Effects of 3-days' intake of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate, on oesophageal motility.

BACKGROUND: Nitric oxide plays an important role in gastrointestinal motility. We evaluated the effects of a sustained-release preparation of the nitric oxide donor isosorbide dinitrate on swallow-initiated oesophageal contractions and the lower oesophageal sphincter. METHODS: Twelve healthy men, aged 23-32 years, received, at 1-week intervals and under random double-blind conditions, for 3 days either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate or placebo twice daily (b.d.). One hour after a further dose on day 4, oesophageal motility was recorded for 30 min using a multilumen catheter with a Dent sleeve straddling the lower oesophageal sphincter and side-hole openings 0, 3, 6 and 9 cm proximal to the sleeve. Contractile responses to twelve 5-mL water swallows were evaluated. RESULTS: Amplitude, duration, propagation velocity and onset latency of oesophageal contractions were not affected by either dosage of isosorbide dinitrate. Lower oesophageal sphincter resting pressure was significantly lower after 40 mg (15.1 mmHg +/- 1.2 S.E.M.) and 20 mg isosorbide dinitrate b.d. (15.0 +/- 1.0 mmHg) than after placebo (17.9 +/- 1.7 mmHg; P < 0.025). Headache was reported by all subjects on 40 mg isosorbide dinitrate, seven subjects on 20 mg and by one on placebo. CONCLUSIONS: Twenty and 40 mg sustained-release isosorbide dinitrate twice daily had no effect on swallow-initiated oesophageal contractions but decreased lower oesophageal sphincter resting pressure.

Gastric emptying of semisolid meal unaltered by 3 days' administration of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate.

BACKGROUND: Evidence has accumulated that nitric oxide is involved in the regulation of gastrointestinal motor activity. We investigated whether nitric oxide derived from a sustained-release isosorbide dinitrate (Cedocard retard) had an effect on gastric emptying and on subjective feelings. METHODS: Twelve healthy males aged 23-32 years received at weekly intervals, for 3 days twice daily, either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate, or placebo, under random double-blind conditions. After a further dose on day 4, subjects ate a 1168 kJ semisolid meal, the emptying of which was recorded scintigraphically for 50 min. RESULTS: Neither dosage of isosorbide dinitrate had an effect on emptying which differed from the effect of placebo and the effects of the two dosages were the same. The radioactivity remaining in the stomach 50 min postprandially was 68.5% +/- 4.5 S.E.M. after placebo, 65.4 +/- 5.6% after 20 mg isosorbide dinitrate and 66.1 +/- 4.4% after 40 mg isosorbide dinitrate. With 40 mg isosorbide dinitrate, all 12 subjects complained of persistent headache, whereas only slight headache was reported by 7 subjects on 20 mg isosorbide dinitrate and by 1 subject on placebo. CONCLUSION: Twenty and 40 mg doses of sustained-release isosorbide dinitrate twice daily had no effect on the gastric emptying of a semisolid meal, but dose-dependently induced headaches.

Sublingual nitroglycerine: effects on contractile activity of the distal oesophagus and lower oesophageal sphincter in healthy men.

BACKGROUND AND AIMS: Nitric oxide plays an important role in the control of gastrointestinal motility. This study assessed the effects of graded doses of the nitric oxide-releasing agent, nitroglycerine, on distal oesophageal motor activity and lower oesophageal sphincter resting pressure. METHODS: Eight healthy young men received at 1-week intervals placebo, 0.2 mg, 0.4 mg or 0.8 mg nitroglycerine sublingually under random double-blind conditions. Sphincter pressure was recorded using a Dent sleeve and oesophageal motility using sensors 1, 4, 7 and 10 cm orad the sleeve during two 15-min periods before and four 15-min periods after drug administration. In minutes 4 to 6 of each period, subjects swallowed 5 mL water at 30 s intervals. RESULTS: After 0.2 mg and 0.4 mg nitroglycerine, amplitude, duration and area under curve of swallow-initiated contractions were smaller than after placebo. After 0.8 mg nitroglycerine, amplitude, duration and area under curve were slightly greater than after placebo and significantly greater than after the lower nitroglycerine doses. No effects were discernible on onset latency and propagation velocity of contractions as well as on lower oesophageal sphincter resting pressure. CONCLUSIONS: Sublingual nitroglycerine had modest, dose-dependent effects on oesophageal peristaltic amplitude and duration, but did not affect the tone of the lower oesophageal sphincter.

Effects of the prodrug loperamide oxide, loperamide, and placebo on jejunal motor activity.

This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.

Lack of systematic effects of the 5-hydroxytryptamine 3 receptor antagonist ICS 205-930 on gastric emptying and antral motor activity in patients with primary anorexia nervosa.

1. The 5-hydroxytryptamine 3 receptor antagonist, ICS 205-930, has been reported to have potent effects on gastric smooth muscle and to enhance gastric emptying in animals, but findings in man have been inconsistent. 2. This study investigated the effects of ICS 205-930 on gastric emptying of an isotopically labelled semisolid 1168 kJ meal and on antral contractility in patients with primary anorexia nervosa, a condition frequently associated with impaired gastric motor function. 3. Thirteen female patients (age 18-39 years, median 22 years; percentage of ideal body weight 52-90%, median 66%) participated each in two studies, in which 0.15-0.18 mg kg-1 ICS 205-930 or placebo were infused i.v. in crossover, double-blind fashion. Gastric emptying and antral contractility were recorded scintigraphically for 50 min. 4. ICS 205-930 did not affect gastric emptying: the mean percentage of meal remaining in the stomach after 50 min (69.6% +/- 3.2 s.e. mean) was nearly identical to that after placebo (70.7 +/- 3.3%). 5. Amplitude, frequency and propagation velocity of antral contractions differed only little after ICS 205-930 and placebo, respectively. 6. The results show that ICS 205-930 has no effect on the impaired gastric motor activity in primary anorexia nervosa and thus provide further evidence that the compound does not have prominent prokinetic effects in man.

Effects of the 5-HT3 receptor antagonist, ICS 205-930, on oesophageal motor activity and on lower oesophageal sphincter pressure: a double-blind cross-over study.

The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has potent effects on gastrointestinal motor activity in vitro and in vivo. This double-blind, crossover study compared the effects of 20 mg of ICS 205-930 infused intravenously with those of a placebo on the motor activity of the oesophageal body and the lower oesophageal sphincter (LOS). Each of twelve healthy young men participated in two recording sessions one week apart. Oesophageal pressures were recorded using a catheter assembly with orifices 2, 5, 8, 11, and 14 cm above the oral border of the LOS and a Dent sleeve for measurement within the LOS. During and after the infusion of ICS 205-930, amplitude and duration of swallow-initiated contractions in the smooth muscle oesophagus increased slightly, the area under the curve as a measure of contraction strength being significantly greater than after placebo (P less than 0.05). LOS resting pressure increased slightly during ICS 205-930 infusion and was significantly higher than it was in the case of the placebo (P less than 0.001). Propagation velocity of contractions, incidence of tertiary contractions and relaxation of LOS upon swallowing remained unaffected. ICS 205-930 was well tolerated. It is concluded that ICS 205-930 has slight but distinct stimulatory effects on contraction strength in the smooth muscle oesophagus and LOS resting pressure.

Effects of the 5-HT3 receptor antagonist ICS 205-930 on fat-delayed gastric emptying and antral motor activity.

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.

Effects of a 5-hydroxytryptamine3 receptor antagonist (ICS 205-930) on colonic motor activity in healthy men.

1. ICS 205-930 (Sandoz) is a selective antagonist at 5-hydroxytryptamine3 receptors and exerts marked effects on gastrointestinal motility in animals. 2. This study investigated, under random double-blind conditions, the effects of 10 and 20 mg ICS 205-930 infused intravenously in comparison with placebo on colonic motor activity. 3. Twelve healthy men participated each in three studies in which they received, in random double-blind fashion, each of the treatments. Colonic pressures were recorded pneumohydraulically with four catheter orifices 20-40 cm from the anal verge. Treatments were administered after a basal 30 min. One hour later, subjects ingested a 4200 kJ meal and 90 min thereafter, 1 mg neostigmine was administered intramuscularly and recording continued for another 90 min. 4. After both doses of ICS 205-930, the number of contractions as averaged over the entire recording time was slightly but significantly higher than after placebo. 5. After 10 mg but not after 20 mg ICS 205-930, amplitude of contractions and area under the curve as averaged over the entire recording time were significantly higher than after placebo. 6. ICS 205-930 induced few and mild side effects, but significantly more self-rated drowsiness and tiredness than placebo.

Effects of cisapride on postcibal jejunal motor activity.

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisapride's effects on the fed pattern of the jejunum. Starting 5 min after a phase 3 of the migrating motor complex, 18 healthy men received 5 or 10 mg cisapride or placebo orally in random double-blind fashion and ingested meals containing 1000 and 4200 kJ, respectively. Jejunal pressures were recorded pneumohydraulically with five catheter orifices 10-30 cm aboard the ligament of Treitz. After the 4200-kJ meal, total number and number of propagated contractions as well as area under the curve increased significantly more than after 1000 kJ. Following the 1000-kJ but not the 4200-kJ meal, 10 mg cisapride increased total number of contractions, number of propagated contractions, mean amplitude, and area under curve significantly more than placebo. Fed-pattern duration increased with the meal's caloric content but was not influenced systematically by cisapride. In conclusion, cisapride stimulates jejunal motor activity and induces a propagative pattern after a 1000-kJ but not after a 4200-kJ meal, suggesting that it can produce no further stimulation when motor activity is near maximally enhanced already.

Effects of graded oral doses of a new 5-hydroxytryptamine/noradrenaline uptake inhibitor (Ro 15-8081) in comparison with 60 mg codeine and placebo on experimentally induced pain and side effect profile in healthy men.

1. Ro 15-8081 (Hoffmann-La Roche, Basle, Switzerland) is a novel mixed 5-HT/noradrenaline uptake inhibitor producing potent antinociceptive effects in animal pain models. 2. In healthy man, two models with electrically and thermally induced pain, respectively, have been shown to reliably discriminate between the effects of opioid as well as of antipyretic analgesics and placebo. 3. This study investigated the effects of single oral doses of 10, 25, and 50 mg Ro 15-8081 in comparison with 60 mg codeine and placebo on threshold and tolerance to electrically induced pain and on threshold to thermally induced pain. Furthermore, the effects on psychomotor function, self-rated subjective feelings, and side effect profile were studied. 4. Twenty healthy males participated each in five experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised two series of measurements before and twelve after drug administration, carried out at 30 min intervals. 5. Ro 15-8081 produced marked elevations of threshold and tolerance to electrically and of threshold to thermally induced pain. The effects of all doses of Ro 15-8081 were significantly superior to those of placebo. Threshold and tolerance to electrically induced pain were not affected differently by the three doses of Ro 15-8081, whereas the threshold to thermally induced pain was elevated significantly more by 50 mg than by 10 and 25 mg Ro 15-8081. 6. Codeine 60 mg had a more rapid onset of action and greater maximal effects than Ro 15-8081.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral cisapride on interdigestive jejunal motor activity, psychomotor function, and side-effect profile in healthy man.

Intravenous cisapride was shown to induce a phase-2-like pattern of human interdigestive jejunal motor activity containing an increased number of propagated contractions. This study investigated the effects of oral cisapride in 12 fasting healthy males. Jejunal pressures were recorded by a pneumohydraulic system and five catheter orifices positioned 10-30 cm aborad the ligament of Treitz. Single oral doses of 5 and 10 mg cisapride, administered 5 min after an activity front under random double-blind conditions, induced a phase-2-like jejunal motor pattern with a significantly higher number and amplitude of contractions and significantly more aborally propagated waves than placebo (P less than 0.001), while the number of subjects with activity fronts decreased with increasing dose. Five and 10 mg cisapride administered tid for three days affected psychomotor function, subjective feelings, and side-effect frequency, apart from increases in systolic blood pressure and heart rate, no more than placebo. It is concluded that in fasting man, oral cisapride induces a highly propagative phase-2-like jejunal motor pattern causing only minor side effects.

Effects of cisapride on jejunal motor activity in fasting healthy humans.

The effects of cisapride on jejunal interdigestive motor activity were studied in 12 healthy men participating in three experiments each. Five minutes after an activity front (phase III) they received, in random double-blind fashion, 10 mg of cisapride, 4 mg of cisapride, or saline placebo by intravenous injection. Motor activity was recorded for 4 h. A pneumohydraulic perfusion system and five catheters with orifices positioned 10-30 cm beyond the ligament of Treitz were used. Cisapride increased phase II-type activity (p less than 0.001) and reduced the number of activity fronts dose-dependently. Compared with phase II after placebo, the activity prevailing after cisapride was characterized by a significantly higher number and amplitude of contractions as well as by a significantly greater area under the pressure curve. Moreover, a significantly higher proportion of contractions was propagated aborally. Self-rated abdominal grumbling increased dose-dependently. Except for mild sedative effects, no side effects occurred. We conclude that cisapride induces a prolonged and highly propagative phase II-like jejunal motor activity in fasting humans.

Experimental pain induced by electrical and thermal stimulation of the skin in healthy man: sensitivity to 75 and 150 mg diclofenac sodium in comparison with 60 mg codeine and placebo.

Models with experimentally induced pain in healthy man might be useful for the screening for analgesic effects of new drugs. Experimental pain models have been shown to discriminate reliably between the effects of opioid analgesics and placebo but their sensitivity to nonsteroidal anti-inflammatory agents is disputed. This study investigated whether it would be possible by using electrically and thermally induced cutaneous pain to discriminate reliably the effects of single oral doses of 75 and 150 mg diclofenac sodium on the one hand and 60 mg codeine on the other from those of placebo. Forty-eight healthy subjects participated each in four experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised eight series of measurements, two before and six after drug administration, carried out at 30 min intervals. Diclofenac sodium produced significant dose-related increases of threshold and tolerance to electrically and threshold to thermally induced pain. Codeine 60 mg was significantly superior to placebo in all pain measures. Its analgesic effects were stronger than those of diclofenac 75 mg but weaker than those of diclofenac 150 mg. Neither 150 mg nor 75 mg diclofenac caused more side effects than placebo, whereas codeine 60 mg elicited a high frequency of side effects. No severe adverse effects occurred after any one treatment. The results suggest that both electrically and thermally induced cutaneous pain are well suited to evaluate analgesic effects not only of opioids but also of nonsteroidal anti-inflammatory drugs.

Ceruletide increases dose dependently both jejunal motor activity and threshold and tolerance to experimentally induced pain in healthy man.

The effects of ceruletide on jejunal motility and experimentally induced pain were studied in 16 healthy men, who participated each in four experiments and received in random double blind fashion 5, 10, or 20 micrograms ceruletide intramuscularly or placebo. Jejunal pressures were recorded by three perfused catheters with orifices between 10 and 20 cm aboral of the ligament of Treitz. Ceruletide dose dependently diminished phase I and increased phase II type activity and tended to reduce the number, but not the duration, of activity fronts. The number and amplitude of contractions as well as the area under the curve increased significantly and dose dependently as did threshold and tolerance to electrically and threshold to thermally induced pain. Only mild sedative and other side effects occurred.

Effects of graded oral doses of meptazinol and pentazocine in comparison with placebo on experimentally induced pain in healthy humans.

The opioid agonist/antagonist meptazinol has proven to exert significant analgesia in a series of painful conditions. This study investigated the effects of single oral doses of meptazinol 100, 200, and 400 mg in comparison with pentazocine 50 and 100 mg and with placebo on experimentally induced pain. In addition, the side effect profiles were assessed. Twenty-four healthy subjects participated each in six experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised 10 series of measurements, two before and eight after drug administration, carried out at 30 min intervals. Meptazinol produced significant dose-related increases of threshold and tolerance to electrically and thermally induced pain. Meptazinol 400 mg was significantly superior to placebo in all pain measures and proved as effective as pentazocine 50 and 100 mg, which yielded about equal effects. Meptazinol 200 mg was significantly weaker than pentazocine 50 mg and differed significantly from placebo only in its effects on pain tolerance. Meptazinol did not cause any severe side effects or systematic alterations of respiration, blood pressure, heart rate and central nervous functions. Pentazocine caused a higher number and more severe side effects, one subject reporting severe dysphoria after pentazocine 100 mg. The results give further evidence that meptazinol is well suited to replace other opioid analgesics compromised by a high incidence of adverse effects.

Dose-related effects of the synthetic met-enkephalin analogue FK 33-824 on esophageal motor activity in healthy humans.

The effects of FK 33-824, a methionine enkephalin analogue, 313, 625, 1250, 2500, and 5000 ng/kg body wt intramuscularly, on esophageal motor activity and cardiovascular and central nervous functions were studied in 8 healthy men. In the lower one-third of the esophagus, amplitude and duration of swallow contractions increased dose-dependently within 15 min after administration. In the middle one-third, amplitudes increased only slightly, whereas no systematic changes occurred in the upper one-third. The propagation velocity of the deglutitive wave accelerated dose-dependently between 15 and 10 cm as well as between 10 and 5 cm above the lower esophageal sphincter, the acceleration being more pronounced in the distal segment. Heart rate and systolic and diastolic blood pressure increased dose-relatedly, while no effects were found on electroencephalogram and reaction time. These results, together with earlier findings, support the notion of a participation of enkephalins in the regulation of the smooth muscle esophagus.

Ceruletide increases threshold and tolerance to experimentally induced pain in healthy man.

UNLABELLED: Previous studies suggested that ceruletide might be endowed with analgesic and sedative properties. To investigate the effects of ceruletide on experimentally induced pain and on central nervous functions, two studies, each involving 24 healthy subjects, were carried out in random double-blind fashion. Every subject participated in three experiments one week apart. In study 1, 120 and 60 ng/kg/hr ceruletide IV increased threshold and tolerance to electrically and threshold to thermally induced cutaneous pain significantly more than saline (p less than 0.001), the higher dose being slightly more active. Only mild sedative effects occurred. Study 2 compared the effects of 60 and 6 ng/kg/hr ceruletide IV to those of 0.4 mg/kg/hr pentazocine IV and investigated whether these effects were naloxone reversible. Both ceruletide doses, 60 ng/kg/hr slightly more than 6 ng/kg/hr, elevated threshold and tolerance to electrically induced and threshold to thermally induced pain markedly, pentazocine acted stronger and longer than ceruletide (p less than 0.001). Naloxone reversed the effects of pentazocine but not of ceruletide. CONCLUSION: ceruletide (1) exerts potent naloxone resistant analgesic effects, which, however, are inferior to those of pentazocine, and (2) produces only mild sedation.

Ceruletide decreases food intake in non-obese man.

Cholecystokinin decreases food intake in animals and in man. This study investigated whether the structurally related ceruletide reduces food intake in healthy non-obese man. Twelve females and 12 males participated, after an over-night fast, in each of two experiments. During the basal 40 min, saline was infused IV. Thereafter, the infusion was, in random double blind fashion, either continued with saline or switched to 60 or 120 ng/kg b. wt/hr ceruletide. Butter was melted in a pan and scrambled eggs with ham were prepared in front of the subjects, who were instructed to eat, together with bread and mallow tea, as much as they wanted. With 120 ng/kg/hr ceruletide, the subjects ate significantly less (16.8 percent) than with saline (3725 kJ +/- 489 SEM and 4340 kJ +/- 536, respectively; p less than 0.025). They also reported less hunger (p less than 0.005) and activation (p less than 0.005) and activation (p less than 0.01), and had longer reaction times (p less than 0.01) and a weaker psychomotor performance (p less than 0.025). 60 ng/kg/hr ceruletide decreased food intake only slightly (6.6%; 3089 kJ +/- 253 and 3292 kJ +/- 300 respectively) and no significant changes in the above measures occurred. In conclusion, ceruletide reduces food intake in man, thus resembling the effects of cholecystokinin.

Cholecystokinin octapeptide decreases intake of solid food in man.

Cholecystokinin octapeptide (CCK-OP) was reported to decrease the intake of liquid food in lean and in obese man. This study investigated the effect of CCK-OP on the consumption of real life food, i.e., of standardized sandwiches. Sixteen young non-obese females and males participated, after an overnight fast, each in two experiments. After a basal 30 min, saline or CCK-OP, 1.5 or 3.0 Ivy Dog Units/kg body weight/15 min, was infused in random double blind fashion, while sandwiches were placed in front of the subjects. For the next three 15-min periods, the subjects were instructed to eat as much as they liked. In the first 15 min after 3.0 as well as 1.5 U CCK-OP/kg/15 min significantly fewer sandwiches (50 and 17 percent) were eaten than after saline (p less than 0.01 and p less than 0.05) and less hunger was reported (p less than 0.02 and p less than 0.05). Self-reported activation decreased only with 3.0 U CCK-OP (p less than 0.005). Reports of well-bring , electroencephalogram, heart rate, and respiration were not altered. The results support the notion that CCK is involved in the regulation of food intake.

Stimulatory effects of the synthetic enkephalin analogue FK 33-824 on colonic motor activity antagonized by naloxone.

Enkephalins inhibit guinea pig ileum contractions in vitro; in vivo they increase gastric contraction strength and small intestinal spike activity in dogs and stimulate tonic and phasic contractile activity of the human colon. This study investigated the question as to whether the stimulatory effect of the synthetic met-enkephalin analogue FK 33-824 on the human colon is antagonized by the narcotic antagonist naloxone. On 3 experimental days 12 healthy young males received in random order (a) 4 mg (subjects 1-6) or 10 mg (subjects 7-12) naloxone i.v. followed by 1 mg FK 33-824 i.m., (b) saline i.v. followed by 1 mg FK 33-824 i.m. and (c) saline i.v. followed by saline i.m. FK 33-824 following saline produced a rapid increase of tonic intraluminal pressure (mean increase: 9.9 +/- 2.5 SEM mmHg; P less than 0.001), an increase in contractions from 1.6 +/- 0.4 to 3.3 +/- 0.8 per min (P less than 0.001), a shift in the dominant frequency of rhythmic contractions from 1.0 +/- 2.5 to 2.5-3.5 cycles per min, an increase in the amplitude of contractions from 10.1 +/-0 2.1 to 15.0 +/- 3.2 mmHg (P less than 0.01), and in the sum of the amplitudes as an overall measure of contractile activity from 148.6 +/- 36.7 to 482.9 +/- 136.9 mmHg (P less than 0.01). All effects lasted for more than 70 min; peak changes occurred in the first 15 min and subsided slowly in intensity. The effects of FK 33-284 were greatly attenuated by premedication of 4 mg naloxone, and abolished, at least for 15-30 min, by 10 mg naloxone. Saline caused no changes. It is concluded that the stimulatory effects of FK 33-824 on human colonic motility are antagonized by naloxone.