Chung Owyang

Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma

BACKGROUND Patients with scleroderma may have abnormal motility of the small intestine, with pseudoobstruction and bacterial overgrowth. Standard stimulatory agents are often ineffective in such patients. Because the somatostatin analogue octreotide evokes intestinal motor activity in normal subjects, we hypothesized that it might increase motility in patients with scleroderma. METHODS We studied the effects of octreotide on intestinal motility and plasma motilin concentrations in five fasting patients with scleroderma who had bacterial overgrowth and in six fasting normal subjects. The motor effects of octreotide were correlated with its effects on abdominal symptoms and bacterial overgrowth as determined by the level of breath hydrogen excretion. RESULTS In the normal subjects, octreotide (10 micrograms subcutaneously) increased the mean (+/- SD) frequency of intestinal migrating complexes, which reflect intestinal motility, from 1.5 +/- 1.0 to 4.1 +/- 1.1 every three hours. In the patients with scleroderma, who had no spontaneous migrating complexes, octreotide (100 micrograms) induced 3.6 +/- 2.3 complexes every three hours. These complexes propagated at the same velocity and had two-thirds the amplitude of the spontaneous complexes in normal subjects. Plasma motilin concentrations, which were higher in the patients with scleroderma (229 +/- 74 pmol per liter) than in the normal subjects (112 +/- 37 pmol per liter), were inhibited by octreotide, suggesting that intestinal activity evoked by octreotide is independent of motilin. Treatment of the patients with scleroderma with octreotide (50 micrograms every evening) for three weeks reduced breath hydrogen excretion while they were fasting from 25 +/- 5 to 4 +/- 2 ppm (P = 0.001) and breath hydrogen excretion after they ingested 50 g of glucose from 46 +/- 24 to 8 +/- 7 ppm (P = 0.015); these reductions were accompanied by a significant decrease in nausea, bloating, and abdominal pain and by less frequent emesis. CONCLUSIONS Octreotide stimulates intestinal motility in normal subjects and in patients with scleroderma. In such patients, the short-term administration of octreotide reduces bacterial overgrowth and improves abdominal symptoms. This agent may be useful for the treatment of intestinal dysmotility in patients with scleroderma.

Serum glucose concentration as a modulator of interdigestive gastric motility

The objective of this study was to examine the effect of serum glucose concentration on interdigestive gastrointestinal motility and plasma motilin levels in humans. Motility studies were performed for a 3-h baseline period and a 3-h test period during which serum glucose levels were maintained with a glucose clamp at 250, 175, 140, or 120 mg/dl. During the basal recording, three phases of the interdigestive migrating motor complex (MMC) were easily recognizable, with a mean cycle duration of 97 +/- 12 min. Plasma motilin levels fluctuated in phase with the MMC. Gastric contractions were nearly absent at a serum glucose level of 250 mg/dl and markedly reduced at 175 and 140 mg/dl. Gastric phase III activity was inhibited during these infusions. Gastric contractions and phase III activity were not affected by glucose infusion at 120 mg/dl. In contrast, the frequency of duodenal phase III activity was unchanged at all levels of glucose infusion. Mean motilin levels were significantly reduced during glucose infusion at 250 and 175 mg/dl (p less than 0.05), but not at 140 and 120 mg/dl. We conclude that hyperglycemia inhibits the occurrence of the MMC in the stomach and suppresses plasma motilin levels. The differential sensitivity of motility and motilin concentration to different degrees of hyperglycemia suggests that hyperglycemia can inhibit antral motility independent of plasma motilin. In contrast, the duodenal MMC appears to be insensitive to hyperglycemia. This suggests that the antral and duodenal MMCs are mediated by different mechanisms. Our observations indicate the importance of serum glucose in regulating gastric motility.

Impaired gastric acid secretion in gastrin-deficient mice

To further understand the role of the peptide hormone gastrin in the development and function of the stomach, we have generated gastrin-deficient mice by gene targeting in embryonic stem cells. Mutant mice were viable and fertile, without obvious visible abnormalities. However, gastric function was severely affected by the loss of gastrin. Basal gastric acid secretion was abolished and could not be induced by histamine, carbachol, or gastrin. Histological analysis revealed alterations in the two cell types primarily involved in acid secretion, parietal and enterochromaffin-like (ECL) cells. Parietal cells were reduced in number with an accumulation of immature cells lacking H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase). ECL cells were positioned closer to the base of the gastric glands, with markedly lower expression of histidine decarboxylase. Gastrin administration for 6 days reversed the effects of the gastrin deficiency, leading to an increase in the number of mature, H(+)-K(+)-ATPase-positive parietal cells and a partial restoration of acid secretion. The results show that gastrin is critically important for the function of the acid secretory system.To further understand the role of the peptide hormone gastrin in the development and function of the stomach, we have generated gastrin-deficient mice by gene targeting in embryonic stem cells. Mutant mice were viable and fertile, without obvious visible abnormalities. However, gastric function was severely affected by the loss of gastrin. Basal gastric acid secretion was abolished and could not be induced by histamine, carbachol, or gastrin. Histological analysis revealed alterations in the two cell types primarily involved in acid secretion, parietal and enterochromaffin-like (ECL) cells. Parietal cells were reduced in number with an accumulation of immature cells lacking H+-K+-adenosinetriphosphatase (H+-K+-ATPase). ECL cells were positioned closer to the base of the gastric glands, with markedly lower expression of histidine decarboxylase. Gastrin administration for 6 days reversed the effects of the gastrin deficiency, leading to an increase in the number of mature, H+-K+-ATPase-positive parietal cells and a partial restoration of acid secretion. The results show that gastrin is critically important for the function of the acid secretory system.

Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin.

Feedback regulation of pancreatic enzyme secretion occurs in rats. Whether such a system exists in man remains unsettled and the responsible mechanism is unknown. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Intraduodenal perfusion of trypsin-inhibited phenylalanine-, oleic acid-, and meal-stimulated chymotrypsin and lipase outputs in a dose-related manner. The minimal concentration of bovine trypsin needed to inhibit pancreatic enzyme secretion was 0.5 g/liter. 1 g/liter caused a maximal suppression of 35 +/- 4% of the phenylalanine-stimulated chymotrypsin release. This inhibitory effect was protease-specific. Intraduodenal perfusion of phenylalanine and oleic acid increased plasma cholecystokinin (CCK) from a basal level of 0.9 +/- 0.06 to 5.3 +/- 0.9 pM and 7.2 +/- 1.3 pM, respectively. Addition of bovine trypsin to the perfusates significantly reduced the plasma CCK level to basal values. This inhibitory effect of trypsin on CCK release was dose dependent and specific to proteases. Therefore, the present studies indicate that feedback regulation of pancreatic enzyme secretion is operative in man and it is mediated by release of CCK.

Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins

BACKGROUND/AIMS Antral hypomotility and gastric dysrhythmias occur in diabetic gastroparesis. This study tested the hypothesis that acute hyperglycemia suppresses fed antral contractions and disrupts slow-wave rhythmicity via prostaglandin pathways. METHODS Six normal volunteers underwent electrogastrography and antroduodenal manometry under control, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions before and after administration of indomethacin (50 mg orally three times daily for 3 days). RESULTS Hyperglycemic clamping to 230 mg/dL evoked a 4-fold increase in tachygastric activity and a 2.6-fold increase in arrhythmic activity (P < 0.05), whereas 140 and 175 mg/dL did not induce dysrhythmias. Antral motility indexes were reduced by 58% +/- 14% at 175 mg/dL and 70% +/- 8% at 230 mg/dL after a 750-kcal meal. Euglycemic, hyperinsulinemic clamping to insulin levels observed with the highest glucose infusions did not produce tachyarrhythmias or hypomotility. After indomethacin, hyperglycemic clamping to 230 mg/dL did not induce tachyarrhythmias. In contrast, indomethacin did not prevent the reduction in motility evoked by hyperglycemic clamping. CONCLUSIONS Acute hyperglycemia, but not hyperinsulinemia, inhibits fed antral motility and induces gastric dysrhythmias at higher plasma glucose levels. Induction of dysrhythmias, but not hypomotility, is dependent on endogenous prostaglandin synthesis. These findings offer insight into the myoelectric disturbances of diabetic gastroparesis and suggest a possible therapeutic role for prostaglandin synthesis inhibitors for gastric dysrhythmias in this condition.

Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.

To establish the mechanism(s) and site(s) of action of cholecystokinin (CCK) on pancreatic secretion under physiological conditions, we used an in vivo model using anesthetized rats with pancreaticobiliary cannulas. Infusion of CCK-8 (10-160 pmol/kg per h) produced a dose-dependent increase in plasma CCK levels. CCK-8 infusion at 40 pmol/kg per h produced a plasma CCK level of 7.9 +/- 1.5 pM and an 80% increase in pancreatic protein output over basal. This level was closely approximated by a postprandial peak plasma CCK level by 6.2 +/- 1.1 pM. Pretreatment with atropine or hexamethonium completely abolished pancreatic protein response to low doses of CCK-8 (10-40 pmol/kg per h) but had only partial effect on doses > 40 pmol/kg per h. Bilateral vagotomy also abolished the pancreatic responses to low doses of CCK-8. Similarly perivagal treatment with a sensory neurotoxin, capsaicin, caused a complete inhibition of pancreatic protein secretion in response to CCK-8 infusion. In contrast, pancreatic protein responses to bethanechol were similar in control and capsaicin-treated rats. In separate studies we demonstrated that gastroduodenal but not jejunal application of capsaicin for 30 min abolished pancreatic protein secretion in response to physiological doses of CCK-8. In conclusion, CCK at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway originating from the gastroduodenal mucosa.

Characterization of vagal pathways mediating gastric accommodation reflex in rats.

1 We investigated the vagal pathways mediating the gastric accommodation reflex in the rat stomach. 2 Gastric distension (6 ml) evoked an increase of 9.0 ± 1.0 cm H2O of intragastric pressure in vivo. Pretreatment with tetrodotoxin (TTX) caused a significant pressure increase by gastric distension, reaching 17.0 ± 1.7 cm H2O, suggesting mediation by neural pathways. 3 The pressure increase evoked by gastric distension was significantly enhanced in vivo by acute truncal vagotomy (TV), hexamethonium (C6), and NG‐nitro‐L‐arginine methyl ester (l‐NAME), but not by vasoactive intestinal polypeptide (VIP) antiserum, guanethidine, or splanchnicotomy. 4 Gastric distension (6 ml) evoked a much larger intragastric pressure in the denervated, vascularly isolated, perfused rat stomach in vitro. Intra‐arterial application of TTX and l‐NAME did not cause further pressure increases evoked by gastric distension. 5 The pressure increase evoked by gastric distension remained high 2 weeks after TV in vivo. However, the accommodation reflex was fully restored 4 weeks after TV in vivo. This reflex was antagonized by TTX, C6 and l‐NAME, but not by VIP antiserum, guanethidine and splanchnicotomy. 6 Similar to in vivo studies, gastric distension caused a smaller increase in intragastric pressure in response to gastric distension in the denervated, vascularly isolated, perfused stomach obtained from rats 4 weeks after vagotomies in vitro. The pressure increase evoked by gastric distension was significantly enhanced by l‐NAME, hexamethonium and TTX. 7 It is suggested that the vago‐vagal reflex plays an important role in mediating the accommodation reflex. This involves a vagal efferent pathway that uses nitric oxide as a final neurotransmitter mediating gastric relaxation in intact rats. It is also suggested that the adaptive mechanism mediating the accommodation reflex following vagotomy occurs in the gastric myenteric plexus.

Vagal control of nitric oxide and vasoactive intestinal polypeptide release in the regulation of gastric relaxation in rat.

1. Gastric motility and neurotransmitter release in response to vagal stimulation were studied using a vascularly isolated perfused rat stomach. Gastric motor responses were recorded by a strain gauge force transducer implanted on the proximal stomach. 2. Electrical stimulation of vagal trunk (0.5‐20 Hz) produced a triphasic response which was composed of a rapid transient relaxation (first phase) followed by a phasic contraction (second phase) and a delayed prolonged relaxation (third phase). Maximum responses of the first, second and third phase were observed at 2.5, 5 and 10 Hz, respectively. Intra‐arterial infusion of tetrodotoxin (0.1 microM) or hexamethonium (100 microM) completely abolished the triphasic response. 3. The nitric oxide (NO) biosynthesis inhibitor NG‐nitro‐L‐arginine (L‐NNA; 100 microM) significantly antagonized the rapid relaxation but had no effect on the delayed relaxation, while vasoactive intestinal polypeptide (VIP) antagonist (1 microM) significantly reduced the delayed relaxation without affecting the rapid relaxation. 4. In response to vagal stimulation, NO production ([3H]citrulline formation in gastric tissue preloaded with [3H]arginine) was maximum at 2.5 Hz, whereas VIP release into the venous effluent was largest at 10 Hz. Hexamethonium abolished vagal‐stimulated NO production and VIP release. L‐NNA had no effect on VIP release in response to vagal stimulation. 5. The nicotinic receptor agonist 1,1‐dimethyl‐4‐phenylpiperizinium (DMPP; 100 microM) also caused a triphasic response similar to that observed with vagal stimulation and produced a significant increase in VIP and NO formation. DMPP‐evoked VIP release was not affected by L‐NNA. Similarly, DMPP‐evoked NO production was not antagonized by VIP antagonist. 6. These results suggest that vagus nerve stimulation evokes NO and VIP release via nicotinic synapses which cause different modes of relaxation of the stomach. There is no interaction between NO and VIP release in response to vagal stimulation.

The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids

It is unknown how the interdigestive migrating motor complex influences the gastric emptying of liquids. Therefore, the gastric emptying rate of 50- and 200-mL volumes of phenol red solution were measured while monitoring contractile activity. Motor activity was recorded using a hydraulic manometric system and expressed as either the proximity of dosing time to time of appearance of phase III or as a motility index, defined as (contractile area)/(sampling interval time). After an initial lag period, emptying was log linear. With a 50-mL oral dose, the mean gastric emptying rate of the log-linear phase was successively faster during phase I (0.018 +/- 0.003 min-1), phase II (0.083 +/- 0.031 min-1), and late phase II/III (0.171 +/- 0.066 min-1) (P less than 0.05). Similarly, the mean lag time decreased successively with phases I, II, and late II/III (19.1 +/- 12.4, 7.6 +/- 5.6, and 3.8 +/- 2.8 minutes, respectively). At a 200-mL oral dose, there was no difference in the emptying rate between phase I and phase II (0.104 +/- 0.0014 vs. 0.110 +/- 0.041 min-1), but the emptying rate during late phase II/III was significantly greater (0.236 +/- 0.069 min-1); lag time was not dependent on phase. There was a statistical difference in the overall mean emptying rate between the 50- and 200-mL volumes. Also, during phase I, the emptying rate was faster for the 200-mL volume. This study shows a strong dependence of liquid gastric emptying rate and lag time on interdigestive antral motility, the emptying of small volumes being more dependent on motility phase than that of large volumes. Phase-related fluctuations in contractile activity can account for much of the reported variability in gastric emptying data. Furthermore, this study suggests that dose volume and interdigestive motor activity at the time of drug administration can affect absorption and onset of therapeutic response for some drugs.

Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats

BACKGROUND & AIMS Similar to cholecystokinin (CCK), non-CCK-dependent duodenal factors stimulate vagal mucosal afferent fibers to mediate pancreatic enzyme secretion via a common cholinergic pathway. We tested the hypothesis that 5-hydroxytryptamine (5-HT) released from enterochromaffin (EC) cells plays an important role in the transduction of luminal information to the central nervous system via vagal afferent fibers to mediate pancreatic secretion. METHODS Pancreatic secretions were examined in conscious rats after intragastric administration of chopped rodent chow in the presence and absence of CCK or 5-HT(3) and 5-HT(2) antagonists. Pancreatic responses to intraduodenal administration of maltose, hyperosmolar NaCl, and light mucosal stroking were examined in rats pretreated with various pharmacological antagonists or after surgical or chemical ablation of vagal and 5-HT neural pathways. RESULTS Administration of L364, 718 inhibited 54% of pancreatic protein secretion evoked by intragastric administration of rodent chow. L364,714 and ICS 205-930, a 5-HT(3) antagonist, combined produced a 94% inhibition. Vagal afferent rootlet section eliminated pancreatic secretions evoked by intraduodenal stimuli. p-Chlorophenylalanine, a 5-HT synthesis inhibitor, but not 5,7-hydroxytryptamine, a 5-HT neurotoxin, also eliminated the pancreatic response to these luminal stimuli. The 5-HT(3) antagonist markedly inhibited pancreatic secretion induced by maltose and hyperosmolar NaCl. 5-HT(2) and 5-HT(3) antagonists combined inhibited the pancreatic response to light stroking of the mucosa. CONCLUSIONS Luminal factors such as osmolality, disaccharides, and mechanical stimulation stimulated pancreatic secretion via intestinal vagal mucosal afferent fibers. It is likely that 5-HT originating from intestinal EC cells activated 5-HT(3) and 5-HT(2) receptors on vagal afferent fibers to mediate luminal factor-stimulated pancreatic secretion.