Effect of novel motilide ABT-229 versus erythromycin and cisapride on gastric emptying in dogs.

ABT-229 (8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine. The objective of this study was to determine the effect of ABT-229 on canine gastric emptying (GE) and contractile activity of the antrum and duodenum in response to a solid meal. Six beagles were used to determine GE of a solid meal and contractile activity in response to either vehicle, ABT-229 (0.17, 0.83, 2.5, or 5.0 microg/kg/min), ERY (33.3 microg/kg/min), or cisapride (CIS) (10 microg/kg/min). Lag (t(lag)), half-emptying (t(1/2)), and complete emptying (t(full)) times were determined. Contractile data were analyzed for motility index and gastroduodenal coordination. Compared with vehicle, ABT-229 dose dependently accelerated GE, t(lag) was decreased at the two highest doses, t(1/2) was decreased compared with vehicle at the three highest doses, and t(full) was decreased at all doses compared with vehicle. ERY also decreased t(1/2) and t(full), whereas CIS decreased all GE parameters. The slopes of the linear phase of GE curves for all drugs and doses were greater than those for vehicle. ABT-229 dose dependently increased the motility index as well as gastroduodenal coordination. ABT-229 (two highest doses) and CIS accelerated GE of a solid meal by decreasing the lag phase and increasing the rate of GE, whereas ERY only increased the rate of GE. The data suggest that ABT-229 is 7- to 40-fold more potent than ERY in accelerating GE.

Interaction between blood flow and motility in normal and inflamed ileum.

The alterations in local and superior mesenteric blood flow during ileal inflammation and their correlations with motility in the normal and the inflamed ileum were investigated in the conscious state. Ileal inflammation decreased the local mesenteric blood flow but had no significant effect on the superior mesenteric blood flow. A significant reduction or an increase in local mesenteric blood flow in the normal or the inflamed ileum had no effect on local contractile activity. The vascular reactivity to vaso-dilators and vaso-constrictors was significantly reduced during inflammation. Local mesenteric blood flow increased significantly in the descending segment ahead of a caudal propagating giant migrating contraction. The local mesenteric blood flow oscillated during a migrating motor complex (MMC) cycle. We conclude that a several-fold increase or decrease in local mesenteric blood flow lasting for several minutes does not affect contractility. Ileal inflammation decreases local mesenteric blood flow but does not affect the total blood flow to the small intestine.

Postprandial motor activity and its relationship to transit in the canine ileum.

BACKGROUND: The purpose of this study was to elucidate the mechanism of reduced intestinal transit rate in the ileum as compared with the jejunum. METHODS: Twenty-one dogs were each instrumented with 12 strain gauge transducers, 2 collection cannulas, and an infusion catheter defining a 100 cm study in the midjejunum (n = 11) and midileum (n = 10). Postprandial motor activity and intestinal transit were measured 1 hour after ingestion of a 650 kcal solid meal. Contractile activity was analyzed by means of computer programs that determine frequency, amplitude, and propagation behavior of circular smooth muscle contractions. RESULTS: Postprandial ileal contractions occurred with greater frequency (13.7 +/- 2.5 versus 11.5 +/- 0.4; p = 0.04) and displayed a higher incidence of propagation (61% +/- 2% versus 44% +/- 3%; p = 0.0001) than jejunal contractions, but traveled at significantly slower rates (1.0 +/- 0.7 cm/sec vs 3.7 +/- 0.9 cm/sec; p = 0.0001). The net result was significantly slower transit in the ileum compared with the jejunum (4.7 +/- 0.7 cm/min versus 13.1 +/- 1.5 cm/min; p = 0.0006). Within each region, transit correlated with parameters of propagating contractions. Stepwise regression of the combined data revealed that contraction velocity was the most important variable determining intestinal transit rate (r = 0.64; p < 0.001). CONCLUSIONS: Contrary to previous thinking, postprandial ileal contractions display a high degree of temporal and spatial organization. Slow ileal transit is mainly due to reduced propagation velocity, which is intrinsic to the circular smooth muscle.

Vasopressin responses to corticotropin-releasing factor and hypertonicity after truncal vagotomy in dogs.

Infusion of corticotropin-releasing factor (CRF) augments the plasma vasopressin response to infusion of hypertonic saline in conscious dogs. Furthermore, afferent vagal nerve input from the abdomen is involved in the control of vasopressin release and may be altered by CRF. The purpose of the present study was to characterize the effect of CRF on the vasopressin response to hypertonic saline and to determine if it is mediated by afferent input carried from the abdominal vagus. Conscious male dogs (n = 5) underwent infusion of isotonic saline (vehicle), CRF (10 or 20 ng.kg-1.min-1), hypertonic saline (0.2 mmol.kg-1.min-1), or the combination of CRF and hypertonic saline. Hypertonic saline increased plasma sodium from 147 +/- 1 to 153 +/- 1 meq/1 and plasma vasopressin from 2.5 +/- 0.1 to 5.8 +/- 0.4 pg/ml. CRF infusion alone had no effect on plasma vasopressin. The addition of 10 or 20 ng.kg-1.min-1 CRF augmented the vasopressin response to hypertonic saline to 7.7 +/- 1.7 and 6.9 +/- 0.3 pg/ml, respectively. Truncal vagotomy did not attenuate the vasopressin response to hypertonic saline with or without CRF infusion. We conclude that CRF augments the vasopressin response to hypertonic saline and that this effect is not mediated via afferents from the abdominal vagus.

Nonopioid analgesics shorten the duration of postoperative ileus.

Morphine inhibits propagating and stimulates nonpropagating colon contractions in monkeys and humans. The use of morphine or other opioids that inhibit propulsive contractions prolongs postoperative ileus. In contrast, ketorolac tromethamine, a nonsteroidal analgesic, has no effect on colon contractions in monkeys. In 14 patients having elective abdominal operations, bipolar electrodes were implanted on the right (n = 13) and left (n = 10) colon. Group A (n = 8) received ketorolac, 30 mg IM q6h, for pain relief. Group B (n = 6) needed supplemental morphine, 2-10 mg IV or IM, plus ketorolac to control their pain. Myoelectric activity was recorded from each subject on postop Days 1-5 and analyzed by computer for electrical control activity (ECA), short and long electrical response activity (ERA), and propagation of long ERA. There was a difference between the two groups in return of propagated long ERA bursts that correlated with clinical recovery from postoperative ileus. Postoperative analgesia with ketorolac resulted in faster resolution of ileus compared to morphine plus ketorolac because opioid-induced motor abnormalities in the colon were avoided.

Human colonic smooth muscle electrical activity during and after recovery from postoperative ileus.

Colon smooth muscle electrical control (ECA) and response activities (ERA) were recorded for up to 4 wk postoperatively for 48 patients after major abdominal operations. Bipolar electrodes were implanted into right and left colon circular muscle and exteriorized through the flanks, and signals were tape recorded for 2-24 h daily beginning on the 1st postoperative day. A computer program was used for data reduction and analysis. Recorded signals were digitized and filtered. The ECA frequency components were identified by fast Fourier transformation, and their relative tenancy in low, mid, and high frequency ranges was determined. Short and long ERA burst duration and frequency and number and velocity of propagating long ERA bursts were determined. ECA was omnipresent and exhibited a downshift of the dominant frequency from the mid to the low range as recovery from postoperative ileus progressed. Concurrently, first in the right and then in the left colon, the frequency of long ERA bursts increased, followed by the appearance of propagating long ERA. After the 6th postoperative day, no further significant changes in parameters of colon electrical activity occurred with time.

Opioid and nonopioid analgesic drug effects on colon contractions in monkeys.

Opioid drugs administered postoperatively for pain relief cause increased frequency of nonpropulsive phasic contractions but decreased to absent propulsive migrating contractions in the colon, thus importantly influencing the duration of postoperative ileus. Ketorolac is thought to permit earlier return of bowel function postoperatively compared to morphine. Four monkeys had sets of three strain gauge force transducers implanted on the right and left colon at laparotomy. After recovery, animals were fasted overnight and had colon contractions recorded. After a 1-hr baseline period, 200 micrograms/kg morphine sulfate or 1 mg/kg ketorolac tromethamine was injected intramuscularly and recording continued. Each animal received four injections of each drug. Records were analyzed visually for frequency of phasic on migrating contractions. There was no difference in the frequency of phasic or migrating contractions after injection of ketorolac. Morphine, as expected, increased the frequency of phasic and decreased the frequency of migrating contractions in the colon. Ketorolac does not affect the frequency of colon contractions.

Effects of transection and reanastomosis on postprandial jejunal transit and contractile activity.

BACKGROUND: The purpose of this study was to determine how transection and reanastomosis of the intestinal wall influences postprandial motor activity and transit in the small intestine. METHODS: Six dogs were each instrumented with 12 strain gauge transducers, two collection cannulas, and an infusion catheter defining a 100 cm study segment in the midjejunum. The animals underwent baseline measurements of postprandial motor activity and transit rate after 650 kcal solid and liquid meals. Postprandial motor activity was analyzed by computer methods that identify frequency, duration, amplitude, and propagation behavior of smooth muscle contractions. After the baseline measurements were performed, each animal underwent transection and reanastomosis of the intestinal wall at sites marked during the initial laparotomy. Measurements of postprandial motor activity and transit were repeated and compared with control values. RESULTS: Transection decreased frequency, amplitude, and percent propagation for postprandial contractions. Total propagating area per minute significantly decreased from 382 +/- 20 gram-seconds/minute to 190 +/- 66 gram-seconds/minute after transection (p < 0.05). Intestinal transit decreased from 13.5 +/- 1.5 cm/min to 8.5 +/- 2.4 cm/min (p < 0.05). The change in transit was related primarily to a change in frequency of propagating contractions (r = 0.767; p = 0.004). CONCLUSIONS: Transection and reanastomosis of the intestinal wall changes the temporal and spatial organization of contractions distal to the transection site. The net result is fewer distally propagating contractions and slower intestinal transit.

Identification and characterization of the esophagoglottal closure reflex in a feline model.

To identify a suitable animal model and to delineate the neural pathway and target organs of the esophagoglottal closure reflex we studied three species. Study showed the existence of an esophagoglottal closure reflex in cats. The presence of this reflex could not be documented in the opossum. In monkeys, because of the inadequacy of the available recording devices, its presence could not be ascertained. In the feline model, the closure response of the vocal folds to the abrupt generalized and segmental distension of the esophagus was similar to that of the humans. Study findings indicate that among glottal adductor muscles at least interarytenoid and lateral cricoarytenoid muscles are involved as target organs of the esophagoglottal closure reflex. Decerebration did not change the frequency of glottal closure response to esophageal distension, supporting the notion that this reflex is completely under brain stem control. Bilateral cervical vagotomy abolished the glottal closure induced by esophageal distension indicating that this reflex is mediated by the vagus nerve. Upper esophageal sphincter (UES) pressure response to esophageal distension by air was variable, suggesting that glottal and UES response to esophageal distension, although closely coordinated, are not dependent on one another. In summary, an esophagoglottal closure reflex exists in feline species, and many similarities in the elicitation and mediation of this reflex have been found with that of humans. This model could be used for further physiological studies.

Motor activity and transit in the autonomically denervated jejunum.

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

Nitric oxide regulates migrating motor complex cycling and its postprandial disruption.

We investigated the role of nitric oxide (NO) in the regulation of migrating motor complex (MMC) cycling during the fasting state and its postprandial disruption. Intravenous infusion of N omega-nitro-L-arginine methyl ester (L-NAME) first produced a premature MMC and then disrupted MMC cycling for the rest of the day. The cycle length of the MMCs was significantly shorter than the control on the 2nd, 3rd, and 4th day after L-NAME infusion. The gastric cyclic motor activity (CMA) did not usually exhibit a premature cycle on the day of L-NAME infusion but was disrupted by L-NAME infusion; the duration of CMA disruption in the stomach was significantly longer than that of MMC disruption in the small intestine. Infusion of N omega-nitro-L-arginine (L-NNA) exhibited similar effects. The intravenous infusion of L-NAME also significantly shortened the duration of MMC disruption by a meal. L-Arginine alone had no significant effect on gastrointestinal motor activity during the fasting or the fed state, but when infused with L-NAME, it blocked the effects of NO synthase inhibition. Angiotensin II increased the mean arterial pressure to a level similar to that produced by L-NAME but had no significant effect on the fasting or the fed pattern of gastrointestinal motor activity. We conclude that NO containing nonadrenergic noncholinergic (NANC) neurons play a significant role in regulating MMC and CMA cycling during the fasting state and their disruption by a meal. However, NO may not be the only NANC neurotransmitter to inhibit contractions in the gut; phase I activity in the small intestine persisted during NO synthase inhibition by L-NAME or L-NNA.

Selective adrenergic agonists and colon motility in monkeys.

Sympathetic stimulation during and after laparotomy and other surgical procedures may be a factor inducing postoperative ileus. In experiments conducted in fasting monkeys, the effects of the selective sympathetic agonists alpha 1 (phenylephrine), alpha 2 (ST-91), beta 1 (dobutamine), and beta 2 (terbutaline) on colon contractile activity were measured. Strain gauges were implanted on the colon. Recordings were made for 1 hour (control) and then for an additional hour during continuous infusion by one of a range of doses of each drug (experimental). The drug doses were chosen to cover both physiologic and pharmacologic concentrations. All of the sympathetic agonists caused a dose-dependent decrease in the frequency of colon contractions. The beta-agonists did so at a concentration that is sufficiently low to support a hypothesis that beta-stimulation leading to inhibition of smooth-muscle contraction may play an important role in the genesis of postoperative ileus.

Arginine vasopressin inhibits phasic contractions and stimulates giant contractions in monkey colon.

Abdominal cramps and urgent defecation are common side effects of clinical doses of arginine vasopressin, indicating that the drug may have stimulating effects on colonic motor activity. Four strain-gauge transducers were implanted on the colon in six monkeys. A blood flow probe was fixed on the inferior mesenteric artery. After a 1-hour control recording, vasopressin, 0.13, 1.3, or 13.0 ng.kg-1.min-1, was infused intravenously for 90 minutes. The frequency of basal colonic contractions was reduced with increasing doses of vasopressin, but their mean amplitude and duration were not altered. Giant migrating contractions associated with defecation were initiated by the highest dose of vasopressin. Atropine had no effect on these giant migrating contractions but completely inhibited normal phasic contractions. Hexamethonium completely inhibited both giant migrating contractions and phasic contractions. Parasympathetic denervation of the colon did not inhibit giant migrating contractions initiated by vasopressin. Our findings suggest that the physiological concentrations of serum vasopressin present perioperatively may transiently inhibit spontaneous colon contractions but are unlikely to be the major cause of postoperative ileus. The giant migrating contractions initiated by vasopressin may account for the defecation associated with pharmacological doses of vasopressin. The initiation of giant migrating contractions by vasopressin may be mediated through a neural pathway.

Vagal influence on colonic motor activity in conscious nonhuman primates.

We investigated the role of the vagi in modulation of colonic motor activity in the fasted and fed states and determined the extent of vagal influence on colon motility in conscious monkeys. Monkeys were implanted with force transducers on the colon. A vagal cooling chamber was implanted supradiaphragmatically, and a vagal stimulating electrode was implanted just distal to the chamber. One week was allowed for recovery. After an overnight fast, control recordings were made for 1 h, and then the monkeys were either fed or remained fasting, with or without adrenergic blockade (propranolol and phentolamine). Then while recordings continued the vagi were cooled to their predetermined denervation temperature for 1 h. In a second set of experiments, adrenergic blockers were injected, and the vagi were stimulated during vagal cooling with or without atropine administration. In both the fasted and fed states, the contractile frequency was decreased during vagal cooling, with or without adrenergic blockade. With adrenergic blockade, however, the frequency of colon contractions was greater during cooling than during cooling without such blockade. Inhibition of colonic contractions during cooling decreased in magnitude from the proximal to the distal colon. Vagal efferent stimulation increased contractile frequency at all sites, but after atropine it decreased contractile frequency. We conclude that the vagi have either a direct or indirect influence on fasting and fed colonic motor activity throughout the colon, and that a nonadrenergic, noncholinergic inhibitory pathway is under vagal control.

Morphine effects on human colonic myoelectric activity in the postoperative period.

Colonic myoelectrical activity was studied in 25 patients, 18 of whom received morphine sulfate, using bipolar electrodes placed in the ascending and descending colon during laparotomy. Baseline myoelectrical activity was recorded daily, then morphine (3 to 15 mg) was administered intravenously, intramuscularly, or epidurally, and recordings continued. Seven activity patterns were observed during recovery from postoperative ileus. During the first 2 postoperative days, morphine at any dose did not affect colon myoelectrical activity. From the third postoperative day on, morphine given intravenously or intramuscularly initiated clusters of short, nonmigrating, phasic spike bursts occurring on each successive slow wave in 14 of 18 patients, which lasted for 30 to 45 minutes. When morphine was administered epidurally, there was no colonic response in any patient. These findings suggest that: (1) morphine intravenously or intramuscularly induces predominantly nonmigrating colonic spike bursts; (2) morphine-induced activity alters the normal pattern of colonic motility during recovery from postoperative ileus; and (3) these phenomena are not due to direct action of morphine on the spinal cord since epidural morphine had no effect.

Trichinella spiralis infection alters small bowel motor activity in the fed state.

The effect of Trichinella spiralis infection on small intestinal transit and motor activity in the fed state during the intestinal phase of infection was studied. Contractions were recorded by strain gauge transducers, and mean transit time was measured by marker dilution technique. The mean amplitude and area of individual phasic contractions decreased, but no change occurred in their mean duration during trichinosis. The total amplitude and area of phasic contractions also decreased; this was caused by a decrease in the frequency of contractions as well as a decrease in the mean parameters. The reduction in the total duration was entirely caused by the decrease in frequency. The reduction in the total parameters of all contractions was the result of a reduction in the same parameters for both propagating and nonpropagating contractions. However, the decrease in the parameters of propagating contractions was much greater. Also, there was a decrease in the distance of propagation of phasic contractions. The transit time as a result of phasic contractions increased during T. spiralis infection. Additionally, T. spiralis infection induced giant migrating contractions in the fed state that were never observed during control. Chyme was propelled very rapidly and effectively by giant migrating contractions. The findings of the present study suggest that during diarrhea induced by T. spiralis infection, the phasic contractions may act to decrease transit and, hence, allow more contact time for absorption of water and nutrients. However, this response may be counter-balanced by giant migrating contractions that rapidly propel chyme into the colon and compound the diarrhea associated with T. spiralis infection.

Effect of T. spiralis infection on intestinal motor activity in the fasted state.

We sought to determine the effects of Trichinella spiralis infection on small intestinal motor activity in the fasted state in dogs and relate it to clinical symptoms during the intestinal phase of trichinosis. Motor activity was recorded by strain gauge force transducers. Infection with T. spiralis resulted in a significant increase in the incidence and proximal origination of giant migrating contractions (GMCs) during the first 5 days postinfection. This was also the time when the dogs had diarrhea. The dogs were often restless and showed signs of discomfort during proximally originating GMCs. The incidence of retrograde giant contractions (RGCs) increased significantly on the 2nd and 3rd day postinfection. RGCs were followed by vomiting 71% of the time during infection. The migrating motor complex cycle length increased significantly, and this was due to intestinal "amyogenesia" and "dysmyogenesia". During these phenomena, electrical control activity was almost completely obliterated in the proximal half of the small intestine (amyogenesia) and became irregular and unstable in the distal half (dysmyogenesia). Intestinal amyogenesia and dysmyogenesia lasted up to 4 h and were terminated by a GMC. We conclude that diarrhea induced by T. spiralis infection is closely associated with an increase in the incidence and proximal origin of GMCs. These GMCs may also be the motor correlates of abdominal cramping and pain during the intestinal phase of trichinosis.

Relation between small intestinal motor activity and transit in secretory diarrhea.

Our objective in this study was to correlate small intestinal motor activity with transit time in the fed state under normal conditions and in the secretory state induced by cholera toxin. In the control state, transit time was strongly and inversely correlated with the mean distance of propagation and to a lesser degree with frequency and total duration of all contractions. By contrast, transit time was not correlated with total amplitude and area of all contractions. When contractions were separated into propagating and nonpropagating contractions, there was a highly significant inverse correlation between transit time and all parameters of propagating contractions but no relation with any parameter of nonpropagating contractions. Similar results were obtained during the secretory state induced by cholera toxin. The control data were used to develop a mathematical model to predict transit time from contractile parameters and was validated using the data obtained in the secretory state. Our findings demonstrate that transit through the small intestine in the normal and secretory states is strongly related to the parameters of propagating contractions but not to parameters of nonpropagating contractions.