Pentagastrin Infusion Research Articles

Omeprazole induces high intraglandular pressure in the rat gastric mucosa

BACKGROUND & AIMS: In a few patients receiving high doses of omeprazole for a prolonged period, cystic changes have developed in the gastric mucosa, possibly consisting of enlarged gland lumina. To investigate this question, the luminal pressure in gastric glands was studied after omeprazole treatment in Inactin-anesthetized rats. METHODS: The gland luminal pressure and mucus thickness were measured with microelectrodes. For pressure measurements (servo-null technique) the microelectrode was inserted into a gland at an angle of approximately 30 degrees to the mucosal surface. RESULTS: Animals given omeprazole by gavage, 400 micromol/kg daily for 1 week, showed high gland luminal pressures (27.4 +/- 2.4 mm Hg). Similar values were found in animals given an intravenous omeprazole injection (40 micromol/kg). Much lower pressures were noted after vehicle or pentagastrin infusion. The thickness of the lower, firm mucus layer was not altered by omeprazole treatment. CONCLUSIONS: The significantly higher gland luminal pressure after treatment with omeprazole, compared with the values during pentagastrin or vehicle infusion, cannot be explained by increased mucus thickness. The results suggest accumulation of fluid in the gland lumen caused by increased resistance to outflow from the gland. This might explain the proposed enlargement of gland lumina. (Gastroenterology 1997 Apr;112(4):1221-30)

Activation of Amygdala CholecystokininBReceptors Potentiates the Acoustic Startle Response in the Rat

The acoustic startle reflex is a sensitive index of "anxiety" and "fear." Potentiation of startle by conditioned and unconditioned fear stimuli appears to be mediated by the amygdala. CholecystokininB (CCKB) agonists increase "anxiety" in laboratory animals and induce "panic" in humans. Here, we investigate the role CCKB receptor-mediated mechanisms in the amygdala in the potentiation of startle. First, intra-amygdala infusions of the CCKB receptor agonist pentagastrin (0, 0.01, 0.1, 1, and 10 nM) produced a dose-related potentiation of acoustic startle responses. At the highest dose, startle amplitudes were increased up to 90% above preinfusion baseline levels. Second, similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that increases in startle responsivity after infusions of pentagastrin are not attributable to nonspecific changes in motor activity. Third, infusions of similar doses of pentagastrin into the striatum or nucleus accumbens did not potentiate startle responses. Fourth, pretreatment with the CCKB receptor antagonist L-365,260 (0.1 mg/kg, i.p.) attenuated the potentiation of startle produced by intra-amygdala infusions of pentagastrin. Finally, intra-amygdala infusion of the CCKB receptor-selective antagonist PD-135158 (10 micro;g) blocked the potentiation of startle produced by i.c.v. infusions of pentagastrin, suggesting that i.c.v. infusions of pentagastrin potentiate startle responses via activation of amygdala CCKB receptors. These results show that amygdala CCKB receptor-mediated mechanisms are involved in the potentiation of acoustic startle responses.

Gastric mucosal blood flow regulation in response to different stimuli.

We compared changes in gastric mucosal blood flow (GMBF) and left gastric artery blood flow (LGABF) in response to pharmacological, physiological, and pathological stimuli. GMBF and LGABF were measured by the hydrogen gas clearance and perivascular ultrasonic transit time techniques, respectively, under baseline conditions and following intravenous infusion of vasopressin or pentagastrin, isovolemic hemodilution, or gastric perfusion with HCl-taurocholate. Blood flow changes following vasopressin or hemodilution were significantly larger in the left gastric artery than in the gastric mucosa. In contrast, the increment in blood flow associated with pentagastrin-stimulated acid secretion was significantly greater in the gastric mucosa than in the extramural artery. Barrier disruption with acid-taurocholate induced similar changes in both measurement sites. The gastric hyperemia induced by either mechanism was significantly attenuated by blockade of NO synthesis. These data demonstrate that although functional changes in GMBF are primarily supported by changes in blood flow at the extramural gastric arteries, the gastric mucosal microvasculature is also under the influence of independent local control mechanisms.

Mechanism of gastric hyperemic response during acid secretion in rats: relation to nitric oxide, prostaglandins, and sensory neurons.

The mechanism of gastric mucosal hyperemic response during pentagastrin-induced acid secretion was investigated in anesthetized rats in relation to prostaglandins (PGs), nitric oxide (NO), and sensory neurons. A rat stomach was mounted in an ex vivo chamber and perfused with saline or glycine (200 mM), and the mucosal blood flow (GMBF), determined by laser Doppler flowmetry, and acid secretion was measured simultaneously. Intravenous infusion with a submaximal dose of pentagastrin (60 micrograms/kg/h) caused a significant increase in GMBF as well as acid secretion. Such GMBF responses were totally attenuated when acid secretion was inhibited by omeprazole and cimetidine or when the luminal H+ was buffered by mucosal perfusion with glycine (200 mM). Tripelennamine, an H1 antagonist, did not have any affect on acid secretory and GMBF responses to pentagastrin. On the other hand, prior administration of NG-nitro-L-arginine methyl ester (L-NAME), the NO synthase inhibitor, significantly mitigated the increase of GMBF induced by pentagastrin without any influence on acid secretion, and this effect was antagonized by simultaneous administration of L-arginine. The gastric hyperemic response to pentagastrin was also significantly mitigated by indomethacin or sensory deafferentation after capsaicin pretreatment, with no effect on acid secretion, and was totally inhibited by combined treatments with indomethacin plus L-NAME in addition to sensory deafferentation. Pentagastrin infusion for 8 h did not by itself cause macroscopic damage in the stomach, but additional treatments with L-NAME and indomethacin plus sensory deafferentation provoked severe lesions in the gastric mucosa. These results suggest that the gastric hyperemic response to pentagastrin (submaximal dose) is totally dependent on H+ and that this process is mediated by endogenous NO and PGs as well as by capsaicin-sensitive sensory neurons and plays a pivotal role in maintaining mucosal integrity during acid secretion.

Effect of omeprazole on sodium and potassium output in pentagastrin-stimulated equine gastric contents

Abstract Objective To better characterize the source of the large nonparietal secretory response to pentagastrin (PG) expressed in gastric contents of cannulated horses. Animals Adult cross-bred horses: 4 geldings and 1 mare. Procedure Horses were prepared by surgical insertion of a silastic gastric cannula from which gastric contents after feed was withheld could be continuously collected by gravity drainage. During experiments, the horses were lightly restrained in stocks, the gastric cannula was opened, and a catheter was inserted into a jugular vein. Over the next 5 hours, gastric contents were collected in 15-minute aliquots for which volume, pH, [Na+], and [K+] were measured. During the first hour, treatment was not administered. At the start of the second hour, either 0.5 mg of omeprazole (OME; dissolved in glycerol formal)/kg of body weight, or 0.9% NaCI (PSS) of comparable volume, was given IV at random as a bolus. At the start of the third hour, IV infusion of PG (6 µg/kg/h) was started and continued for the next 2 hours. Results The response to PG in the PSS-treated horses was similar to that previously seen-significant decrease in pH and increase in volume of gastric contents, and no change in [K+] and [Na+], but a modest volume-related increase in their respective outputs. After OME treatment, pH of the contents increased sharply and remained between 5 and 6 throughout PG infusion. Sodium concentration significantly increased after OME and virtually paralleled the pH response throughout the rest of the experiment; volume of gastric contents significantly increased in response to PG infusion and resulted in a significant increase in Na output. There was no change in K output in OME-treated animals. Conclusions PG induces a marked, nonparietal, secretory response into the gastric contents of cannulated horses. The volume and [Na+] of this response was maintained after pretreatment with OME, although the pH of the contents became basic, indicating that this nonparietal response is not mediated by an OME-sensitive proton pump. (Am J Vet Res 1996;57:1640–1644)

The effect of ethanol, beer, and wine on histamine release from the dog stomach

The mediator for the action of ethanol on the parietal cell of the stomach is not known. However, because the action the ethanol on gastric acid secretion was proposed to involve the release of histamine, we decided to investigate the effects of ethanol and some alcoholic beverages (red wine and beer) on histamine release from the dog stomach. After performing a splenectomy in anaesthetized beagle dogs, the gastrosplenic vein draining the corpus of the stomach was cannulated for blood withdrawal to evaluate the local release of gastrin and histamine by RIA. Intragastric administration of 200 ml of beer (4.8% ethanol) or red wine (12.5% ethanol) caused a significant enhancement in gastric and histamine concentrations in venous blood from the stomach. By contrast, intragastric administration of pure ethanol in distilled water at the same concentrations of wine or beer did not significantly modify gastrin and histamine release. Integrated histamine responses for 20 min to beer and wine paralleled gastrin concentrations and were of the same magnitude of those induced by intravenous infusion of pentagastrin at 1 and 6 μg/kg/h, respectively. We conclude that: 1) beer and red wine, but not pure ethanol, are potent releasers of histamine; 2) histamine release seems to be related to the gastrin response and probably occurs at the level of enterochromaffin-like (ECL) cells; 3) the ethanol content of these drinks is not important for their stimulant effect, indicating that some other components of beer and wine are responsible for gastrin and histamine release from the dog stomach.

Intracerebroventricular infusion of the CCKB receptor agonist pentagastrin potentiates acoustic startle

The acoustic startle reflex is increased by stimuli associated with aversive events (such as the delivery of shock) and so has been used as a sensitive index of ‘anxiety’ or ‘fear’. Administration of cholecystokininB (CCKb) receptor agonists produces a constellation of behaviors associated with ‘anxiety’ in laboratory animals and humans. Here, intracerebroventricular infusions of the CCKB agonist, pentagastrin (0, 1, 10, 100 nM), produced a long-lasting, dose-related potentiation of acoustic startle responses. Similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that changes in startle responsivity following infusions of pentagastrin are not due to nonspecific changes in motor activity.

Intracerebroventricular infusion of the CCK B receptor agonist pentagastrin potentiates acoustic startle

The acoustic startle reflex is increased by stimuli associated with aversive events (such as the delivery of shock) and so has been used as a sensitive index of ‘anxiety’ or ‘fear’. Administration of cholecystokinin B (CCK b) receptor agonists produces a constellation of behaviors associated with ‘anxiety’ in laboratory animals and humans. Here, intracerebroventricular infusions of the CCK B agonist, pentagastrin (0, 1, 10, 100 nM), produced a long-lasting, dose-related potentiation of acoustic startle responses. Similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that changes in startle responsivity following infusions of pentagastrin are not due to nonspecific changes in motor activity.

Modulation of pentagastrin-induced histamine release by histamine H3 receptors in the dog.

The histamine H3 receptor has been shown to inhibit pentagastrin-induced gastric acid secretion in dogs. Since pentagastrin releases histamine in dogs, we have now assessed whether the effects of H3-receptor ligands may be indirectly mediated by changes in gastric histamine release. Pentagastrin infusions (1 or 6 micrograms/kg/h), alone or together with the H3-receptor agonist (R) alpha-methylhistamine (1.2 mumol/kg/h) or the antagonist thioperamide (0.1 mumol/kg/h), were performed in dogs. One group (anaesthetized) was used for enzyme immunoassays of plasma histamine and, when required. (R) alpha-methylhistamine in the gastrosplenic vein, and another group (non-anaesthetized) for measurement of gastric acid secretion. Histamine levels were increased five- and eight-fold after 1 and 6 micrograms/kg/h pentagastrin, respectively, whereas acid output was nearly maximal at the lower dosage. (R) alpha-methylhistamine, at a plasma concentration of 0.15 microM, inhibited histamine release by 78% (P < 0.007) and 37% (not significant) and the total acid output by 44% (P < 0.05) and 19% (not significant) after infusion of 1 and 6 micrograms/kg/h pentagastrin, respectively. Thioperamide, together with pentagastrin in low dose, significantly increased histamine release by 212% (P < 0.05), whereas acid output increased by 34% (not significant). The histamine H3 receptor mediates a negative feedback control of pentagastrin-induced release of gastric histamine. It is tonically activated by endogenous histamine after pentagastrin in low dosage. The control of acid secretion by the H3 receptor seems to involve modulation of endogenous histamine release, possibly by means of enterochromaffin-like cells.

Gastric acid secretion after blockade of angiotensin AT 1 receptors in the Na +-depleted rat

This study tested the hypothesis that angiotensin II acting through the angiotensin AT 1 receptor plays an important role in the control of gastric acid secretion. Basal gastric acid secretion and gastric blood flow were lower in Na +-depleted animals, in which the renin-angiotensin system was activated, than in animals maintained on a normal Na + diet. Intravenous infusion of pentagastrin at 0.6 μg/kg/min increased gastric acid secretion to a greater extent in normal Na + than in Na +-depleted animals. In addition to stimulating gastric acid secretion, pentagastrin increased gastric blood flow by proportionally the same amount in both normal and low Na + animals. However, because basal gastric blood flow was considerably reduced in Na +-depleted animals, the increase produced by pentagastrin extended only to the levels observed in non-pentagastrin-treated normal Na + animals. Lower gastric blood flow in response to pentagastrin may explain the smaller increase in gastric acid secretion observed in Na +-depleted animals. In Na +-depleted animals, the selective angiotensin AT 1 receptor antagonist losartan did not affect basal gastric acid secretion or gastric blood flow, suggesting the involvement of mechanisms other than angiotensin II. Following blockade of angiotensin AT 1 receptors, pentagastrin significantly increased gastric blood flow in Na +-depleted animals to levels observed with infusion of the pentapeptide in normal Na + animals. The results suggest that the decrease in pentagastrin-stimulated acid secretion in Na +-depleted animals is mediated by angiotensin II acting through the angiotensin AT 1 receptor, most probably through vascular mechanisms.

8-OH-DPAT stimulates gastric acid secretion through a vagal-independent, adrenal-mediated mechanism

Serotonin (5-hydroxytryptamine, 5-HT) is a neuroendocrine component of the gastrointestinal tract. 5-HT 1A receptors exist both in the brain and have been demonstrated autoradiographically in high density in the rat stomach. However, the physiologic role of 5-HT 1A receptors in modulating gastric function is not known. The effect of the selective 5-HT 1A receptor agonist, (±)-8-hydroxy-2-( n-dipropylamino)tetralin (8-OH-DPAT), on gastric acid secretory function was compared to 5-HT in acute, urethane-anesthetized gastric-fistulated rats during pentagastrin infusion. 5-HT inhibited, but 8-OH-DPAT stimulated, gastric acid secretion in a dose-dependent manner. Bilateral cervical vagotomy or celiac ganglionectomy did not reverse the effect of 8-OH-DPAT on acid secretion. However, the enhancement of acid by 8-OH-DPAT was attenuated by acute adrenalectomy or close intra-arterial administration of spiperone, but not idazoxan. Thus, the data suggest that the selective 5-HT 1A receptor agonist 8-OH-DPAT may augment gastric secretory function via an adrenal-dependent mechanism.

Effect of electrical stimulation on gastric electrical activity, motility and emptying.

The aim was to measure the effect of gastric electrical stimulation on the frequency of canine antral pacesetter potentials (PPs), the strength of antral contractions, and the rate of gastric emptying while fasting, after feeding and with pentagastrin stimulation. Four conscious dogs with a stimulating electrode placed 10 cm proximal to the pylorus and recording electrodes and strain gauges placed 7, 5 and 3 cm proximal to the pylorus underwent myoelectric and strain gauge recordings while fasting, after feeding (250 ml 5% dextrose labelled with polyethylene glycol), and during pentagastrin infusion (0.5 micrograms kg-1 min-1) on four separate days. On each day, electrical stimulation was done using one of four stimulation frequencies (0, 6, 30 and 1200 stimuli per minute [s.p.m.]). Stimulation at 6 and 30 s.p.m. increased the fasting and fed PP frequency, whereas 1200 s.p.m. stimulation did not. Feeding decreased the maximum driven frequency, and pentagastrin increased it. Neither the motility index nor the gastric emptying rate were consistently changed by stimulation at any frequency. In conclusion, canine proximal antral stimulation at 6 and 30 s.p.m. sped PP frequency during fasting and after feeding, but stimulation over a wide range of frequencies had little effect on gastric contractions and emptying.

Endotoxin inhibition of distension-stimulated gastric acid secretion in rat: mediation by NO in the central nervous system.

1. The involvement of nitric oxide in the acute inhibitory effects of low doses of endotoxin, following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration, on gastric acid secretion stimulated by distension or i.v. infusion of pentagastrin has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. The i.c.v. administration of E. coli endotoxin (800 ng kg-1) abolished the acid secretory response induced by gastric distension (20 cm water intragastric pressure) within 30 min of administration. 3. By contrast, submaximal rates of acid secretion induced by i.v. infusion of pentagastrin (8 micrograms kg-1 h-1) were not inhibited by i.c.v. administration of endotoxin (800 ng kg-1). 4. Prior i.c.v. administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 800 micrograms kg-1) restored the acid secretory responses to distension in rats treated with endotoxin (i.c.v.). 5. Likewise, i.v. administration of endotoxin (5 micrograms kg-1) abolished the acid secretory response induced by gastric distension within 30 min of administration. Prior i.c.v. injection of L-NAME (800 micrograms kg-1) or its i.v. administration (10 mg kg-1) restored acid secretory responses in rats receiving i.v. endotoxin. 6. The reversal by L-NAME (i.v.) of the acid inhibitory effects of endotoxin (i.v.) was prevented by L-arginine (12 mg kg-1, i.c.v. or 100 mg kg-1, i.v.), but not by its enantiomer D-arginine. 7. The present results imply the existence of an acute response to endotoxin involving NO synthesis in the brain. NO may act as a neuromodulator or neurotransmitter in a nervous reflex leading to the inhibition of acid secretion stimulated by gastric distension.

Gastric inhibitory polypeptide and gastric acid secretion in pregnant rats

The effects of pregnancy on the basal and pentagastrin-stimulated gastric acid secretion and the level of plasma gastric inhibitory polypeptide (GIP) in rats were studied on pentobarbital-anaesthetized non pregnant rats and rats in the 1st, 2nd, or 3rd week of gestation. Acid output was determined by titration of the gastric perfusate. Basal secretion was collected for 45 min before a 30 min infusion of pentagastrin (8 μg/ml/300g body weight). Concentration of plasma GIP was measured by a radioimmunoassay (RIA). The immunoreactivity of GIP-like substance in the extract of the rat placenta collected from the rat at day 21 of gestation was examined by RIA. The biological activity of GIP-like substance in the rat placenta extract was tested by the reduction of pentagastrin-stimulated gastric acid secretion in male rats. The basal level ofgastric secretion was higher in late pregnancy as compared with the non pregnant rats. Pentagastrin induced a greater increase of gastric acid secretion in early but not late pregnant rats as compared with the non-pregnant animals. The basal and postpentagastrin level of plasma GIP was higher in rats in late pregnancy. Both immunoreactivity and biological activity of GIP exist in the rat placenta extract. These results suggest that the normalization of gastric acid secretion in late pregnant rats is at least in part due to the production of GIP-like substance from placenta.

Activation of somatostatin receptor subtype 2 inhibits acid secretion in rats.

Somatostatin is a potent inhibitor of gastric acid secretion. Recently, at least five distinct somatostatin receptor subtypes (SSTR) have been characterized and evaluated using relatively selective peptide analogues of somatostatin. We sought to determine which somatostatin receptor subtypes are involved in peripheral regulation of gastric acid secretion. Fasted, male Sprague-Dawley rats were anesthetized and were implanted with a double-lumen cannula in the stomach. Acid secretion was measured in gastric samples collected every 10 min by backtitration to pH 7. After a 30-min basal period, a 2-h intravenous infusion of pentagastrin (24 micrograms.kg-1.h-1 i.v.) was started. During the second pentagastrin hour, a 1-h intravenous infusion of either vehicle (0.1% canine serum albumin in 0.9% saline) or somatostatin receptor agonists was begun. The somatostatin receptor agonists included peptides with relative specificity for SSTR1-5 (somatostatin-14; 10 nmol.kg-1.h-1); SSTR2, SSTR3, and SSTR5 [SMS-(201-995); 10 nmol.kg-1.h-1]; SSTR2 (1-1,000 nmol.kg-1.h-1); SSTR3 (10-1,000 nmol.kg-1.h-1); and SSTR5 (10-1,000 nmol.kg-1.h-1). The SSTR2 agonist decreased pentagastrin-stimulated acid secretion dose dependently, from 82 +/- 7% of maximum acid output at 1 nmol.kg-1.h-1 to 4 +/- 7% of maximum at 100 nmol.kg-1.h-1. At 10 nmol.kg-1.h-1, the SSTR2 agonist inhibited acid secretion (40 +/- 7% of maximum) similarly to somatostatin (37 +/- 4% of maximum) and SMS-(201-995) (31 +/- 4% of maximum). The SSTR2 agonist inhibited acid secretion approximately 10- to 100-fold more potently than either the SSTR3 or the SSTR5 agonist. These results indicate that somatostatin regulates gastric acid secretion by activation of SSTR2 receptors.

Somatostatin antibody does not influence bombesin-induced inhibition of gastric acid secretion in rats

The influence of peripheral somatostatin immunoneutralization on intravenous (i.v.) and intracerebroventricular (ICV) bombesin-induced inhibition of gastric acid secretion (GAS) was investigated with the somatostatin monoclonal antibody, CURE.S6, in rats. The somatostatin antibody, injected i.v. in conscious rats with a chronic gastric fistula and i.v. catheter, did not modify basal GAS, whereas in urethane-anesthetized rats the basal GAS was increased by 150%. In conscious rats, somatostatin (15 micrograms/kg/h, i.v.) inhibited basal GAS by 50% after injection of control antibody but not after pretreatment with the somatostatin antibody. With pretreatment with a control antibody, bombesin (10 micrograms/kg/h, i.v.) inhibited basal GAS by 60% in conscious rats and by 50% the acid response to pentagastrin infusion in urethane-anesthetized rats. Bombesin injected ICV (3 and 10 ng/10 microliters/rat) inhibited basal GAS by 50% and 70%, respectively, in conscious rats pretreated with a control antibody. The somatostatin antibody injected i.v. before i.v. or ICV injection of bombesin did not influence bombesin-induced inhibition of GAS in conscious or anesthetized rats. These results show that peripheral somatostatin does not play a major role in the inhibition of gastric acid secretion induced either by ICV or i.v. administration of bombesin or basal acid secretion in conscious rats.

Low doses of pentagastrin stimulate gastric lipase secretion in man.

Gastric lipase is an important enzyme for dietary triglyceride digestion in normal subjects. Its regulation is unknown, as is the relation between the quantity and activity of the enzyme. In a dose-response study we investigated the effect of low doses of pentagastrin (less than 1000 ng/kg/h) on the output of gastric lipase measured by a kinetic assay and an enzyme-linked immunosorbent assay (ELISA). In five healthy volunteers stepwise intravenous pentagastrin infusions of 0, 50, 100, 500, and 1000 ng/kg/h resulted in a stepwise increase in the lipase output, as measured with ELISA. However, the lipolytic activity, measured with a kinetic assay, decreased as the pH of the gastric contents decreased. We conclude that secretion of the gastric lipase is stimulated by pentagastrin, but the simultaneous secretion of acid counteracts the lipolytic activity of the enzyme when food is not present.

Role of endogenous nitric oxide in the control of gastric acid secretion, blood flow and gastrin release in conscious dogs

Nitric oxide (NO) was shown to mediate gastric hyperemia following secretory stimulation but its role in the control of gastric secretion has not been clarified. Secretory studies were carried out on conscious dogs with chronic gastric fistula, Heidenhain pouch and esophageal fistula, while changes in gastric blood flow were measured in the mucosa of Heidenhain pouuch by laser Doppler flowmetry. Plasma gastrin was determined by radioimmunoassay. Infusion of N G - nitro- l-arginine ( l-NNA) (bolus i.v. injection of 2.5 mg/kg followed by infusion of 0.5 mg/kg/h), a potent inhibitor of nitric oxide synthase, failed to affect basal gastric secretion or plasma gastrin level but suppressed an increase of this secretion induced by sham-feeding, ordinary meat feeding or i.v. infusion of bombesin (0.5 μg/kg/h), pentagastrin (4 μg/kg/h) or histamine (40 μg/kg/h). In tests with feeding and bombesin infusion, l-NNA caused a significant and dose-dependent reduction in plasma gastrin levels. The inhibition by l-NNA of gastric acid secretory response to pentagastrin, histamine or feeding was accompanied by a decline in blood flow. Addition of l-arginine (bolus i.v. dose of 50 mg/kg followed by infusion of 5 mg/kg/h) significantly attenuated the l-NNA induced inhibition of gastric secretion and the reduction in plasma gastrin response as well as in the fall of gastric blood flow. We conclude that endogenous nitric oxide affects the gastric secretion and that this effect is mediated, at least in part, by the changes in the gastrin release and gastric blood flow.

Pentagastrin infusions in patients with panic disorder I. Symptoms and cardiovascular responses

Cholecystokinin (CCK) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders. The study of CCK receptor systems in psychiatric patients has, however, been severely limited by the lack of available probes. We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls. Pentagastrin produced substantial symptomatology, including anxiety, and increases in heart rate and blood pressure, in both patients and controls. Patients were more sensitive to the panicogenic effects of the pentagastrin. Panic attacks occurred in 70% of patients and 0% of controls. Patients' symptom responses were very similar to their “typical” panic attacks and to symptoms produced by CCK 4. Pentagastrin provides a readily available alternative to CCK 4 for studying the CCK receptor system and exploring its involvement in human anxiety.

Pentagastrin enhances gastric mucosal defenses in vivo: luminal acid-dependent and independent effects

Stimulation of acid secretion is associated with enhanced resistance of the gastric mucosa to damage by luminal acid. We studied the mechanism by which gastric mucosal defenses are modulated in a system in which mucus gel thickness, intracellular pH (pHi), gastric mucosal blood flow, and acid secretion can be measured simultaneously in vivo, using a recently developed microfluorometric technique. Intravenous infusion of pentagastrin in a dose associated with maximal acid secretion increased mucus gel thickness, pHi, and mucosal blood flow during superfusion with a neutral solution. Subsequent superfusion with an acidic buffer (pH 1.7) further increased blood flow to nearly three times basal. During superfusion with luminal acid, pHi fell more slowly and recovered toward baseline more quickly in pentagastrin-infused rats than in controls. Pretreatment with the H2-receptor antagonist cimetidine abolished the increased blood flow associated with pentagastrin, impairing pHi homeostasis, although cimetidine increased mucus gel thickness in the absence of pentagastrin. We conclude that gastric defense mechanisms at the preendothelial and postepithelial levels are enhanced during acid secretion as part of a histamine-dependent homeostatic mechanism that balances gastric protective mechanisms with acid secretion. The net result of these enhanced defenses is the preservation of gastric surface cell pHi despite the presence of a large proton gradient between lumen and blood.