Vagal efferent nerve-dependent inhibitory action of pancreatic polypeptide and peptide YY in conscious rats: comparison with somatostatin

The release of pancreatic polypeptide (PP) and peptide YY (PYY) is regulated by the vagal nerve, and the inhibitory effect of these peptides on pancreatic exocrine secretion shows indirectly via a neural mechanism. To determine the role of the vagal nerve on the inhibitory action of these peptides on the pancreas, we compared the effect on the pancreatic response to bile and pancreatic juice diversion in conscious rats with and without vagotomy. We also studied this response in rats treated with capsaicin, because bile-pancreatic juice diversion is the most potent endogenous stimulation of pancreatic secretion in conscious rats. In addition, since somatostatin potently inhibits of pancreatic enzyme secretion, the effects of PP and PYY were compared with somatostatin. An intravenous infusion of 2.5 nmol/kg per h of PP and PYY significantly inhibited the pancreatic responses of bile and pancreatic juice diversion in animals with an intact vagal nerve and in those treated with capsaicin, whereas the same dose of peptides failed to inhibit pancreatic secretion in vagotomized rats. Somatostatin inhibited pancreatic secretion under all conditions tested. We concluded that the inhibitory action of PP and PYY on pancreatic secretion is fully mediated by the vagal efferent nerve although other multiple mechanisms are involved for the inhibitory action of somatostatin.     

Cytokines serum levels as the markers of thyroid activation in Graves'' disease

We examined whether central somatostatin prevents an inhibitory effect of central calcitonin-gene related peptide (CGRP) on pancreatic secretion in conscious male Wistar rats (330-330 g). Rats were prepared with separate cannulas for draining bile and pancreatic juice and with a duodenal cannula and an extrajugular vein cannula. In addition, another cannula was stereotactically implanted into the left lateral cerebral ventricle. Rats were placed in restraint cages and experiments were conducted 4 days after the operation without anesthesia. An injection of CGRP (0.1, 1.0 nmol/10 microl) into the left lateral cerebral ventricle (i.c.v.) inhibited pancreatic secretion dose-dependently. To confirm the inhibitory effect of CGRP (i.c.v.) was mediated via sympathetic nerves, phentolamine was injected intravenously (i.v.) bolus (0.5 mg kg(-1)) 0.5-h before CGRP (i.c.v.), followed by continuous infusion of 0.2 mg kg(-1) h(-1). Phentolamine (i.v.) reversed the inhibition produced by CGRP (i.c.v.). An injection of 4 nmol/10 microl somatostatin (i.c.v.) 5 min prior to CGRP injection diminished the inhibitory effect of CGRP (i.c.v.). It is concluded that centrally administered somatostatin diminished the inhibitory action of CGRP (i.c.v.) on pancreatic secretion, probably via inhibiting autonomic (sympathetic) nerve excitation at the central site.     

Rectal sexual trauma including foreign bodies

We used a potent and specific monoclonal antibody to somatostatin to test the physiologic inhibitory role of the tetradecapeptide somatostatin on pancreatic secretion. Somatostatin immunoneutralization increased both the total amylase and volume of pancreatic secretion. Cholecystokinin-A receptor antagonism abolished the stimulatory effect of somatostatin immunoneutralization. We conclude that somatostatin tonically inhibits, pancreatic secretion in fasted rats via inhibition of the release or action of cholecystokinin. Furthermore, the source of these peptides is likely islet delta cells and intrapancreatic neurons, respectively.     

Inhibitory effect of somatostatin analogue, SMS 201-995, on secretin-stimulated exocrine secretion in isolated perfused rat pancreas

In order to clarify the effect of somatostatin of the ductal secretion of the exocrine pancreas, we measured pancreatic juice and protein secretion stimulated with 10 pM secretin and/or 10 pM cholecystokinin (CCK) in the presence or absence of somatostatin analogue, SMS 201-995 (SMS) utilizing the isolated perfused pancreas of rats. SMS significantly inhibited both pancreatic juice flow and protein output elicited by 10 pM secretin without affecting basal secretion. The inhibitory effect of SMS was dose-dependent and maximal inhibition was observed with 1-10 nM. Half-inhibitory dose of SMS for juice secretion was 140 pM. Because CCK is thought to potentiate secretin action on the ductal system, we examined the effect of SMS on pancreatic secretory response to 10 pM secretin in combination with 10 pM CCK. In the experimental system we used, the amounts of pancreatic juice and protein secreted during a 30-min stimulation with secretin and CCK were additive. SMS inhibited both pancreatic juice and protein secretion to the level comparable with that obtained with either stimulus and SMS. SMS had no effect on CCK-stimulated pancreatic juice secretion but significantly inhibited protein output. The present study demonstrated, therefore, that SMS inhibits ductal secretion in response to physiological concentration of secretin.     

Role of secretin in negative feedback regulation of postprandial pancreatic secretion in dogs

BACKGROUND: A negative feedback regulation of pancreatic exocrine secretion has been observed in fasting rats, pigs, and humans, but this phenomenon could not be found in fasting dogs. The aims of the present study were to investigate whether or not postprandial pancreatic secretion is regulated by a negative feedback mechanism and to determine if the mechanism is mediated by secretion and/or cholecystokinin (CCK) in dogs. METHODS: In eight dogs prepared with gastric and Herrera's pancreatic cannulas, pancreatic juice was collected for 3 hours after feeding a mixed meal to measure volume, bicarbonate, and trypsin output. Peripheral venous blood was obtained to determine plasma immunoreactive secretin and CCK levels. Four groups of experiments were performed while pancreatic juice was diverted from the duodenum: (1) diversion of pancreatic juice alone, (2) intraduodenal infusion of fresh pancreatic juice while pancreatic juice was diverted, (3) intraduodenal infusion of 150 mg/h of trypsin and 300 mg/h of chymotrypsin, and (4) intraduodenal infusion of 0.1 mol/L NaHCO3. RESULTS: Pancreatic secretion during diversion of pancreatic juice was significantly greater than that obtained while pancreatic juice was returned. Diversion-induced pancreatic hypersecretion was significantly suppressed by intraduodenal administration of pancreatic proteases, but it was not influenced significantly by 0.1 mol/L NaHCO3. The suppression by either pancreatic juice or proteases paralleled the decrease in plasma secretin response, whereas the CCK response remained unchanged. The inhibitory effect of pancreatic proteases on pancreatic secretion was blocked by a physiological dose of exogenous secretin, 0.06 clinical U.kg-1.h-1. CONCLUSIONS: In dogs, postprandial pancreatic secretion is controlled by a negative feedback mechanism mediated mainly by the release of secretin, but not by CCK.     

Regulation of the action of the novel cholecystokinin-releasing peptide diazepam binding inhibitor by inhibitory hormones and taurocholate

Diazepam binding inhibitor (DBI1-86) has recently been isolated in search for a cholecystokinin (CCK)-releasing peptide in the duodenum that is responsible for the feedback regulation of exocrine pancreatic secretion. Synthetic porcine DBI1-86 stimulates CCK release in vivo and in vitro from isolated intestinal mucosal cells. We postulated that DBI intraduodenally releases CCK in a paracrine fashion and might be the missing link in the feedback regulation of exocrine pancreatic secretion. Somatostatin, peptide YY (PYY) and taurocholate are known to inhibit feedback-stimulated CCK release in the rat. In this study, we investigated the effect of somatostatin, PYY and taurocholate on DBI-stimulated CCK secretion. Dispersed rat intestinal mucosal cells were prepared from the proximal small bowel and continuously perfused. The perfusate was collected and the release of CCK into the medium was measured. DBI1-86 dose-dependently stimulated CCK release, with a maximal effect at 10(-9) M. Somatostatin blocked the DBI-stimulated CCK release. Pretreatment of the cells with pertussis toxin fully reversed the inhibitory effect of somatostatin on DBI-stimulated CCK secretion, suggesting that somatostatin exerts its action by an inhibitory G-protein. In contrast, PYY (10(-6) M) and taurocholate (10(-6) M) did not affect DBI stimulated CCK levels, indicating that they act through different mechanisms to inhibit feedback-stimulated CCK release.     

Effects of intraduodenal administration of tarazepide on pancreatic secretion and duodenal EMG in neonatal calves

The influence of CCK-A receptor antagonism on pancreatic exocrine secretion and duodenal EMG, and the mechanism(s) involved in CCK-induced pancreatic secretion were studied in conscious calves. Seven 1-week-old calves were fitted with a pancreatic duct catheter, duodenal cannula and duodenal electrodes. Pancreatic exocrine secretion and duodenal EMG were studied following intraduodenal CCK-A receptor antagonist (Tarazepide), intravenous atropine, and intravenous or intraduodenal CCK-8 administrations. Tarazepide decreased duodenal electric activity, reduced interdigestive pancreatic secretion, especially protein; reduced cephalic and early postprandial (milk) induced secretion of bicarbonate and protein. Pancreatic protein secretion to intravenous CCK-8 was little affected by atropine, but was significantly reduced by Tarazepide+/-atropine; in contrast, protein secretion to intraduodenal CCK-8 was abolished by Tarazepide or atropine. We conclude that pre- and especially early postprandial pancreatic secretion are partly controlled via CCK-A (mainly mucosal) mediated mechanisms.     

Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach

BACKGROUND & AIMS: The role of histamine H3 receptors in the regulation of gastric acid secretion is unclear. The present study was designed to characterize the location of H3 receptors in the fundus of the stomach and the mechanism by which these receptors regulate acid secretion. METHODS: Acid, somatostatin, and histamine secretions were measured in the isolated mouse stomach. RESULTS: Thioperamide (H3 antagonist) increased somatostatin and decreased histamine and acid secretion in a concentration-dependent manner. (r)-alpha-Methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine and acid secretion. The pattern implies that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Somatostatin antibody increased basal histamine secretion and abolished the decrease in histamine and acid secretion induced by thioperamide, confirming that changes in histamine and acid secretion induced by the activation of H3 receptors reflected changes in somatostatin secretion. Similar effects were obtained when acid secretion was stimulated by histamine: thioperamide augmented somatostatin and thus inhibited acid secretion, and (r)-alpha-methylhistamine attenuated somatostatin and increased acid secretion. CONCLUSIONS: Reciprocal inhibitory paracrine pathways link histamine and somatostatin cells in the gastric fundus. Histamine, acting via H3 receptors, augments acid secretion by eliminating the inhibitory influence of somatostatin.     

beta-Endorphin-induced hyperglycemia is mediated by increased central sympathetic outflow to adrenal medulla

Synthetic human beta-endorphin increased plasma glucose concentration when administered intracisternally in chronically cannulated, conscious, unrestrained, adult male rats. This hyperglycemic effect of beta-endorphin was blocked by prior systemic administration of naloxone, supporting mediation of the effect at opioid receptors in brain. Adrenal denervation blocked the beta-endorphin-induced increase in plasma glucose, supporting a thesis that this effect is mediated at least in part by increased epinephrine secretion. The hyperglycemic response to intracerebral beta-endorphin was also blocked by either intracerebral hemicholinium-3 or somatostatin, supporting both a cholinergic link and a somatostatin neuron in the brain mechanism regulating endorphin-induced stimulation of sympathetic outflow.     

Somatostatin-induced inhibition of neurotransmission in the mouse isolated vas deferens is resistant to pertussis toxin

The potential effects of pertussis toxin pretreatment on the inhibitory effect of somatostatin (SRIF) and the selective SRIF receptor agonist, seglitide, were studied in mouse vas deferens and these were compared with its effect on the negative chronotropic action of carbachol in mouse atria. Somatostatin and seglitide caused a concentration-dependent inhibition of neurogenically mediated contractile responses in the vas deferens (EC50 values of 15 and 0.6 nM respectively). There was no difference in their potencies in preparations removed from pertussis toxin pretreated mice. In contrast, the negative chronotropic action of carbachol in mouse atria was abolished by pretreatment with pertussis toxin. We conclude that, in contrast to muscarinic receptor activation in mouse atria, the inhibitory effect of somatostatin in the vas deferens is not mediated by a pertussis toxin sensitive G-protein. The high potency of seglitide suggests that the SRIF receptor involved is of the SRIF1 type.     

Inhibition of intestinal glucagon-like immunoreactivity (GLI) secretion by somatostatin in man

This work was undertaken to investigate the effect of somatostatin on intestinal glucagon-like immunoreactivity (GLI) secretion in man. In normal subjects GLI release is slightly stimulated by oral glucose while this sugar evokes a much greater GLI response in gastrectomized patients. Therefore, our study was performed in a group of such patients (N = 6). As expected, in the control experiments glucose ingestion elicited a clear-cut elevation of GLI plasma levels as measured with two antisera, 78J and R-8 (maximal peaks: 340% and 150% above basal values, respectively). Somatostatin infusion did not modify fasting GLI concentrations but completely abolished GLI response to glucose. Termination of the infusion was followed by a rebound of circulating GLI. The well-known suppressor effect of somatostatin on glucagon and insulin secretion was also detected. Finally, during somatostatin infusion the initial elevation of blood sugar after oral glucose, in the absence of insulin response, appeared considerably delayed. Our data demonstrate that somatostatin behaves as a potent inhibitory agent of GLI secretion in man. A retarding effect of somatostatin on glucose absorption is also compatible with our results.     

Anesthetic experience in congenital arthrogryposis multiplex

Rat pancreatic juice (RPJ) reduced the mean uptake of 57CoB12 bound to rat intrinsic factor (IF) by perfused rat intestinal segments from 30.1 +/- 2.4 (pg 57CoB12 per cm intestine +/- S.E.M.) to 26.7 +/- 2.4 (p less than 0.05). RPJ activated with enterokinase reduced the uptake from 22.8 +/- 2.8 to 16.1 +/- 1.9 (p less than 0.05). RPJ also reduced the uptake from 15.8 +/- 2.3 to 8.3 +/- 2.0 (p less than 0.01) in segments from partially pancreatectomized rats. Rat bile abolished the inhibitory effect of RPJ. The results indicate that in the absence of bile the exocrine pancreatic secretion is capable of inhibiting the intestinal uptake of vitamin B12.     

Inhibition of stimulated amylase secretion by adrenomedullin in rat pancreatic acini

Adrenomedullin is a novel hypotensive peptide originally isolated from human pheochromocytoma and recently localized to PP cells of the pancreatic islets of Langerhans. Based on the pancreatic islet-acinar axis model, we investigated the effect of adrenomedullin on regulated exocytosis of exocrine pancreas. Using rat [125I]-adrenomedullin, specific binding sites were localized to rat pancreatic acini. We next examined the effect of adrenomedullin on 100 pM cholecystokinin (CCK)-stimulated amylase release from pancreatic acini. Adrenomedullin inhibited amylase secretion in a dose-dependent manner by approximately 50% at maximum, and the IC50 was 1.1 pM. However, adrenomedullin did not affect rat [125I]CCK binding to isolated acini or reduce the intracellular free Ca2+ concentration increased by CCK. Adrenomedullin also inhibited amylase secretion induced by 1 microM calcium ionophore A23187, suggesting that adrenomedullin inhibits stimulated amylase secretion by functioning at a step(s) distal to the ligand-receptor binding system and intracellular calcium mobilizing mechanism. In streptolysin-O permeabilized acini, 10 nM adrenomedullin shifted the calcium dose-response curve to the right, indicating that adrenomedullin inhibits calcium-induced amylase secretion by reducing calcium sensitivity of the pancreatic exocytotic machinery. In addition, pretreatment of pancreatic acini with pertussis toxin abolished the inhibitory effect of adrenomedullin on CCK-stimulated amylase secretion. These results indicate that adrenomedullin inhibits stimulated amylase secretion by reducing the calcium sensitivity of the exocytotic machinery of the pancreatic acini. A pertussis toxin-sensitive GTP-binding protein(s) is also involved in this mechanism.     

Effect of somatostatin on metabolic and hormonal changes induced by nicotinic acid in insulin-dependent diabetics

The study investigated the respective influences of nicotinic acid and somatostatin on plasma concentrations of blood glucose, free fatty acids, glucagon, growth hormone and cortisol in insulin-dependent diabetic subjects. After administration of nicotinic acid alone, marked depression of plasma FFA was accompanied by significant increases of plasma glucagon, growth hormone and cortisol. The glucagon and growth hormone responses to nicotinic acid were significantly reduced when plasma FFA were raised by intravenous administration of heparin and triglycerides. Somatostatin alone induced a significant decrease in blood glucose, plasma glucagon and growth hormone concentrations. Plasma FFA remained unchanged. Somatostatin did not modify the nicotinic acid-induced fall in plasma FFA, but completely blocked the corresponding increments in glucagon and growth hormone. The cortisol rise was not altered by somatostatin. Rebound of glucagon and growth hormone levels were seen upon discontinuation of the somatostatin administration. These results demonstrate that the plasma FFA concentration plays a role in the regulation of glucagon and growth hormone secretion in insulin-dependent diabetics. Furthermore, they indicate that somatostatin, previously shown to be capable of negating the stimulatory effect of various factors on glucagon and growth hormone secretion, also affects the response of these hormones to FFA depression.     

Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine

Pancreatic proteases in the duodenum inhibit the release of cholecystokinin (CCK) and thus exert feedback control of pancreatic exocrine secretion. Exclusion of proteases from the duodenum either by the diversion of bile-pancreatic juice or by the addition of protease inhibitors stimulates exocrine pancreatic secretion. The mechanism by which pancreatic proteases in the duodenum regulate CCK secretion is unknown. In this study, we isolated a trypsin-sensitive peptide that is secreted intraduodenally, releases CCK, and stimulates pancreatic enzyme secretion in rats. This peptide was found to be identical to the porcine diazepam binding inhibitor by peptide sequencing and mass spectrometry analysis. Intraduodenal infusion of 200 ng of synthetic porcine diazepam binding inhibitor1-86 in rats significantly stimulated pancreatic amylase output. Infusion of the CCK antagonist MK-329 completely blocked the diazepam binding inhibitor-stimulated amylase secretion. Similarly, diazepam binding inhibitor33-52 [corrected] also stimulated CCK release and pancreatic secretion in a dose-dependent manner although it was 100 times less potent than the whole peptide. Using a perfusion system containing isolated mucosal cells from the proximal intestine of rats, porcine diazepam binding inhibitor 10(-12) M) dose dependently stimulated CCK secretion. In separate studies, it was demonstrated that luminal secretion of the diazepam binding inhibitor immunoreactivity (7.5 X 10(11) M) could be detected in rat's intestinal washing following the diversion of bile-pancreatic juice. The secretion of this peptide was inhibited by atropine. In conclusion, we have isolated and characterized a CCK-releasing peptide that has a sequence identical to the porcine diazepam binding inhibitor from pig intestinal mucosa and that stimulates CCK release when administered intraduodenally in rat. This peptide may mediate feedback regulation of pancreatic enzyme secretion.     

Effect of somatostatin immunoneutralization on gastric acid and pancreatic enzyme secretion in anesthetized rats

The involvement of somatostatin in urethane-anesthesia-evoked suppression of gastric acid secretion has been described. The present study has examined the role of endogenous somatostatin in diminished pancreatic enzyme secretion during anesthesia, while monitoring acid secretion concurrently. Rats were anesthetized with either urethane or sodium pentobarbital. An indwelling catheter was placed into the right jugular vein. The esophagus and the pylorus were ligated, and the stomach was perfused with saline. The common bile duct was ligated at the hepatic hilum, and cannulated at the duodenal end of the duct for collecting pure pancreatic juice. Purified somatostatin monoclonal antibody (CURE.S6) or control antibody (keyhole limpet hemacyanin, KLH) was injected iv in increasing doses (0.05; 0.15; 0.5; and 1.5 mg) every 30 min (n = 6). Gastric acid and pancreatic amylase secretions were measured. The effect of the antibodies on CCK-8-stimulated (0.25-2.50 nmol/kg/h) pancreatic amylase secretion was also tested. During urethane anesthesia somatostatin antibody induced a dose-dependent increase in acid output, while control antibody did not change it. Basal pancreatic amylase secretion was not affected by either somatostatin or by control antibody. Pancreatic secretory responses to high but not to low doses CCK-8 were found to be significantly increased following immunoneutralization of somatostatin. In sodium pentobarbital-anesthetized rats somatostatin antibody stimulated basal acid secretion but did not affect basal pancreatic amylase secretion. Our data indicate that in anesthetized rats endogenous somatostatin mediates suppression of basal gastric acid secretion but not that of basal pancreatic amylase secretion, and this action does not depend on the type of anesthesia. Furthermore, endogenous somatostatin may play a physiological role in modulating stimulated pancreatic enzyme secretion in this species.     

Pancreatic exocrine secretion during the first days after weaning in pigs

Feed replacement at weaning plays an important role in the induction of pancreatic maturation. To understand the changes in the exocrine pancreas at weaning and the relation to postweaning problems, we studied the function of the exocrine pancreas and changes of intestinal hemolytic Escherichia coli in four pigs. The pigs were chronically fitted with pancreatic duct catheters and T-shaped cannula inserted into the duodenum for reintroduction of pancreatic juice. One day before weaning (at 30 d of age), pancreatic juice was collected for 1 h before and 1 h after a morning and an evening suckling. The pigs were not creep fed, but from weaning the pigs received a standard weaning diet ad libitum. On d 1, 2, 3, and 5 after weaning, pancreatic juice was collected continuously for the 24-h period. The total pancreatic secretion was measured at hourly intervals, 1.5-mL samples were taken for analysis, and the remaining juice was returned to the animal. On these days, samples from the duodenum, ileum, and rectum were also taken for analyses of hemolytic E. coli. From the day before to 5 d after weaning, a gradual increase in pancreatic secretion was observed concerning volume (P < .001) and protein (P < .01) and trypsin (P < .02) levels. An increase (P < .01) in hemolytic E. coli in the duodenal contents was also documented during this period. We assume that the gradual increase in the measured variables of pancreatic secretion is related to the increasing consumption of solid feed. However, the appearance of E. coli and disappearance of milk components from the gastrointestinal tract could be other factors stimulating the exocrine pancreas.     

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.     

Inhibitory effect of somatostatin on Helicobacter pylori proliferation in vitro

BACKGROUND & AIMS: Somatostatin regulates gastric function and cell proliferation. We investigated whether exogenous somatostatin modulates Helicobacter pylori proliferation in vitro. METHODS: Bacteria were cultured in 5 mL Brucella broth. Bacterial numbers of H. pylori (ATCC 43504) and Escherichia coli were calculated 48 and 5 hours after incubation, respectively, by counting the colonies on the blood agar. Chemicals were dissolved in absolute methanol and added to the broth at a final methanol concentration of 1%. Intrabacterial guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) levels were measured by radioimmunoassay. RESULTS: Somatostatin significantly suppressed H. pylori proliferation at levels at or above 10(-11) mol/L. A similar antiproliferative effect was observed with 8-bromo-cGMP. At concentrations at or above 10(-8) mol/L, dibutyryl cAMP slightly but significantly stimulated bacterial proliferation. Gastrin had no effect. Somatostatin antibody immunoglobulin G fraction blocked the antiproliferative effect of somatostatin on ATCC 43504. Scatchard plot showed that ATCC 43504 has one class of binding site with relatively high affinity (Kd, 0.31 nmol/L). Somatostatin at 10(-11) mol/L increased cGMP and cAMP in H. pylori 11-fold and 6-fold, respectively. In contrast, somatostatin neither bound E. coli nor affected its proliferation. CONCLUSIONS: Somatostatin, at a similar level in human gastric juice (approximately 10(-11) mol/L), suppresses H. pylori proliferation mediated in part by a cGMP-dependent pathway in vitro, indicating a possible inhibitory effect of somatostatin in the gastric lumen on H. pylori proliferation in humans.     

Effect of ETA receptor antagonists on cardiovascular responses induced by centrally administered sarafotoxin 6b: role of sympathetic nervous system

The present study was carried out to investigate the cardiovascular effects of centrally administered SRT6b in saline, BQ123 and BMS182874 pretreated male Sprague-Dawley rats, using a radioactive microsphere technique. SRT6b (100 ng, ICV) produced a transient increase (40%) in blood pressure at 5 min followed by a sustained decrease (-42%) at 30 and 60 min in control rats. Total peripheral resistance and heart rate were not significantly altered. Cardiac output increased (16%) at 5 min and decreased 30 and 60 min following SRT6b administration. Central venous pressure was not affected by SRT6b. Regional blood flow and vascular resistance did not change at 5 min following administration of SRT6b. However, a significant decrease in blood flow to the brain, heart, kidneys, liver, spleen, gastrointestinal tract and mesentery and pancreas was observed 30 and 60 min following administration of SRT6b in control (saline treated) rats. Pretreatment with ETA selective receptor antagonists, BQ123 (10 micrograms, ICV) or BMS182874 (50 micrograms, ICV) significantly attenuated the pressor and depressor effects of centrally administered SRT6b. SRT6b induced decrease in blood flow was completely blocked by pretreatment with BQ123 or BMS182874. ET-1 (100 ng, ICV) produced an increase followed by a decrease similar to SRT6b. Reserpine (5 mg/kg, IP) pretreatment attenuated the cardiovascular effects of ET-1. Role of sympathetic nervous system was determined by measuring splanchnic nerve activity. SRT6b when administered in the lateral cerebral ventricle did not produce any significant effect at 5 min, however, a significant decrease in sympathetic nerve activity was observed 30 min after its administration. It is concluded that centrally administered SRT6b produces significant changes in systematic and regional blood circulation which can be completely blocked by ETA receptor antagonist. The cardiovascular effects of centrally administered SRT6b appear to be mediated through the sympathetic nervous system.