Prolonged inhibition of acid secretion causes hypergastrinaemia without altering pH inhibition of gastrin release in humans

Hypergastrinaemia induced by potent inhibitors of acid secretion is thought to occur as a result of the elimination of the inhibitory effects of intragastric acid on gastrin release. The present study was designed to determine if the mechanisms responsible for feedback inhibition of gastrin release and acid secretion by intragastric acid are preserved during four weeks of varying degrees of drug-induced acid inhibition. Forty-eight healthy male volunteers were randomly assigned to one of four treatments for four weeks: 10 mg omeprazole o.m., 20 mg omeprazole o.m., 40 mg omeprazole o.m. or 150 mg ranitidine b.d. Gastrin release and acid secretion in response to peptone meals maintained at pH 2.5 and pH 5.5 by intragastric titration, and 24-hour gastrin profiles in response to standard meals were determined before treatment, at the fourth week of treatment and two weeks after discontinuing treatment. As expected, omeprazole produced dose-related effects on acid secretion and gastrin concentrations that were largely reversed after treatment was discontinued. Gastrin release in response to pH 5.5 peptone meals remained significantly greater than gastrin release in response to pH 2.5 meals during treatment with all doses of omeprazole. The ratio of pH 5.5/pH 2.5 peptone meal-stimulated gastrin release was approximately 1.5, and remained constant for all treatment groups throughout the study period. These data indicate that four weeks of drug induced hypochlorhydria causes an apparent increase in overall G-cell function, but it does not interfere with normal feedback inhibition of gastrin release and acid secretion mediated by intragastric acidity.     

Corticotropin Releasing Factor (CRF) increases post-prandial duodenal motor activity in humans

The effects of peripherally administered Corticotropin Releasing Factor (CRF) on post-prandial gastrointestinal motility were studied in normal subjects. Pressure activity was monitored for 90 min pre-and 120 min post-prandially in the antrum and duodenum in 8 healthy male volunteers (mean age 45.5 years). Subjects received, on separate days, ovine CRF (0.6 nmol/kg) or vehicle, infused intravenously over 5 min, 15 min after the beginning of the meal. In all subjects, CRF infusion transiently increased the frequency of contractile events to the frequency of the duodenal slow wave (11.7 ± 0.3 cpm). The postprandial duodenal mobility index (MI) after CRF infusion was significantly greater (7.72 ± 0.29) when compared to vehicle infusion (4.34 ± 0.14) (mean ± SEM; P < 0.001). However, the fraction of propagated contractile events was not altered significantly after CRF when compared to vehicle. In contrast, the antral post-prandial MI was not affected by the CRF application. Serum cortisol levels increased significantly at 60 and 90 min post-CRF injection. These data indicate that CRF transiently switches the post-prandial duodenal motor activity to a band of non-propagated high frequency contractions, but does not affect antral contractions.     

Effects of the corticotropin-releasing factor (CRF) on rectal afferent nerves in humans

Abstract Corticotropin-releasing factor (CRF) released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may play a role in the modulation of rectal afferent function. In the current study we evaluated the effects of peripherally administered CRF on afferent mechanisms in the human rectum. We used rectal balloon distention in seven healthy volunteers to evaluate the effect of CRF (1 μ/kg) on visceral afferents originating in the rectum which are involved in the following functions: thresholds and intensity of conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum using a volume ramp (40 and 400 mL/min), or by intermittent phasic distention. CRF decreased the thresholds and increased the intensity for the sensation of discomfort in response to both ramp and phasic distention. During slow ramp distention, CRF also lowered the stool threshold. CRF increased rectal compliance during slow ramp distention without affecting the rate of receptive relaxation or the inflection point of the compliance curve. CRF had no effect on viscerosomatic referral patterns, or on the rectoanal inhibitory reflex. These findings are consistent with a dual effect of CRF on afferent pathways mediating perception of aversive rectal sensations, and on rectal smooth muscle.     

Time of day effects in, and the relationship between, sleep quality and movement

The study aimed to measure the effects of a 27-h 'day' sleep-wake regime on actigraphic and subjective sleep variables, and to examine the relationships between these variables. Nine subjects spent 30 days and nights in the laboratory. After sleeping 8 h for each of 8 nights, the subjects had an imposed 27-h 'day', for 18 'days', remaining in bed for 9 h on each sleep period. Sleep periods therefore started 3 h later each day, although subjects' circadian rhythms stayed entrained to 24 h, because subjects were not isolated from the natural light-dark cycle. Time asleep, subjective sleep efficiency and subjective sleep quality, but not movement during sleep, were found to be significantly affected by time of going to bed. There were significant decreases in movement during recovery sleeps following each of two episodes of 26 h sleep deprivation. Over the study there were significant within-subject correlations between subjective sleep quality and subjective sleep efficiency (r_av=0.65), movement during sleep and subjective sleep efficiency (r_av=−0.48), and movement during sleep and subjective sleep quality (r_av=–0.26). We conclude that sleep movement, despite its low within-and between-subjects variability, is nevertheless a statistically reliable, but weak, indicator of subjective sleep efficiency and quality.     

Prolonged inhibition of meal-stimulated acid secretion and gastrin release following single subcutaneous administration of octreotide (SMS 201–995) in man

Single subcutaneous doses of the somatostatin analogue, SMS 201-995, were evaluated for the degree and duration of effects on acid secretion, serum gastrin levels, and gastric emptying in eight human male subjects (mean age 44 years) over an 8-h period. All the subjects received subcutaneous 50-micrograms and 100-micrograms doses of SMS 201-995 and placebo on three separate days in a double-blind random order. Drug or placebo was administered at time 0 followed by peptone meals at time 0, 2, 4, and 6-h. Peptone meals were evacuated at time 1, 3, 5 and 7-h to create 'basal' conditions between alternate hours. Gastric acid secretion was determined hourly beginning at time--1. Both the 50-micrograms and 100-micrograms doses of SMS 201-995 significantly inhibited 'basal' and peptone meal-stimulated gastric acid secretion throughout the 8-h measurement period. The minimum effective plasma concentration of SMS 201-995 for inhibition of peptone meal-stimulated gastric acid secretion was approximately 1000 pg/ml. Peptone meal-stimulated plasma gastrin concentrations were inhibited for 5 and 7 h after 50-micrograms and 100-micrograms doses of SMS 201-995, respectively, whereas 'basal' plasma gastrins were inhibited for 4 and 6 h, respectively. Gastric emptying determined by marker dilution was not significantly enhanced compared to placebo. These results indicate prolonged and potent effects of single subcutaneous doses of SMS 201-995 on peptone-meal stimulated acid secretion and gastrin release.     

The effect of octreotide on human gastric compliance and sensory perception

Somatostatin or its analogue octreotide (OCT) has previously been shown to modulate gastric emptying, intestinal motor activity and visceral sensation. In the current study we sought to determine the effect of a single dose of OCT (1.25 μg kg^?1 s.c.), which has previously been shown to have both motor and sensory effects, on proximal gastric compliance and on conscious perception of gastric distention. Gastric distention was performed in 13 healthy male volunteers, by either slow ramp distention (60 ml min^?1) or by intermittent pressure steps (phasic distention; 4–20 mmHg) using an electronic distention device. Compliance curves (pressure–volume relationship), and thresholds for innocuous (fullness) and noxious sensations (discomfort, pain) were determined following vehicle or OCT injection. OCT consistently and significantly reduced the rate of the gastric accommodation reflex by 50%, resulting in a reduced compliance at distention pressures greater than 10 mmHg during phasic distention. In contrast, no effect was observed on the compliance curve obtained during ramp distention. OCT selectively increased the threshold for fullness during both ramp and phasic distention. During phasic distention, OCT decreased the volume thresholds for noxious (pain) sensations experienced at volumes greater than 300 ml, without affecting the corresponding pressure threshold. These findings suggest that at low distension volumes, OCT in the dosage used has a direct inhibitory effect on afferents mediating innocuous gastric sensations. The hyperalgesic effect observed during phasic distention may be secondary to OCT's inhibitory effect on the gastric accommodation reflex.