Wei Ming Sun

Sensory and Motor Responses to Rectal Distention Vary According to Rate and Pattern of Balloon Inflation

Anorectal motor activity and rectal sensation were recorded in 12 normal male subjects during ramp distention of the rectum with water and air at randomized rates of 10, 20, 50, and 100 mL/min and during intermittent rapid distention with air. There were no significant differences between the results of ramp inflation with water or with air, and the repeated infusion of the same medium yielded reproducible results. Ramp distention induced sigmoid pressure-volume profiles. Different sensations occurred at specific points on the pressure-volume curve and were maintained until succeeded by the next sensation. Initial perception of the distention occurred during the initial steep pressure increase, the sensation of wind occurred during the plateau phase, and the desire to defecate occurred at the onset of the final rapid ascent. Rectal sensations were induced at lower volumes at low infusion rates when the slope of the pressure-volume relationship was shallower than at high infusion rates. This suggests that the receptor triggering rectal sensation is not a simple volume or pressure receptor, but is more likely to be a slowly adapting mechanoreceptor lying parallel to the circular muscle of the rectal wall. During rapid intermittent distention, the rectal volumes required to elicit rectal sensations were lower than during ramp distention, although the pressure-volume curve was steeper. Moreover, sensations often only lasted a short period of time but recurred on deflation. These data suggest activation of an additional population of rapidly adapting or high threshold mechanoreceptors. Anal relaxation was always evoked by intermittent rectal distention and was almost always associated with a rectal sensation and an increase in external anal sphincter activity. In contrast, anal relaxation could be absent or delayed during ramp inflation, especially at lower infusion rates, suggesting that internal sphincter can maintain continence for a long period of time while the rectum is slowly filling. Rectal sensation and concomitant external anal sphincter activity was not associated with anal relaxation during ramp inflation; most subjects felt the sensation long after the pressure reached its lowest level. However, under all circumstances the onset of rectal sensation was associated with an increase of external anal sphincter electrical activity. In conclusion, the rectal sensory and anorectal motor responses to distention depend on the rate and pattern of distention, which may activate a different population of receptors. Results from different laboratories cannot be compared directly unless the pattern and rate of distension are the same.

Hyperglycaemia affects proximal gastric motor and sensory function in normal subjects

Objective: Hyperglycaemia delays gastric emptying in normal subjects and patients with diabetes mellitus by uncertain mechanisms and may affect the perception of somatic sensations. The effects of hyperglycaemia on the motor function of the proximal stomach and the perception of gastric distension were evaluated in normal subjects. Design: Paired studies were performed in randomized order in 10 healthy volunteers on separate days during euglycaemia and hyperglycaemia (blood glucose ≈ 15mmol/l). Methods: With a barostat and a balloon positioned in the proximal stomach, fasting subjects underwent a stepwise gastric distension. Each 2mmHg step was maintained at a constant pressure for 2min. The volume of the barostat balloon was measured and perception of the sensations of fullness, desire to belch, nausea, abdominal discomfort and hunger was scored at each step. Results: Hyperglycaemia was associated with an increase in proximal gastric compliance (P<0.01) evident from 2mmHg above basal intragastric pressure. Perception scores for the sensations of nausea and desire to belch were greater during hyperglycaemia than euglycaemia (P<0.05) in relation to both pressure at each step and volume. Hyperglycaemia did not affect perception of the sensations of abdominal discomfort, fullness or hunger. Conclusions: Hyperglycaemia increases proximal gastric compliance, reflecting a reduction in gastric tone. This may contribute to the previously observed delay in gastric emptying associated with hyperglycaemia. Hyperglycaemia appears to increase the perception of some of the sensations induced by gastric distension.

Anorectal function in incontinent patients with cerebrospinal disease

Anorectal manometry and the electrical activity of the external anal sphincter were measured in 20 patients with well-defined, incomplete spinal lesions who were referred because of fecal incontinence and in 30 normal subjects. Six patients had a high spinal lesion, 11 had a low spinal lesion, and 3 had mixed high and low spinal lesions. Patients with high spinal lesions had normal basal pressures but abnormally low squeeze pressures and impaired rectal sensation. Unlike normal subjects, there was no relationship between the depth of sphincter relaxation and the distention volumes. The external sphincter responses to rectal distention and increases in intraabdominal pressure were enhanced, and leakage of perfusion fluid was uncommon. Patients with low spinal lesions had abnormally low basal and squeeze pressures, blunted rectal sensation, and showed impaired external anal sphincter responses to rectal distention or increases in intraabdominal pressures. Most of these patients leaked the infused fluid during these maneuvers. Sphincter function in patients with mixed lesions was more severely impaired than in patients with low and high spinal lesions. Patients with mixed lesions showed abnormally low basal and squeeze pressures, impaired rectal sensation, and no external anal sphincter responses to either rectal distention or increases in intraabdominal pressure. Leakage occurred during these maneuvers in all patients with mixed lesions.

Disturbances in anorectal function in patients with diabetes mellitus and faecal incontinence

Objective: The pathophysiology of faecal incontinence in diabetes mellitus is poorly understood. The study was designed to document the anorectal dysfunctions in diabetic patients with faecal incontinence. Methods: Multiport anorectal manometry and electromyography were done in 11 diabetic patients with faecal incontinence and in 20 healthy controls. Results: Basal and squeeze pressures were reduced (P<0.05) in the diabetic patients compared with the control subjects. During basal recording six patients showed regular oscillations in anal electrical activity and pressure with an amplitude of 10–40 (median: 25)cmH2O and a frequency of 6–10 (median: 8) min-1. Nine patients also exhibited spontaneous transient anal relaxations with an amplitude of 15–50 (median: 40)cmH2O and a duration of 15–720 (median: 60)s, and in six of them leakage occurred as the anal pressure fell below the rectal pressure. None of the control subjects showed oscillation or spontaneous relaxations. In patients there was a greater tendency for repetitive rectal contractions in response to rectal distension and reduced rectal compliance (P<0.01). During rectal distension four patients showed no anal relaxation, and in the remainder relaxation occurred at an abnormally high threshold. However, the residual pressures were lower (P<0.05) than in control subjects and often fell below rectal pressure, whereupon leakage occurred. There was no significant difference in the distension thresholds for rectal sensation between patients and control subjects, but in 9/11 patients the perception of rectal sensation was delayed by more than 2 s (P<0.05). Conclusion: These results indicate that aetiology of faecal incontinence in diabetic patients is multifactorial and, suggest for the first time, that instability of the internal sphincter probably plays a major role.

Pharmacokinetic considerations in gastrointestinal motor disorders

SummaryAlthough it has been recognised that alterations in gastrointestinal motility, whether induced by physiological or pathological processes, have significant effects on the pharmacokinetics of orally administered drugs, this subject has received inappropriately little attention. Studies relating to this topic have focused on healthy volunteers and animals and have largely been confined to the effects of single drug doses. There is limited information about the effects of disease on pharmacokinetics under steady-state conditions.Changes in gastrointestinal motility may affect the pharmacokinetics of orally administered drugs by altering the rate of delivery, bioavailability or mucosal absorption of the drug. In general the rate of absorption and time taken to achieve maximal plasma concentrations for well absorbed drugs may be modified by changes in gastrointestinal motility, but overall bioavailability is not usually affected. In these cases the therapeutic and clinical effects of the alteration in pharmacokinetics will, therefore, depend on which parameters are important for the action of the drug. For poorly absorbed drugs both the rate of absorption and bioavailability are likely to be altered by changes in gastrointestinal motility However, the complex effects of food and disease, as well as the properties and formulation of any drug (solubility, ease of dispersion, delayed release formulation) often make the prediction of the magnitude, or even the direction, of any effect difficult to predict. Drugs with direct effects on gastrointestinal motility may influence their own patterns of absorption.In patients with gastrointestinal motility disorders, drugs administered in a controlled release formulation, or those with poor bioavailability, are most likely to have a poorly predictable therapeutic effect. Care should be taken to ensure that the formulation of the drug, its timing of administration in relation to meals and the use of coadministered drugs optimise, or at least ensure consistent absorption.

Effects of duodenal distention on fasting and postprandial antropyloroduodenal motility in humans

BACKGROUND/AIMS Mechanoreceptors in the proximal small intestine may play an important role in the regulation of gastric emptying. Balloon distention of the duodenum causes fundic relaxation. The purpose of the present study was to determine the effect of stimulation of duodenal mechanoreceptors on both fasting and postprandial antropyloroduodenal motility in humans. METHODS Antropyloroduodenal pressures were recorded in 12 healthy volunteers with a sleeve-sidehole assembly, incorporating two balloons 5 and 20 cm distal to the pylorus. Duplicate proximal and distal duodenal balloon distensions with 10, 20, and 30 mL of air for 2.5 minutes were performed separately and in randomized order both during fasting and after a meal. RESULTS During fasting, proximal and distal distention at all volumes increased the number of isolated pyloric pressure waves (P < 0.05) and basal pyloric pressure (P < 0.05), and the response to proximal distention was greater (P < 0.05). Postprandially, proximal and distal distention increased basal pyloric pressure (P < 0.05) with a greater response to proximal distention (P < 0.05), but had no effect on isolated pyloric pressure waves. Both during fasting and postprandially, there were more synchronous and less antegrade antral waves during distention (P < 0.05). The number of duodenal pressure waves increased during proximal (P < 0.05) but not distal distention. CONCLUSIONS Stimulation of duodenal mechanoreceptors by balloon distention has significant and region-dependent effects on antropyloroduodenal motility that vary between fasting and postprandial states.

Hyperglycemia Affects Gastric Electrical Rhythm and Nausea During Intraduodenal Triglyceride Infusion

Hyperglycemia slows gastric emptying andincreases the intensity of perception of gastricdistension during fasting and small intestinal nutrientstimulation. In order to examine the possibility thatabnormalities of gastric electrical rhythm may be associatedwith the effects of hyperglycemia, the gastricelectrical rhythm (cutaneous electrogastrogram) and theperception rating scores for upper gastrointestinal sensations (visual analog scale) were examined.Studies were performed during intraduodenal triglycerideinfusion in 10 healthy volunteers under euglycemic andhyperglycemic (≈15 mmol/liter) conditions. During fasting, hyperglycemia had no effect oneither gastric electrical rhythm or sensation.Intraduodenal triglyceride infusion was associated withan increase in bradygastria (<2.4 cpm) during botheuglycemia (33 9%) and hyperglycemia (36 ± 10%, P< 0.05 vs baseline for each). During intraduodenaltriglyceride infusion, tachygastria (>3.6 cpm) wasmore prevalent during hyperglycemia when compared toeuglycemia (25 ± 10% vs 1 ± 1%, P <0.05) and the perception rating scores for nausea andabdominal discomfort were greater during hyperglycemia(P < 0.05 for both). The intensity of nauseacorrelated with the proportion of time spent in tachygastria (r = 0.64, P < 0.01).These data are consistent with the concept thatpostprandial upper gastrointestinal symptoms in patientswith diabetes mellitus may be modulated by the bloodglucose concentration.

Effect of oral nicardipine on anorectal function in normal human volunteers and patients with irritable bowel syndrome.

Paired controlled studies were performed in 10 normal volunteers and 32 patients with irritable bowel syndrome to investigate the effect of the calcium channel blocker nicardipine, on the responses of the anorectum to rectal distension and a meal. Nicardipine was administered orally in standard (20 mg) and sustained-release (30 mg twice a day) formulations. In normal volunteers standard nicardipine had no significant effect on the rectal responses to distension but did significantly reduce the postprandial motility index (P <0.05). In the patients with irritable bowel syndrome, standard nicardipine caused a significant reduction in distension-induced rectal motor activity (P <0.05) and increased the rectal sensory thresholds for desire to defecate and discomfort (P <0.02). Slow-release nicardipine caused a significant reduction in distension-induced activity (P <0.05) but did not alter rectal sensory thresholds. Both formulations of nicardipine significantly reduced the postprandial motility index (P <0.05) and symptoms (P <0.05). In conclusion, this study confirms that calcium channel blockers may be useful in the management of irritable bowel syndrome.Paired controlled studies were performed in 10 normal volunteers and 32 patients with irritable bowel syndrome to investigate the effect of the calcium channel blocker nicardipine, on the responses of the anorectum to rectal distension and a meal. Nicardipine was administered orally in standard (20 mg) and sustained-release (30 mg twice a day) formulations. In normal volunteers standard nicardipine had no significant effect on the rectal responses to distension but did significantly reduce the postprandial motility index (P <0.05). In the patients with irritable bowel syndrome, standard nicardipine caused a significant reduction in distension-induced rectal motor activity (P <0.05) and increased the rectal sensory thresholds for desire to defecate and discomfort (P <0.02). Slow-release nicardipine caused a significant reduction in distension-induced activity (P <0.05) but did not alter rectal sensory thresholds. Both formulations of nicardipine significantly reduced the postprandial motility index (P <0.05) and symptoms (P <0.05). In conclusion, this study confirms that calcium channel blockers may be useful in the management of irritable bowel syndrome.

Stereospecific effects of tryptophan on gastric emptying and hunger in humans

The amino acid tryptophan (tryp) is a potent inhibitor of gastric emptying in both animals and humans. Animal studies suggest that this effect may be specific for the L‐enantiomer. The effects of D‐ and L‐tryptophan on gastric emptying, intragastric distribution and appetite in humans were evaluated. Ten volunteers ingested 300 mL of either L‐tryp (50 mmol/L), D‐tryp (50 mmol/L) or normal saline labelled with 99mTc sulfur colloid on three occasions, separated by between 3 and 7 days. Hunger and fullness were measured with a visual analogue scale at ‐2, 15, 30 and 60 min after ingestion of each drink. Saline emptied faster from the stomach than both L‐tryp and D‐tryp (P <0.05) and D‐tryp emptied faster than L‐tryp (P <0.005). Emptying from the proximal stomach was fastest for saline (P <0.05) and faster for D‐tryp than L‐tryp (P <0.005). Emptying from the distal stomach was faster for saline than both D‐ and L‐tryp (P <0.05). A reduction in hunger (P <0.05) and a non‐significant trend for an increase in fullness were observed after all three drinks. At 60 min, fullness was greater after L‐tryp than after ingestion of D‐tryp (P <0.01). These observations indicate that the effect of tryptophan on gastric emptying in humans is stereospecific, consistent with the concept that stereospecific receptors for tryptophan exist in the human small intestine.

Modulation of pumping function of gastric body and antropyloric contractions.

Gastric and antropyloric phasic contractions control transpyloric pulsatile flow, the major mechanism of gastric emptying. Both the occurrence and patterning of phasic gastric contractions are highly modulated by intestinal feedback mechanisms, with resultant variation in gastric emptying. The observed patterns of these contractions can only be plausibly explained by the action of neural influences on gastric motility. These influences derive from several mechanisms driven by intestinal feedback, central nervous system controls, and higher centers, with transmission of signals via intrinsic enteric pathways and extrinsic nerves. It is suggested that the occurrence and patterning of gastric phasic contractions depend on the spatial specificity and local modulation of the intensity of neural stimulation of gastric muscle. The resultant strength of contraction determines the occurrence and timing of lumen occlusion relative to adjacent regions. The timing of lumen occlusion in adjacent regions may be the major determinant of mechanical outcome.