Somatostatin affects gastrointestinal motility and secretion and visceral sensation, but little is known about its effects on the proximal stomach.
Somatostatin affects gastrointestinal motility and secretion and visceral sensation, but little is known about its effects on the proximal stomach.
To evaluate the effects of somatostatin on proximal gastric motor function and perception of symptoms.
Six healthy subjects participated in two experiments performed in random order during continuous intravenous infusion of saline or somatostatin (250 μg/h). Proximal gastric motor function was evaluated using a barostat. We performed pressure and volume distensions and a barostat procedure (minimal distending pressure + 2 mmHg). Symptoms were evaluated at regular intervals using visual analogue scales (VAS).
Neither minimal distending pressure nor gastric fundal tone were significantly different between somatostatin and saline. Pressure–volume curves during distensions were not influenced by somatostatin. However, phasic volume waves were significantly (P < 0.001) reduced by somatostatin, and somatostatin significantly (P < 0.05) reduced symptom perception of fullness and abdominal pressure during stepwise distensions.
Continuous infusion of somatostatin does not influence gastric compliance but it inhibits phasic volume waves and significantly reduces visceral perception.
Somatostatin and its analogue octreotide influence gastrointestinal motility and secretion.1–3 Both inhibit gastric acid and pancreatic enzyme secretion, gall-bladder contraction and delay intestinal transit. Recent studies indicate that octreotide affects visceral perception by increasing the threshold for symptoms during balloon distension. This has been demonstrated for rectal and colonic perception both in healthy subjects and patients with irritable bowel syndrome.3–6 Octreotide influences perception through inhibition of the spinal afferent pathway.4, 6
Little is known about the effect of somatostatin on proximal gastric motor function and symptom perception. Only Mertz et al.,7 using the long-acting somatostatin analogue octreotide, found the gastric accommodation reflex to be reduced, resulting in a less compliant proximal stomach. Octreotide also had an inhibitory effect on the perception of fullness in response to low volume distensions. The aim of our study was to investigate the effect of native somatostatin during continuous intravenous infusion on the motor function of the proximal stomach and visceral perception during volume and pressure distensions. The function of the proximal stomach was measured with an electronic barostat.
Six healthy volunteers (four female, two male, mean age 23 years; range 19–27 years) participated in the study. None had a history of gastrointestinal symptoms, had previously undergone abdominal surgery or was using medication. Informed consent was obtained from each individual. The protocol of the study was approved by the ethics committee of the Leiden University Medical Center.
An electronic barostat (Synectics Visceral Stimulator, Synectics Medical, Stockholm, Sweden) was used to distend the stomach. A polyethylene bag (900 mL maximum capacity) was tied to the end of a multilumen tube (16 French). This catheter was connected to the barostat.
The barostat keeps the pressure in the intragastric bag at a preselected level. When the stomach relaxes, the system injects air. When the stomach contracts, the system aspirates air. Thus, the barostat measures gastric motor activity as changes in intragastric volume at a constant intragastric pressure.8, 9
The barostat is also able to induce gastric distensions at either fixed pressures (isobaric) or fixed volumes (isovolumetric). To produce fixed pressure distensions the barostat maintains a constant pressure level by an electronic feedback regulation of the air volume within the intragastric bag. To produce fixed volume distensions the air pump sets the desired air volume within the intragastric bag at a controlled injection (or aspiration) pressure, and then the pump is blocked.10 Maximal air flow is 38 mL/s.
Pressure (mmHg), volume (mL) and compliance (mL/mmHg) were constantly monitored and recorded on a personal computer connected to the barostat (Polygram for Windows SVS module, Synectics Medical).
The experiments were performed in double-blind, randomized order. The subjects participated in two experiments with an interval of 7 days: (a) control experiment with saline infusion, (b) somatostatin infusion in a dose of 250 μg/h for approximately 120 min. Three subjects received somatostatin first (subject 1, 4 and 6) and three subjects ‘placebo’ (subjects 2, 3 and 5).
The experiments started at 08.30 hours after an overnight fast of at least 10 h. The catheter with bag was introduced through the mouth and positioned in the fundus of the stomach. Correct position was checked by fluoroscopy. To unfold the bag, air (200 mL) was manually inflated under controlled pressure (< 20 mmHg) and the catheter was pulled back carefully until its passage was restricted by the lower oesophageal sphincter. The tube was then introduced a further 2 cm. Thereafter the bag was deflated and connected to the barostat. The subjects were seated in a comfortable lying chair in the semi-recumbent position with the lower extremities just above abdominal level. Cannulas were placed in antecubital veins of both forearms, one for blood sampling, the other for saline or somatostatin infusion.
During the experiments blood samples for measurement of plasma somatostatin were drawn at time – 60 min before introducing the catheter with bag, at time – 20 min and 0 min before the start of infusion and thereafter at regular intervals during the infusion until the end of the experiment (≈ 120 min).
Perception of the sensations of fullness, abdominal pressure, nausea and pain were quantified during the experiment on 100 mm visual analogue scales (VAS). Perception of each sensation was recorded during each step of volume distensions.
The following procedures were performed:
1Minimal distending pressure. The minimal distending pressure is the pressure needed to overcome the intra-abdominal pressure. This is defined as the first pressure level that provides an intragastric bag volume of more than 30 mL.9 This was determined by increasing the intrabag pressure in 1 mmHg steps every 2 min.
2Barostat procedure. The barostat was set to maintain a pressure of 2 mmHg above the minimal distending pressure. During the first 20 min (from – 20 to 0 min) the basal volume of the proximal stomach was measured, then infusion of either saline or somatostatin was begun. The volume was continuously measured for 45 min after the start of the i.v. infusion.
3Isovolumetric distension. Isovolumetric distensions were performed in 100 mL increments every 3 min from 0 mL up to a maximum of 600 mL. The procedure was stopped immediately if the maximal pressure of 25 mmHg during 5 s was reached or if the subject could not tolerate further distension. After this procedure the subjects were allowed a rest of 20 min.
4Isobaric distension. Isobaric distensions were performed in 2 mmHg increments every 3 min from 0 mmHg to a maximum of 14 mmHg. The procedure was stopped immediately if a maximum volume of 750 mL was reached or if the subject could not tolerate further distension.
Gastric volumes measured during the barostat procedure are given as average values over 5 min periods. Cyclic variations in bag volume during tone measurements, so-called ‘volume waves’, were defined as changes in volume openface> 30 mL that revert in less than 2 min to a volume within 50% of the previous level.8, 11 The pressure in the isovolumetric distensions and the volume in the isobaric distensions were measured by averaging the recordings during the last minute before the next distension. Volumes at each pressure level were already corrected for air compressibility by the computer program.
The perception scores were calculated. The values obtained at time 0 min, immediately before the onset of infusion, were used as zero reference values.
Plasma levels of somatostatin were measured by a sensitive and specific radioimmunoassay. Somatostatin antiserum was prepared by immunization of a rabbit with synthetic somatostatin-28 (Sigma, St. Louis, MA). The antiserum has equal affinity for somatostatin-14 and somatostatin-28 but does not bind to other regulatory peptides. I125-Tyr1-somatostatin-14 (New England Nuclear, Boston, MA), with a specific activity of 2200 Ci/mmol, was used as radioactive label.12
Results are expressed as mean ± S.E.M. Data were analysed for statistical significance using multiple analysis of variance ( MANOVA). When this indicated a probability of less than 0.05 for the null hypothesis, Student–Newman–Keuls analyses were performed to determine which values between or within the experiments differed significantly. The significance level was set at P < 0.05.
Oral intubation with subsequent positioning of the bag was well tolerated. Thresholds for pain or nausea were not reached during volume and pressure distensions for either somatostatin or saline infusion. The mean minimal distending pressure was 6.8 ± 0.5 mmHg in the control experiment and 6.7 ± 0.8 mmHg for the somatostatin experiment (before infusion).
Basal plasma somatostatin levels before the start of infusion were not significantly different between the two experiments ( Figure 1). During somatostatin infusion plasma levels increased significantly (P < 0.01), from 6 ± 2 pg/mL (at 0 min) to 4100 ± 340 pg/mL (at 15 min) and remained significantly increased thereafter. During saline infusion no significant alteration in plasma somatostatin over basal level was observed.
The intragastric volume before the start of infusion, at time 0 min, with intragastric pressure set at the minimal distending pressure + 2 mmHg, was 165 ± 27 mL in the control experiment and 170 ± 27 mL before somatostatin infusion. Intragastric volume 45 min after the start of infusion was not significantly different between the control and somatostatin experiments: 181 ± 24 mL vs. 223 ± 38 mL.
During the barostat procedure, under basal conditions, continuous phasic volume waves were observed. The frequency of these volume waves decreased significantly (P < 0.001) from 8.2 ± 2.6 per 10 min (basal) to 0.5 ± 0.5 per 10 min during somatostatin infusion ( Figures 2 and 3 3). This occurred within 2 min of the start of the somatostatin infusion. In the control experiment no significant alterations in these volume waves were observed (from 11.3 ± 1.2 to 12.7 ± 1.2 per 10 min).
Gradual volume distension of the stomach resulted in increasing intragastric pressures during both the control and the somatostatin experiment ( Figure 4). During these volume distensions the corresponding intrabag pressures were not significantly different between the control and somatostatin experiments (at 400 mL volume: 12.8 ± 0.7 mmHg vs. 13.1 ± 1.0 mmHg; at 600 mL volume: 18 ± 1.5 mmHg vs. 18 ± 1.5 mmHg). Thus, gastric compliance was not influenced by somatostatin: 35.2 ± 3.7 mL/mmHg vs. 34.3 ± 3.1 mL/mmHg during somatostatin and saline infusion, respectively.
Whereas stepwise volume distension resulted in increasing perception scores during saline infusion, this did not occur during somatostatin infusion ( Figure 5). At an intrabag volume of 500 mL or higher during inflation and from 600 mL to 200 mL during deflation, perception of abdominal pressure and fullness was significantly (P < 0.05) lower during somatostatin infusion compared to saline. No increases in abdominal pain or nausea were experienced during graded distension, during either saline or somatostatin infusion.
Distensions of the stomach with progressively higher intragastric pressures resulted in increasing intragastric volumes in both the control and somatostatin experiments ( Figure 6). The corresponding intrabag volumes over the pressure steps during somatostatin infusion were not significantly different from saline infusion: at 12 mmHg: 317 ± 29 vs. 409 ± 48 mL; at 14 mmHg: 399 ± 55 mL vs. 460 ± 60 mL.
We have shown that somatostatin does not influence compliance of the proximal stomach but it does decrease perception of abdominal pressure and fullness during graded distensions. Somatostatin also caused a reduction in phasic volume waves to almost zero immediately after the start of infusion.
The compliance of the proximal stomach was not significantly influenced by somatostatin during either volume or pressure distensions. Little is known about the effect of somatostatin on proximal gastric motor function. Koerker & Hansen have shown in monkeys that somatostatin does not influence intragastric pressure and antral contractions.13 Others have reported an inhibitory effect of somatostatin on gastric motility.14 However, it is not clear from this study whether motility in the proximal or in the distal part of the stomach was reduced. Mertz et al.,7 using the somatostatin analogue octreotide, showed that octreotide reduced the rate of the gastric accommodation reflex by 50%, resulting in a reduced compliance at distension pressures greater than 10 mmHg. However, this effect was observed only during phasic distension and not during ramp distension. Our results, i.e. that somatostatin does not affect proximal gastric compliance during stepwise increasing pressure distension, are in line with those of Mertz et al.7 during ramp distension. Depending on the type of gastric distension, different mechanoreceptors are activated.7 Somatostatin can influence gastrointestinal motility through direct neural pathways or by inhibition of secretion of gastrointestinal peptides or hormones.
Results on the effect of somatostatin on gastric emptying are conflicting. Whereas some studies have shown acceleration, others have found gastric emptying to be delayed. Somatostatin inhibits antral motility, which is thought to result in a delay of gastric emptying of solids. In the study by Haruma et al.,15 a single dose of octreotide of 50 μg s.c. significantly reduced postprandial motility of the distal antrum. Okamoto et al.16 demonstrated that octreotide at a dose of 50 μg s.c. delayed gastric emptying of a liquid meal, but did not affect antral motility. The effect of octreotide on gastric emptying occurred in a biphasic pattern. During the first hour gastric emptying was accelerated, but in the late postprandial phase gastric emptying was significantly delayed.16 During the solid meal, octreotide decreased antral contractility through a reduction in the mean amplitude but not by influencing the frequency of contractions. Recently Von der Ohe et al. also found that octreotide resulted in a faster initial emptying of solids from the stomach.2 They suggested that this finding is a result of the inhibitory effect of somatostatin on gastric secretion, which makes the total intragastric volume smaller and gastric emptying faster. Apart from antral motility, however, proximal gastric motor function, pyloric contractions and antroduodenal coordination also determine the rate of gastric emptying. In our study proximal gastric motor function was not influenced by somatostatin and this cannot explain alterations in gastric emptying in response to somatostatin or octreotide. Pylorospasm has been reported after octreotide and may contribute to delayed gastric emptying.17 Somatostatin significantly reduced the frequency and amplitude of phasic volume events. These rapid changes in volume of the bag during constant bag pressure (minimal distending pressure + 2 mmHg) may reflect phasic contractions of the gut. However, the clinical relevance of this is not yet fully understood. After meal ingestion a reduction in volume wave frequency has also been observed.
During continuous intravenous infusion of somatostatin, perception of abdominal pressure and fullness in response to distensions was inhibited. These results are in line with previous studies using the somatostatin analogue octreotide and showing inhibitory effects on the perception of abdominal symptoms in healthy subjects and subjects with functional gastrointestinal disorders.4–7 Bradette et al. showed that octreotide increased the threshold of colonic visceral perception in patients with irritable bowel syndrome without modifying muscle tone.5 Mertz et al. showed that during phasic and ramp distension of the proximal stomach, octreotide increased the threshold for fullness (innocuous sensation), while the volume threshold for pain (noxious sensation) was decreased during phasic distension.7 The hyperalgesic effect was explained as being secondary to the inhibitory effect of octreotide on the gastric accommodation reflex.7
Visceral sensitivity is controlled either in peripheral receptors in the spinal cord by altering signal processing in the dorsal horn or second-order neurons, or in the higher centres above the brain stem, where conscious perception occurs. Mechanoreceptors in the stomach are located in the non-mucosal layer of the gastric wall and use both vagal and splanchnic afferents. These receptors respond to contraction and distension.18 It is thought that somatostatin and octreotide inhibit visceral perception directly by inhibiting these afferent pathways. This has been investigated for rectal perception. Hasler et al. have shown that octreotide reduces the sensation of rectal distension via inhibition of visceral afferent pathways.4 Chey et al. showed that octreotide reduces perception of rectal electrical stimulation by spinal afferent inhibition.6
Previous studies have shown that visceral perception is increased in patients with functional dyspepsia.19, 20 Therefore it would be interesting to further evaluate the effect of somatostatin and of octreotide in patients with functional dyspepsia.
In summary, continuous infusion of somatostatin does not influence human gastric compliance, but inhibits phasic volume waves and significantly reduces visceral perception.