Camilleri, Michael

The amylin analog pramlintide delays gastric emptying in type I diabetics. The effects of multiple doses of pramlintide and the mechanism of action in non-amylin-deficient humans are unknown. We investigated the effects of pramlintide on gastrointestinal and colonic transit and on the plasma pancreatic polypeptide response to the meal in a parallel-group dose-response study with subjects randomized to placebo, or 30 or 60 μg (tid, sc) of pramlintide. Pramlintide delayed gastric emptying [half-time ( t½): 112 min (SE 8.7 min), 169 min (SE 12 min), or 177 min (SE 25 min) after placebo or 30- or 60-μg pramlintide treatment, respectively; P = 0.033]. Pramlintide did not significantly affect small bowel or colonic transit. Pancreatic polypeptide concentrations in the first postprandial hour were lower with pramlintide than with placebo ( P < 0.01 for drug effect). An inverse correlation was observed between mean pancreatic polypeptide concentrations in the first postprandial hour and gastric emptying t½[Spearman correlation coefficient ( Rs) = 0.48; P = 0.044]. Pramlintide at 30 and 60 μg delays gastric emptying in healthy humans without affecting small bowel or colonic transit. Vagal inhibition is a potential mechanism of the effects of pramlintide on gastric emptying.

The effects of pharmacological modulation of adrenergic receptors on colonic motor and sensory function are unclear. We studied 40 healthy volunteers in a single-blind design; 12 received saline, and the remaining 28 received either clonidine, yohimbine, phenylephrine, or ritodrine. A barostat-manometric assembly in the left colon recorded drug effects on fasting and postprandial motor function, compliance, and sensation in response to standardized phasic balloon distensions delivered in random order. Clonidine reduced and yohimbine increased fasting, but not postprandial tone, by 63.2 ± 22.3% and 24.8 ± 8.8% (SE), respectively. Clonidine tended to reduce fasting phasic activity in the descending and sigmoid colon. A power exponential model provided the best fit to the compliance curve. Clonidine significantly increased colonic compliance. Clonidine reduced and yohimbine increased colonic perception of pain but not gas sensation during distension. Phenylephrine and ritodrine did not influence colonic motor or sensory function in the present studies. Thus α2-receptors modulate fasting colonic tone and compliance and alter perception of pain but not gas during mechanical stimulation of the colon.

Increased use of laxatives and constipation are more common among people with diabetes mellitus than matched nondiabetic people in the same community. The mechanism of constipation in diabetes is unclear. Acute hyperglycemia was previously reported to reduce the gastrocolonic response. Our aim was to determine the effects of acute hyperglycemia on the colon compliance and motor response to feeding and on the sensory function of the colon and rectum in healthy human subjects. Eleven healthy individuals were studied under conditions of hyperglycemia (mean blood glucose 280 ± 13 mg/dl) and euglycemia. We evaluated three parameters: 1) colonic motility and compliance by a multilumen manometry and barostatic balloon assembly in the descending colon (motility was studied during fasting and for 2 h postprandially); 2) perception of isobaric distensions of polyethylene balloons in the rectum and colon; and 3) rectal compliance. Initial tonic response to meal ingestion (0–5 min) was slightly lower during hyperglycemia ( P = 0.3). However, colonic tone, motility, compliance, and sensation, as well as rectal compliance and sensation, were not significantly different under the conditions of euglycemia and acute hyperglycemia. In healthy individuals, acute hyperglycemia does not significantly change colonic or rectal motor functions or the perception of mechanosensory stimuli in the colon or rectum compared with euglycemia. These results do not support the hypothesis that hyperglycemia abolishes the colonic response to feeding.

To characterize α2-adrenergic control of motor and sensory functions of gastrointestinal tract and colon, we studied dose-related effects of clonidine (placebo or up to 0.3 mg po) by random assignment in 55 healthy humans. Gastrointestinal transit was measured in all subjects; in 35, we assessed colonic compliance, tone, and sensations of gas and pain during phasic distensions. Clonidine did not significantly alter gastrointestinal or colonic transit, but it increased colonic compliance and reduced fasting tone without altering colonic response to a meal. Clonidine significantly reduced aggregate sensation to distensions overall and had significant linear dose-related sensory effects at 8- and 24-mmHg distensions. Effect on pain (including dose-response relationship) was due to 0.3-mg dose for distensions at 24 mmHg. We confirmed that clonidine relaxes fasting colonic tone and reduces sensation of pain. In this study, gut transit was not altered by clonidine, and novel dose-response characteristics and clonidine's effect on gas sensation are provided. Doses as low as 0.05 mg may be effective and potentially useful in reducing colonic tone and gas sensation.

Central processing of visceral information in humans is incompletely understood. We aimed to demonstrate the feasibility of single photon emission computed tomography (SPECT) and to quantitate the changes in regional cerebral blood flow during rectal distension. Ten healthy volunteers underwent randomized sham and active rectal distensions on separate days, during which cerebral blood flow was assessed by intravenous technetium-99m ethyl cysteinate dimer (99mTc-ECD) SPECT. Three-dimensional coregistration of brain images was used to quantitate activation in four preselected cerebral foci and two control regions. Paired analysis compared blood flow during sham and active distensions. There was increased right anterior cingulate gyrus activity (6.5 ± 2.9%, P = 0.03) with active rectal distension. A 5.4 ± 2.4% reduction in blood flow in the superior parieto-occipital control region ( P = 0.04) suggested blood “redistribution” during stimulation. Marked variability in activation of the frontal cortex, thalamus/basal ganglia complex, and mesiotemporal lobe was noted. Thus rectal distension increases activity in the right anterior cingulate gyrus on average; other foci of cerebral activation are quite variable, suggesting a lack of specific cerebral projections during rectal stimulation.

Increasing interest is focusing on the role of intestinal tone, distensibility, and mechanosensation in the genesis of abdominal symptoms. Experimental approaches usually feature balloon distension of the bowel with measurements of perception, tone, and compliance and/or elastance; however, the methodologies are standardized incompletely. We examined the reproducibility of repeated assessments of sensory perception, basal tone, and compliance and/or elastance of the rectum during distension. We also evaluated the response to inflations that varied in regard to control of pressure or volume, pattern of distension, and rate of inflation. Five healthy volunteers were studied under two separate protocols. The first featured a series of experiments on each of 5 days; the other consisted of 2 separate days of study. Repeated distensions evoked reproducible responses of sensation and compliance and/or elastance on a single day, providing a conditioning distension preceded them. Day-to-day variability was also sufficiently small to allow valid comparisons to be made on different days in healthy persons. The configuration of the distension profile (phasic, staircase, or ramp) and the rate of inflation (from 1 to 40 ml/s) had little effect on distensibility or perception. Perceptions were sometimes transient and sometimes constant, but no relationship was found between these temporal features and the magnitude of the stimulus. These observations help provide a basis as to how the responses to rectal distension can be best studied.

Our first aim was to compare 111In-labeled Amberlite IR-12OP resin pellets and 131I-labeled fiber in the assessment of gastric and small bowel transit and colonic filling in healthy humans. Both radiolabels were highly stable for 3 h in an in vitro stomach model and remained predominantly bound to solid phase of stools collected over 5 days [90.5 +/- 2.1 (SE)% for 131I and 87.4 +/- 1.4% for 111In). The lag phase of gastric emptying was shorter for 111In-pellets (30 +/- 11 min compared with 58 +/- 12 min for 131I-fiber, P less than 0.05). However, the slope of the postlag phase of gastric emptying and the half time of small bowel transit were not significantly different for 111In-pellets and 131I-fiber. Filling of the colon was characterized by bolus movements of the radiolabel (10-80% range, 26% mean) followed by plateaus (periods of no movement of isotope into colon lasting 15-120 min, range; 51 min, mean). Half of the bolus movements occurred within 1 h of the intake of a second meal. Thus 111In-labeled Amberlite pellets provide an excellent marker for the study of gastric and small bowel transit and colonic filling in humans. The ileum acts as a reservoir and transfers boluses of variable sizes into the colon, often soon after the intake of a subsequent meal.

Our aims were to assess the role of adrenergic modulation in the hyperventilation-induced increase in colonic tone. Of 40 healthy volunteers, 12 received placebo (saline) and the remaining 28 received either clonidine, yohimbine, phenylephrine, or ritodrine. Time-frequency mapping of heart rate based on Wigner distribution assessed variations in parasympathetic and sympathetic activity during hyperventilation. Tone in the descending colon was recorded by a barostat balloon before, during, and after 5 min of hyperventilation. Heart rate spectral analysis suggested diminished sympathetic and vagal activity during hyperventilation and increased sympathetic and vagal activity after hyperventilation. Adrenergic agents influenced ( P = 0.01) the tonic response after, but not during, hyperventilation. Yohimbine reduced the increment in colonic tone after hyperventilation compared with saline ( P < 0.05) and clonidine ( P = 0.002); phenylephrine and ritodrine had no effects. Different mechanisms modulate the increase in colonic tone during and after hyperventilation. Yohimbine attenuates the increase in colonic tone after hyperventilation probably by enhancing inhibitory sympathetic input to the colon.

The aim of this study was to assess the relationship between altered axial forces and gastric emptying of solids by experimentally inhibiting or stimulating gastric axial forces by intraduodenal lipid or intravenous erythromycin, respectively. In 15 healthy volunteers, we simultaneously measured gastric emptying of solids by scintigraphy, gastroduodenal motility by manometry, and forces along the longitudinal axis of the distal stomach by an axial force transducer. When 25% of the radiolabel had emptied from the stomach, subjects (n = 5 in each group) received normal saline (controls), intraduodenal lipid, or intravenous erythromycin. The test period consisted of the infusion period (10 min) and the subsequent 30 min. Lipid significantly reduced and erythromycin increased axial forces compared with control (lipid: median 0.6 N [0-1.4 interquartile range (IQR)]; erythromycin: median 18.2 N (16.5-20.5 IQR); control: median 4.7 N (3.9-5.2 IQR); P < 0.01). Similarly, antral phasic pressure activities were different relative to control. Gastric axial forces correlated significantly with gastric emptying (Spearman rank correlation = 0.86; P < 0.01). These data are consistent with the hypothesis that axial forces affect gastric emptying of solids and suggest that measurement of axial forces provides an assessment of overall gastric propulsion during the emptying of solids.

Our aim was to measure axial forces in the stomach and to evaluate their relation to circumferential contractions of the gastric walls and the emptying of gastric content. We used a combination of simultaneous radioscintigraphy, gastroduodenal manometry, and an axial force transducer with an inflatable 2-ml balloon fluoroscopically placed in the antrum. In vitro studies demonstrated that the axial force transducer records only antegrade forces along the longitudinal axis of this probe in an intensity-dependent manner. In vivo studies were performed in five healthy subjects for at least 3 h after ingestion of radiolabeled meals. When administered separately, the emptying of liquids or solids from the stomach is associated with generation of antral axial forces and coincident phasic pressure activity; however, almost 20% (average) of gastric axial forces during emptying of liquids or solids are unassociated with proximal or distal antral pressure activity ("isolated" forces). High amplitude antral axial forces and pressures occur during both lag and postlag emptying phases. During emptying of liquids, there is a trend for axial forces to be coincident more often with proximal than with distal antral pressure activity and vice versa for the emptying of solids (P = 0.015). These data suggest that when placed in the antrum, the transducer can semiquantitatively record axial forces during gastric emptying. By combining these observations with the data from in vitro studies, it appears that axial forces predominantly result from traction on the balloon by the longitudinal vector resulting from circumferential gastric contractions. The combination of radioscintigraphy and measurement of antral axial forces is a promising method to evaluate mechanical forces involved in the emptying of the human stomach.