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Anal manometry measures circumferential pressures but not axial forces that are responsible for defecation and contribute to fecal continence. Our aims were to investigate these mechanisms by measuring axial rectoanal forces with an intra-rectal sphere or a latex balloon fixed at 8, 6, or 4 cm from the anal verge and connected to axial force and displacement transducers. Rectoanal forces and rectal pressures within a latex balloon were measured at baseline (i.e., at rest) and during maneuvers (i.e., squeeze, simulated evacuation, and a Valsalva maneuver) in 12 asymptomatic women and 12 women with symptoms of difficult defecation. Anal resting and squeeze pressures were also assessed by manometry and were similar in control patients and experimental patients. At rest, axial rectoanal forces were directed inward and increased as the device approached the anal verge. Control patients augmented this inward force when they squeezed and exerted an outward force during simulated expulsion and a Valsalva maneuver. The force change during maneuvers was also affected by device location and was highest at 4 cm from the verge. In experimental patients, the force at rest and the change in force during all maneuvers was lower than in control patients. The rectal pressure during a Valsalva maneuver was also lower in experimental patients than in control patients, suggestive of impaired propulsion. In conclusion, a subset of women with defecatory symptoms had weaker axial forces not only during expulsion but also during a Valsalva maneuver and when they squeezed (i.e., contracted) their pelvic floor muscles, suggestive of generalized pelvic floor weakness. anal pressures; axial force; manometry; defecation; continence

Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (C1C-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective C1C-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 [micro]g bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ('satiation') test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo: however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the C1C-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation. colon; secretion; motility; ion channel

CCK influences satiation and gastric and gallbladder emptying. GI181771X is a novel oral CCK-1 agonist; its effects on gastric emptying of solids, accommodation, and postprandial symptoms are unclear. Effects of four dose levels of the oral CCK-1 agonist GI181771X and placebo on gastric functions and postprandial symptoms were compared in 61 healthy men and women in a randomized, gender-stratified, double-blind, double-dummy placebo-controlled, parallel group study. Effects of 0.1, 0.5, and 1.5 mg of oral solution and a 5.0-mg tablet of GI181771X on gastric emptying of solids by scintigraphy, gastric volume by [sup.99m]Tc-single photon emission computed tomographic imaging, maximum tolerated volume of Ensure, and postprandial nausea, bloating, fullness, and pain were studied. On each of 3 study days, participants received their randomly assigned treatment. Adverse effects and safety were monitored. There were overall group effects of GI181771X on gastric emptying (P < 0.01) and fasting and postprandial volumes (P = 0.036 and 0.015, respectively). The 1.5-mg oral solution of GI181771X significantly delayed gastric emptying of solids (P < 0.01) and increased fasting (P = 0.035) gastric volumes without altering postprandial (P = 0.056) gastric volumes or postprandial symptoms relative to placebo. The effect of the 5.0-mg tablet on gastric emptying of solids did not reach significance (P = 0.052). Pharmacokinetic profiles showed the highest area under the curve over 4 h for the 1.5-mg solution and a similar area under the curve for the 0.5-mg solution and 5-mg tablet. Adverse effects were predominantly gastrointestinal and occurred in a minority of participants. GI181771X delays gastric emptying of solids and exhibits an acceptable safety profile in healthy participants. CCK-1 receptors can be modulated to increase fasting gastric volume. accommodation; single photon emission computed tomography; satiation; fasting

To compare the effects of the [kappa]-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake (P = 0.03). Asimadoline decreased colonic tone during fasting (P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension (P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension (P = 0.03) and pain scores at distensions of 8 and 16 mmHg (P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted. sensation; visceral; stomach; colon; barostat

Colonic transit is slowed in patients with disordered rectal evacuation, but the mechanism of this phenomenon is unclear. Our objective was to investigate rectocolonic inhibitory reflexes in humans to provide potential insight into patients with obstructed defecation. In 30 healthy subjects, a barostat-manometric assembly recorded colonic tone and phasic activity in the descending colon during rectal distension and recorded rectal tone during colonic distension. Phasic distensions were 8, 16, and 32 mmHg above balloon operating pressure, and staircase inflations were comprised of balloon inflation then deflation in 2-mmHg increments at 30-s intervals from 0 to 36 mmHg. Colonic balloon volumes increased to a similar extent during phasic rectal distensions 8, 16, and 32 mmHg above operating pressure, reflecting reduced colonic tone; balloon volumes also increased and phasic pressure activity decreased during staircase rectal distensions. In contrast, rectal balloon volume declined, reflecting increased tone during phasic and staircase colonic distensions. Thus rectal distension inhibited colonic motor activity, indicative of a viscerovisceral inhibitory reflex. obstructed defecation; colonic transit

Viramontes, Blanca E., Allison Malcolm, Michael Camilleri, Lawrence A. Szarka, Sanna McKinzie, Duane D. Burton, and Alan R. Zinsmeister. Effects of an [alpha]2-adrenergic agonist on gastrointestinal transit, colonic motility, and sensation in humans. Am J Physiol Gastrointest Liver Physiol 281: G1468-G1476, 2001.--To characterize [alpha]2-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. clonidine; compliance; transit; [alpha.sub.2]-adrenoreceptor Received 24 April 2001; accepted in final form 18 July 2001