and prolonged antagonist of CCK's stimulatory actions on pancreatic acinar and B cells.     

Effect of synthetic human cholecystokinin-33 on pancreatic blood flow in dogs

We have examined the effect of synthetic human cholecystokinin (CCK-33 and CCK-8) on pancreatic blood flow and protein output in anesthetized dogs. Human CCK-33 and CCK-8 increased pancreatic blood flow and protein output in a dose-related manner. There were no significant differences in increasing pancreatic blood flow between human CCK-33 and CCK-8, and increases in blood flow were closely related to the increase of the pancreatic enzyme secretion. L-364,718 (20 nmol/kg) caused a potent inhibition of CCK-stimulated pancreatic blood flow as well as protein output. The degree of inhibition by L-364,718 was dependent on the amount of CCK infused. This study demonstrates that increasing effect on pancreatic blood flow may be one of the biological actions of CCK mediated via CCK receptor. The CCK-33, one of longer molecular forms of CCK, is an important biological stimulator of pancreatic blood flow as well as of exocrine pancreatic secretion.     

The role of gastrointestinal peptides on pancreatic secretion in response to different stimulants in conscious rats

Summary Effects of intragastric food, intraduodenal amino acids, and intravenously administered bombesin and gastrin-releasing peptide (GRP) were examined in conscious rats with pancreatic fistula in terms of responses of exocrine pancreatic secretion, plasma levels gastrin, and cholecystokinin (CCK). Pancreatic juice and blood samples were collected at regular intervals before and after the stimuli. Intragastric food increased pancreatic secretion and plasma levels of gastrin and CCK. Intraduodenal infusion of amino acids had no effect on pancreatic secretion and plasma levels of gastrin and CCK. Intravenous infusion of bombesin at 1 μg/kg/h induced significant increases in pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Bombesin infusion at 10 μg/kg/h resulted in significant increases in pancreatic volume and protein outputs as well as plasma gastrin levels, but had no effect on plasma CCK levels. Intravenous infusion of GRP induced increases in pancreatic volume and protein outputs and plasma gastrin levels, but had no effect on CCK levels. Antrectomy resulted in significant decreases in basal levels of plasma gastrin. GRP-stimulated pancreatic volume and protein outputs were not significantly changed by antrectomy. In rats that underwent antrectomy, GRP infusion significantly increased pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Food-stimulated pancreatic secretion and plasma levels of gastrointestinal peptides of rats were similar to other species, but amino acids, bombesin, or GRP may not be the stimulants for CCK release in rats. The stimuli that release CCK from duodenal mucosa probably varies among species.     

Antagonism of receptors for bombesin, gastrin and cholecystokinin in pancreatic secretion and growth.

The effects of bombesin, gastrin and cholecystokinin (CCK) on amylase secretion from the isolated rat pancreatic acini and on DNA synthesis (as biochemical indicator of trophic action) in the pancreas have been examined in 48-hour fasted and 16-hour refed rats with and without administration of specific receptor antagonists for bombesin, gastrin and CCK. Studies on the isolated rat acini revealed that bombesin, gastrin and CCK-8 all showed the same efficacy in their ability to stimulate amylase release. RC-3095, bombesin pseudo-peptide antagonizing bombesin receptors, was effective only in suppressing the amylase response to bombesin but not to gastrin or CCK. Benzodiazepine receptor antagonists for gastrin (L-365,260) and for CCK (L-364,718) showed higher efficacy in the inhibition of amylase release induced by pentagastrin and CCK, respectively, but failed to affect that induced by bombesin. These peptides administered 3 times daily for 48 h in fasted rats increased the rate of DNA synthesis as measured by the incorporation of [3H]thymidine into DNA. The blockade of bombesin receptors abolished the DNA synthesis induced only by bombesin but not by gastrin or CCK. The blockade of gastrin receptors by L-365,260 suppressed the DNA synthesis induced by gastrin while the antagonism of CCK receptors by L-364,718 was effective only against CCK. Refeeding of 48-hour fasting rats strongly enhanced DNA synthesis which was significantly reduced by blocking only the CCK receptors (with L-364,718), but not the bombesin (with RC-3095) or gastrin receptors (with L-365,260).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of an antral mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic secretion in dogs

The purpose of this study was to determine the role of gastrin and cholecystokinin in the cephalic phase of gastrin release and gastric and pancreatic secretion in conscious dogs. Sham feeding in intact dogs increased gastric acid output to about 65% of histamine maximum and pancreatic protein to 23% of caerulein maximum. Significant increases in plasma gastrin and pancreatic polypeptide but not cholecystokinin occurred. Similar effects were obtained using insulin hypoglycemia or 2-deoxy-D-glucose glucocytopemia. Atropine eliminated gastric acid response to sham feeding, insulin, or 2-deoxy-D-glucose, significantly reduced the pancreatic protein response by about 60%, and abolished plasma pancreatic polypeptide but not plasma gastrin. Blocking of cholecystokinin receptors by L-364,715 did not affect gastric or pancreatic secretory responses to sham feeding, insulin, or 2-deoxy-D-glucose and failed to influence the accompanying increments in plasma gastrin and pancreatic polypeptide. In antral-mucosectomized dogs, sham feeding-induced acid output reached only 17% of histamine maximum but the increase in pancreatic protein output was similar to that in intact dogs. In these animals, background stimulation with G17I (62 pmol/kg per h) potentiated the gastric acid response to sham feeding but had little effect on pancreatic protein output. This study provides evidence that unlike gastric acid, the pancreatic protein response to physiological or pharmacological cephalic stimulation does not depend on vagally released gastrin but probably on direct vagal stimulation of the pancreas.     

Role of cholecystokinin in cholestyramine-induced changes of the exocrine pancreas

This study was an investigation of the role of cholecystokinin (CCK) in the stimulatory action of cholestyramine on rat exocrine pancreas. Postprandial CCK release was significantly enhanced by acute administration of cholestyramine (12.7 +/- 1.8 vs 3.7 +/- 0.5 pmol/L in controls). Over four weeks, rats were fed either regular diet or diet containing 6% cholestyramine, and were treated with the specific CCK receptor antagonist L-364,718 (2 x 0.5 mg/kg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymotrypsin contents. L-364,718 abolished these effects. Concomitant administration of antagonist and cholestyramine elevated amylase content, compared to controls. CCK levels in fasted animals did not differ between the four groups. The effect of the same dose of L-364,718 on pancreatic enzyme depletion, induced by the protease inhibitor camostate, was studied in a control experiment. A single dose of camostate (200 mg/kg) caused a 44-68% decrease in enzyme content. L-364,718 reversed this effect for all enzymes. We conclude that CCK is the mediator of cholestyramine-induced pancreatic hypertrophy and increase in content of proteases. After long-term administration, the CCK receptor antagonist, in combination with cholestyramine revealed an agonistic effect on individual, pancreatic enzyme content.     

Effect of the prokinetic drug cisapride on gastrointestinal hormone release

The influence of the prokinetic drug cisapride on the release of gastrointestinal hormones was studied in volunteers. First, acute effects of single doses of cisapride compared with saline were investigated. Cisapride at doses of 8 mg and 20 mg intravenously significantly increased plasma concentrations of pancreatic polypeptide (hPP) by 145% and 146%, respectively. Cholecystokinin (CCK) levels were increased by 176% at 8 mg cisapride, whereas gastrin and insulin levels remained unchanged. Enhancement of PP and CCK secretion was almost completely abolished by pretreatment with 1 mg atropine. Carbachol (250 micrograms subcutaneously) increased PP release by 62% but did not affect the other hormones. Second, the influence of a 1-week treatment (10 mg three times daily, given orally) on plasma hormone levels was studied. After 1 week the postprandial CCK release was diminished by 58%. Basal levels and postprandial responses of gastrin, PP, and insulin were not altered by prolonged cisapride administration. It is concluded that acute application of cisapride stimulates secretion of PP and CCK via atropine-sensitive mechanisms and that chronic treatment with cisapride diminishes CCK release by an unknown mechanism.     

Liver Disease in α1-Antitrypsin Deficiency: Aspects of Incidence and Prognosis

The influence of the prokinetic drug cisapride on the release of gastrointestinal hormones was studied in volunteers. First, acute effects of single doses of cisapride compared with saline were investigated. Cisapride at doses of 8mg and 20 mg intravenously significantly increased plasma concentrations of pancreatic polypeptide (hPP) by 145% and 146%, respectively. Cholecystokinin (CCK) levels were increased by 176% at 8 mg cisapride, whereas gastrin and insulin levels remained unchanged. Enhancement of PP and CCK secretion was almost completely abolished by pre-treatment with 1 mg atropine. Carbachol (250 ug subcutaneously) increased PP release by 62% but did not affect the other hormones. Second, the influence of a 1-week treatment (10 mg three times daily, given orally) on plasma hormone levels was studied. After 1 week the postprandial CCK release was diminished by 58%. Basal levels and postprandial responses of gastrin, PP, and insulin were not altered by prolonged cisapride administration. It is concluded that acute application of cisapride stimulates secretion of PP and CCK via atropine-sensitive mechanisms and that chronic treatment with cisapride diminishes CCK release by an unknown mechanism.     

The effect of galanin on canine plasma glucose and gastroenteropancreatic hormone responses to oral nutrients and intravenous arginine

Intravenous infusion of galanin into conscious dogs during ingestion of oral glucose or a mixed meal or during iv infusion of arginine resulted in significant blunting of plasma insulin responses and significant increases in plasma glucose levels compared to those in control experiments. Galanin infusions did not significantly alter plasma gastric inhibitory peptide responses to oral glucose or a mixed meal, or plasma gastrin, pancreatic polypeptide, or pancreatic glucagon responses to a mixed meal. Similarly, galanin infusions did not significantly alter pancreatic glucagon responses to iv arginine. In all experimental situations, on cessation of the galanin infusions, prompt elevation of plasma insulin levels occurred. These results suggest that in the conscious dog, galanin administration produces a relatively selective, but readily reversible, inhibition of insulin secretion stimulated by oral nutrients or iv arginine.     

Subtypes of muscarinic receptors in canine pancreatic secretion in vivo and in vitro

In conscious dogs with esophageal, gastric and pancreatic fistulae, sham-feeding and meat feeding increased the pancreatic protein secretion to a peak, reaching about 39% and 69% of CCK8 maximum, and raised plasma pancreatic polypeptide (PP) levels. Pirenzepine given intravenously (i.v.) (30 nmol.kg-1 or 3 mumol.kg-1) reduced dose-dependently the pancreatic protein and plasma PP responses to sham-feeding and meat feeding, being about 100 times less potent as an inhibitor than atropine. Neither pirenzepine nor atropine affected near-maximal pancreatic bicarbonate and protein responses to secretin (164 pmol.kg-1.h-1) and CCK8 (170 pmol.kg-1.h-1), but both antimuscarinic agents significantly inhibited pancreatic responses to lower doses of these secretagogues. When added to the incubation medium of dispersed canine pancreatic acini, pirenzepine reduced dose-dependently the amylase responses only to urecholine, and not to CCK or gastrin, being about 1000 times less potent as an inhibitor than atropine. This report provides an evidence that pirenzepine inhibits pancreatic secretion in a similar manner to atropine, but that pirenzepine, in both in vivo and in vitro studies, is 2-3 orders of magnitude less potent as an inhibitor than atropine, indicating that the muscarinic pathway of the exocrine pancreas has a low affinity for pirenzepine and may thus involve M2-receptors.     

Effects of cholecystokinin and gastrin antagonists on pancreatic exocrine secretion stimulated by gastrin-releasing peptide.

The effects of a specific cholecystokinin (CCK) receptor antagonist (L364,718) and a gastrin receptor antagonist (L365,260) on gastrin-releasing peptide-10 (GRP-10)-stimulated pancreatic secretion were investigated in the anesthetized rat. GRP-10 stimulated pancreatic exocrine secretion in a dose-dependent manner. A dose of 1.0 nmol/kg/h elicited a significant increase in pancreatic protein output. L364,718 (2.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous CCK-8 (3.0 nmol/kg/h) on pancreatic secretion, did not suppress the excitatory effect of GRP-10. L365,260 (5.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous gastrin (20 micrograms/kg/h) on gastric acid secretion, did not suppress the excitatory effect of GRP-10 either. We concluded that CCK or gastrin do not mediate the excitatory mechanism of bombesin/GRP on pancreatic secretion. Since CCK and gastrin are the most probable candidates for excitatory mediator of bombesin/GRP, these results support the hypothesis that bombesin/GRP directly stimulates the exocrine pancreas in the rat.     

Comparison of loxiglumide, a cholecystokinin receptor antagonist, and atropine on hormonal and meal-stimulated pancreatic secretion in man

The effects of loxiglumide, a potent cholecystokinin (CCK)-receptor antagonist, and atropine, a muscarinic receptor blocker, on exocrine pancreatic secretion stimulated by hormones (secretin plus CCK) and a Lundh test meal were studied in healthy young volunteers. Loxiglumide infused intravenously in gradually increasing doses (2-16 mumol/kg-h) caused a dose-dependent inhibition of pancreatic enzyme secretion induced by intravenous infusion of a constant dose of secretin (82 pmol/kg-h) plus CCK-8 (85 pmol/kg-h) but had relatively smaller influence on duodenal volume flow and bicarbonate output. Atropine (20 nmol/kg) also caused a significant reduction in pancreatic enzyme secretion but failed to affect the volume flow or bicarbonate secretion induced by secretin plus CCK, possibly owing to the high doses of secretin and CCK used in these tests. Both loxiglumide and atropine inhibited the pancreatic enzyme response to a Lundh meal, but atropine was more effective in the early phase and loxiglumide in the late phase of the postprandial secretion. Neither loxiglumide nor atropine affected the plasma gastrin and CCK levels, but both antagonists reduced plasma pancreatic polypeptide responses to the Lundh meal. We conclude that 1) loxiglumide results in a relatively stronger suppression of the pancreatic enzyme than aqueous-alkaline secretion induced by secretin plus CCK, whereas atropine inhibits only enzyme secretion; and 2) both loxiglumide and atropine suppress the pancreatic enzyme responses to the meal stimulation without affecting the postprandial plasma gastrin and CCK responses.     

Role of secretin and CCK in the stimulation of pancreatic secretion in conscious dogs. Effects of atropine and somatostatin

The role of gut hormones, such as secretin and CCK, in the stimulation of pancreatic secretion by duodenal HCl or oleate and by meat feeding has been studied in conscious dogs before and after pretreatment with atropine and somatostatin. Plasma hormones were measured by specific and sensitive radioimmunoassays. Duodenal perfusion with HCl and oleate stimulated dose-dependently pancreatic HCO3 and protein secretion and raised plasma levels of secretin and CCK, respectively. Atropine reduced significantly both HCO3 and protein secretion but did not affect plasma secretin and CCK levels in these studies. Both exocrine pancreatic secretion and plasma secretin and CCK levels were suppressed by somatostatin. Meat feeding caused a marked pancreatic HCO3 and protein secretion accompanied by a significant increase in plasma secretin and CCK which seem to play an important role in the postprandial pancreatic stimulation. Both atropine and somatostatin reduced the pancreatic secretion induced by exogenous hormones but only somatostatin, but not atropine, significantly decreased plasma secretin and CCK responses to intestinal stimulants. We conclude that both atropine and somatostatin reduce the pancreatic responses to duodenal HCl or oleate or to meat feeding but only somatostatin is capable of suppressing the release of secretin and CCK.     

Addition of albumin to solutions of cholecystokinin (CCK)--effect on pancreatic secretion, plasma CCK level and release of pancreatic polypeptide (PP)

Dissolving basic peptides such as insulin, secretin, and somatostatin in albumin-containing solutions increases the biologic potency. As CCK-33 also constitutes a basic peptide, it should have similar qualities. In four conscious dogs with chronic gastric and pancreatic Thomas fistulas, we studied the effect of CCK-33 solutions with and without addition of albumin on pancreatic secretin, plasma PP concentration, CCK-like immunoreactivity in plasma and infusion lines. The response of pancreatic protein output (mg/15 min) to increasing doses of 99% pure CCK-33 (0.5; 1; 2; 4 IDU/kg/h) was significantly higher (p less than 0.05) when CCK was dissolved in 0.154 M NaCl with albumin than in NaCl alone. These results were confirmed by measuring plasma CCK-immunoreactivity by CCK-RIA and CCK-immunoreactivity in samples from tips of infusion lines by gastrin-RIA. CCK evoked PP release at increasing doses of CCK-33, which was significantly (p less than 0.05) higher when CCK was dissolved in an albumin-containing solution. There was a significant (p less than 0.02) correlation between plasma PP concentration and pancreatic protein output. Our study shows addition of albumin to solutions of CCK-33 to cause an increase of CCK-33 activity, probably by preventing adsorption of the peptide to glass and plastic surfaces. This is valid for its effect on pancreatic protein secretion as well as PP release.     

Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT(2) receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10(-8) -10(-5) M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.     

Cholecystokinin antagonist prevents hyperamylasemia and improves pancreatic exocrine function in cerulein-induced acute pancreatitis.

Supramaximal cerulein administration induces acute pancreatitis, which markedly impairs pancreatic secretion in conscious rats. We hypothesized that pretreatment with the potent cholecystokinin antagonist, L-364,718, improves the pancreatic secretory impairment associated with cerulein-induced acute pancreatitis. Rats were surgically prepared with gastric, duodenal, bile, and pancreatic fistulas and jugular vein catheters. On postoperative day 4, groups of rats were administered (a) L-364,718 1 mg/kg intraduodenally, (b) cerulein 5 micrograms/kg/h for 6 h intravenously, (c) L-364,718 1 mg/kg intraduodenally followed by cerulein 5 micrograms/kg/h for 6 h intravenously, and (d) safflower oil carrier intraduodenally. On postoperative day 5, we studied cholecystokinin (CCK)-stimulated pancreatic secretion. Plasma amylase was measured at the time of surgery and at the conclusion of experiments on postoperative days 4 and 5. The duodenally administered CCK antagonist had no effect, 24 h later, on CCK-evoked protein secretion and prevented the pancreatic exocrine impairment and hyperamylasemia caused by supramaximal cerulein administration. These observations suggest that cerulein-induced acute pancreatitis is mediated by a CCK-receptor mechanism.     

Correlation between gastric emptying time and both plasma gastrin and pancreatic polypeptide in streptozotocin diabetic dogs

Correlation between gastric emptying time and both plasma gastrin and pancreatic polypeptide (PP) levels after meal was studied in 9 normal and 5 streptozotocin (STZ) diabetic dogs. Moreover, the effects of exogenous insulin at doses of 0.2 and 0.4 U/kg on gastric emptying and plasma hormone levels were also studied in STZ diabetic dogs. The time required to reach the peak of plasma acetaminophen level, which is the indirect indicator of gastric emptying rate, was significantly delayed in STZ diabetic dogs than in control dogs. Plasma gastrin response was delayed slightly in STZ diabetic dogs, but the plasma levels were not significantly different between the two groups. Plasma PP levels both in the basal and after postprandial state were significantly higher in STZ dogs than in normal dogs. Infusion of insulin did not affect plasma levels of acetaminophen and gastrin, while it produced a dose-dependent suppression of postprandial PP rise in STZ diabetic dogs. The foregoing data indicate that high level of plasma PP observed in STZ dogs did not correlate with gastric emptying but with insulin deficiency.