Propagation of giant migrating contractions between the small intestine, cecum and colon during radiation.

BACKGROUND: Radiation increases the frequency of small intestinal and colonic giant migrating contractions (GMCs). These contractions contribute to the diarrhea and cramping after radiation therapy and are coordinated with one another across the ileocolonic (IC) junction. METHODS: We investigated the coordination of contractile activity between the small intestine, cecum and colon in five canines following circumferential myotomy on the ileum at the IC junction and compared it to intact animals. Studies were performed before and during a radiation schedule. KEY RESULTS: Myotomy increased the frequency of small intestinal GMCs prior to irradiation. In intact animals, the duration and amplitude of cecal GMCs decreased when multiple contractions occurred in rapid succession. This is in contrast to small intestinal and colonic GMCs and suggests a different mechanism of propagation for GMCs within the cecum. Ileal myotomy dramatically decreased the frequency of propagating radiation-induced colonic GMCs. The total number of colonic GMCs was not altered. Colonic contractile activity was disrupted in intact animals during irradiation. However, after ileal myotomy, irradiation did not affect the pattern of colonic contractile states. Diarrhea in irradiated animals with myotomy started earlier than intact animals. This may be related to the frequency of small intestinal GMCs. CONCLUSIONS & INFERENCES: Our findings suggest importance of the enteric neural connections at the IC region to contractile disorders of both the small and large intestine. The anatomic relationship between the canine IC junction is similar to the human ileo-appendiceal-colonic region and surgical manipulations of this area may likewise affect human contractile activity.

Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition.

BACKGROUND: Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiological requirements and pathophysiological demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as antiangiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease (IBD). The effect of curcumin on human intestinal angiogenesis is not defined. METHODS: The antiangiogenic effect of curcumin on in vitro angiogenesis was examined using primary cultures of human intestinal microvascular endothelial cells (HIMECs), stimulated with vascular endothelial growth factor (VEGF). RESULTS: Curcumin inhibited proliferation, cell migration and tube formation in HIMECs induced by VEGF. Activation of HIMECs by VEGF resulted in enhanced expression of cyclo-oxygenase-2 (COX-2) mRNA, protein and prostaglandin E(2) (PGE(2)) production. Pretreatment of HIMECs with 10 microM curcumin as well as 1 microM NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE(2) production. Similarly COX-2 expression in HIMECs was significantly inhibited by Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (MAPK; SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor (PD098059). CONCLUSIONS: Taken together, these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMECs via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE(2) production, suggesting that this natural product possesses antiangiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.

Radiation induced small bowel "web" formation is associated with acquired microvascular dysfunction.

BACKGROUND AND AIMS: Radiation therapy of abdominal and pelvic solid tumours results in late intestinal toxicity of a severe nature in approximately 5% of cases. These manifestations may include ischaemia and stricture formation, which may present as "webs". These webs are likely to play a role in the pathogenesis of recurrent bowel obstruction. The mechanisms of microvascular injury to the bowel in the setting of radiation have not been defined. We hypothesised that microvascular dysfunction with impaired vasodilation to acetylcholine (Ach) would be an acquired pathophysiological abnormality in radiation and "web" formation. METHODS: A 40 year old patient treated with radiation, two years previously, for an anal squamous cell cancer presented with recurrent small bowel obstruction. "Webs" in the distal ileum were detected using wireless capsule endoscopy, after small bowel barium radiographs failed to demonstrate a lesion. Following resection, freshly isolated 50-150 mum diameter arterioles from the "web" and adjacent normal calibre bowel were analysed with histology and microvessel physiological studies. RESULTS: After constriction (30-50%) with endothelin, dilation to graded doses of Ach (10(-9)-10(-4) M) was observed in vessels dissected from the stricture and the adjacent normal calibre area. Ach dilation was reduced in vessels from "web" (mean diameter 7 (2)%; n = 3, p < 0.01) compared with the adjacent unaffected bowel (mean diameter 85 (5)%). Dihydroethidine and dichlorofluorescein diacetate intravital staining demonstrated increased reactive oxygen species production in microvessels from "web" compared with adjacent normal calibre bowel. Histology from the strictured bowel demonstrated narrowing of the arterial lumen due to intimal and muscularis propria fibrosis, with endothelial preservation. CONCLUSIONS: External radiation is associated with acquired microvascular endothelial dysfunction and "web" formation in the small bowel.

Deficient iNOS in inflammatory bowel disease intestinal microvascular endothelial cells results in increased leukocyte adhesion.

Microvascular endothelial cells play a key role in inflammation by undergoing activation and recruiting circulating immune cells into tissues and foci of inflammation, an early and rate-limiting step in the inflammatory process. We have previously [Binion et al., Gastroenterology112:1898-1907, 1997] shown that human intestinal microvascular endothelial cells (HIMEC) isolated from surgically resected inflammatory bowel disease (IBD) patient tissue demonstrate significantly increased leukocyte binding in vitro compared to normal HIMEC. Our studies [Binion et al., Am. J. Physiol.275 (Gastrointest. Liver Physiol. 38):G592-G603, 1998] have also demonstrated that nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) normally plays a key role in downregulating HIMEC activation and leukocyte adhesion. Using primary cultures of HIMEC derived from normal and IBD patient tissues, we sought to determine whether alterations in iNOS-derived NO production underlies leukocyte hyperadhesion in IBD. Both nonselective (N(G)-monomethyl-L-arginine) and specific (N-Iminoethyl-L-lysine) inhibitors of iNOS significantly increased leukocyte binding by normal HIMEC activated with cytokines and lipopolysaccharide (LPS), but had no effect on leukocyte adhesion by similarly activated IBD HIMEC. When compared to normal HIMEC, IBD endothelial cells had significantly decreased levels of iNOS mRNA, protein, and NO production following activation. Addition of exogenous NO by co-culture with normal HIMEC or by pharmacologic delivery with the long-acting NO donor detaNONOate restored a normal leukocyte binding pattern in the IBD HIMEC. These data suggest that loss of iNOS expression is a feature of chronically inflamed microvascular endothelial cells, which leads to enhanced leukocyte binding, potentially contributing to chronic, destructive inflammation in IBD.

Nitric oxide production is diminished in colonic circular muscle from acquired megacolon.

PURPOSE: Nitric oxide modulates human colonic smooth muscle function. To determine whether nitric oxide production is altered in colon from acquired megacolon, we measured cholinergic nerve-mediated contractions in vitro before and after inhibition of nitric oxide synthase. METHODS: Intramural nerves in circular smooth muscle from histologically normal colon (n = 12) and acquired megacolon (n = 3) were activated by electrical field stimulation. RESULTS: In controls blockade of nitric oxide synthase by N(G)-Nitro-L-Arginine induced increases (P < 0.05) in amplitude of contractions; these increases in amplitudes were blocked by L-Arginine (analysis of variance; P < 0.05). By contrast, blockade of nitric oxide synthase did not increase amplitudes of contractions with circular smooth muscle from acquired megacolon. An immediate phasic contraction was blocked by atropine sulfate. CONCLUSIONS: The results support the concept that nitric oxide production modulates cholinergic nerve-mediated contractions in normal colonic circular muscle, whereas acquired megacolon is associated with altered release of this inhibitory neurochemical. Potential explanations include depletion of tissue L-Arginine, decreased capacity to recycle citrulline to arginine, or decreased release of vasoactive intestinal peptide from circular smooth muscle in acquired megacolon.

Decreased vasoactive intestinal peptide levels and glutathione depletion in acquired megacolon.

We reported decreased vasoactive intestinal peptide levels in acquired megacolon. The origin of altered neuropeptide levels is unknown, but recent work suggested that tissue antioxidants may function as neuroprotectants. Our hypothesis was that altered levels of inhibitory neurotransmitters in human colon are associated with depletion of the tripeptide thiol, glutathione. Normal colon samples (N = 10; from patients 41-80 years old) and acquired megacolon samples (N = 10; from patients 31-98 years old) were obtained at surgery. Vasoactive intestinal peptide levels were decreased in muscularis externa from acquired megacolon (P = 0.01), while there was a modest increase in NADPH diaphorase activity in muscularis externa from megacolon (P = 0.10). Glutathione in acquired megacolon was detectable in muscularis externa from only five specimens (P < 0.05), but was not significantly different (P > 0.05) in the mucosal-submucosal layer. The results supported the presence of vasoactive intestinal peptide and NADPH diaphorase in distinct subpopulations of nerves in human colon. The results also supported the hypothesis that glutathione functions as a neuroprotectant in a subset of patients with acquired megacolon.

Multidisciplinary management of altered body image in the patient with an ostomy.

Many clinical studies have found patients with ostomies to be a group facing multiple adjustment demands. One of these demands is coping with a significant change in body image. At the Medical College of Wisconsin, a team approach has been initiated; the ET nurse, the psychologist, and the surgeon deal with body image concerns together. Problems requiring counseling have included difficulty with personal acceptance, personal and social body-image disruption, sexual concerns, reduced self-care skills, and the management of surgical complications. This article represents a study employing a methology of selected case presentations. Cases were chosen to outline the types of problems encountered and were selected from referrals made for psychologic intervention by the surgeon and ET nurse. The patients included four women and three men, ranging in age from 22 to 79 years. Data were compiled by examining the records of the surgeon, ET nurse, and psychologist. The primary needs revolved around personal or social acceptance of altered body image. By addressing these needs in a straightforward, time-limited manner, postsurgical counseling was delivered effectively for these patients. In conclusion, we have demonstrated the multidisciplinary approach to be successful in facilitating adaptation to an altered body image.

Fractionated irradiation alters enteric neuroendocrine products.

Radiation profoundly alters the contractile activity of the small intestine and colon. We hypothesized that some motor changes of the gut might be secondary to impaired neural input to smooth muscle or abnormal release of gut endocrine peptides. The density of products within peptidergic and cholinergic nerves and gut endocrine cells was estimated in six normal controls and six dogs who had received 1500 cGy in six equal fractions of 250 cGy. Choline acetyltransferase, acetylcholinesterase, vasoactive intestinal peptide (VIP), substance P, peptide YY (PYY), and motilin were measured in tissue specimens divided into mucosal-submucosal (MS) and muscularis externa (ME) layers. Tissue samples were obtained from the duodenum, jejunum, ileum, and proximal and distal colon. In addition, serum levels of motilin and PYY were determined before and during the administration of 1500 cGy in four separate dogs instrumented to record upper gut contractile activity. Intrinsic cholinergic activity as estimated by choline acetyltransferase activity was unchanged, while acetylcholinesterase activity increased in the MS layers of distal small bowel and colon. VIP was increased in the MS layers of jejunum and proximal colon as well as in the ME layers the jejunum and ileum. By contrast, substance P increased in the jejunal and proximal colonic MS layers and in the ME layers of the jejunum and ileum. Duodenal and jejunal motilin levels markedly decreased after radiation exposure, while serum motilin levels continued to cycle at a decreased peak level with migrating motor complexes. Colonic PYY remained unchanged but serum PYY levels decreased after irradiation. Increased neuronal synthesis and inhibition of neurotransmitter release are potential explanations for elevated tissue concentrations of VIP, substance P, and acetylcholinesterase. There appeared to be differences in the sensitivity of gut endocrine cells to irradiation. Changes in gut regulatory peptides and cholinergic enzyme activity occur with fractionated doses of abdominal irradiation, while the same schedule of irradiation produces striking changes in the canine small intestinal and colonic motor activity. It is therefore likely that alterations of contractile events may be produced by changes in gut neuroendocrine products.

Expression of mRNA for vasoactive intestinal peptide in normal human colon and during inflammation.

The availability of colon provides a ready source of human neurons. Among the products of nerve cell bodies, vasoactive intestinal peptide is a neuropeptide that serves as a marker of non-adrenergic, non-cholinergic inhibitory nerves in colon. These nerves have been proposed to be involved in regulation of immune function, secretion, and smooth muscle function. In previous work, we identified decreased tissue levels of vasoactive intestinal peptide in a disorder of chronic colonic mucosal inflammation, ulcerative colitis. We hypothesized that diminished gene expression of vasoactive intestinal peptide could result in decreased tissue levels of this neuropeptide. Sigmoid colon was obtained at surgery from controls (n = 6) and patients with ulcerative colitis (n = 6). Vasoactive intestinal peptide mRNA was quantified by Northern blot hybridization and tissue levels of vasoactive intestinal peptide were determined by radioimmunoassay. Tissue vasoactive intestinal peptide was decreased only in the mucosal-submucosal layer of ulcerative colitis (p = .02). There was a single 1.7 kbase vasoactive intestinal peptide transcript identified in both control colon and ulcerative colitis. Normalized vasoactive intestinal peptide mRNA levels were increased by 260% in ulcerative colitis compared to controls (p < .01). These observations suggest that decreased vasoactive intestinal peptide gene expression or abnormal post-transcriptional processing are not primary defects in this disorder of chronic inflammation. The findings support the alternative hypothesis that axonal degeneration in ulcerative colitis could result in increased expression of neuronal vasoactive intestinal peptide mRNA.

Neural control of small intestinal giant migrating contractions.

We investigated the neural mechanisms of control of giant migrating contractions (GMCs) in five conscious dogs. After control recordings, a Thiry-Vella loop was prepared from the middle segment, and the remaining two segments were reanastomosed. GMCs were stimulated by intravenous administration of fentanyl and erythromycin lactobionate, oral administration of loperamide and erythromycin stearate, and gastric or intraluminal administration of cider vinegar in the loop. In the intact state, the agents stimulated GMCs in all three segments, and they propagated uninterruptedly from the point of their origin to the terminal ileum. The propagation velocity of GMCs increased, whereas that of migrating motor complexes (MMCs) decreased distally. After Thiry-Vella loop formation, the agents stimulated GMCs independently in the three segments, and they propagated only to the end of the segment in which they started. In the intact small intestine, the GMCs produced ascending and descending inhibition of spontaneous phase II contractions but did not interrupt the caudad propagation of the ongoing MMC. After Thiry-Vella loop formation, the ascending inhibition was unaltered, but the descending inhibition occurred only in the segment containing the GMC. We conclude that the propagation of GMCs in the small intestine is controlled by the enteric nerves. The extrinsic nerves control the ascending inhibition produced by GMCs, whereas the enteric nerves control the descending inhibition.

Altered motility causes the early gastrointestinal toxicity of irradiation.

PURPOSE: Total abdominal radiation produces symptoms of nausea, vomiting abdominal cramping and diarrhea. Each of these symptoms is associated with disordered intestinal motility. This article reviews studies of large and small intestinal contractile activity following radiation exposure. METHODS AND MATERIALS: Studies of motility utilize strain gauge transducers surgically implanted on the seromuscular layer of the small intestine. All studies were performed in mixed breed dogs to record the occurrence of normal contractions, giant migrating contractions (GMCs) and retrograde giant contractions (RGCs) before, during and after irradiation (22.5 Gy in 9 fractions at 3 fractions/week). Giant migrating contractions and retrograde giant contractions are infrequent in the healthy state. However, in diseased states, GMCs are associated with abdominal cramps and diarrhea, and RGCs precede vomiting. RESULTS: In fasted animals, fractionated abdominal irradiation dramatically increased the frequency of GMCs, with the incidence peaking after the second dose. The increased frequency of GMCS occurred as early as a few hours after the first radiation fraction, and returned to normal within days of cessation of radiation. RGCs were also significantly increased after abdominal irradiation. The frequency of RGCs was greatest on the first and sixth dose of radiation. Clinically, the dogs developed nausea, vomiting and diarrhea as early as the first day of irradiation. In dogs studied in the fed state, decreased amplitude, duration, and frequency of postprandial contractions occurred. These changes may slow intestinal transit during irradiation. Radiation also produced a striking increase in the frequency of colonic GMCs; these changes in colonic motor activity were associated with diarrhea as early as the second irradiation. CONCLUSION: Changes in GI motility during fractionated irradiation precede the appearance of histopathological lesions in the GI tract. Thus, the symptoms of nausea, vomiting, and diarrhea experienced during radiotherapy (particularly those within the first week) are directly related to changes in bowel motility. It is hoped that further understanding of the etiology of these distressing symptoms will help to guide their treatment.

Gene expression and transcript size of the prepro-peptide VIP/PHM-27 in normal human tissue.

The transcript size of VIP/PHM-27 mRNA (vasoactive intestinal peptide/peptide histidine methionine) and the relative distribution of VIP/PHM-27 gene expression in 10 normal human tissues was examined. After mRNA extraction from tissue, VIP/PHM-27 transcript size and relative abundance of mRNA was determined by Northern blot analysis and densitometry of the autoradiograms. VIP/PHM-27 mRNA was detectable in brain, pancreas, colon, ileum and striated muscle while no hybridization signal was observed in liver, kidney, lung, heart, prostate and placental tissue. VIP/PHM-27 transcript in human brain and gut was a single band of 1.7 kb; by contrast, a 7.0-kb transcript was detected in striated skeletal muscle. The highest relative levels of mRNA were observed in brain and pancreas.

Normal physiology of small intestinal motility.

The small intestine produces a number of different contractions in various spatial and temporal patterns that promote efficient digestion, absorption, and propulsion of ingested material. The small bowel also serves a protective role through the use of special situation contractions that rapidly propel enteric contents into the stomach or colon, from which they may be expelled. Contractile activity of the small intestine is coordinated by an interplay of myogenic, neural, and chemical controls.

Acquired megacolon is associated with alteration of vasoactive intestinal peptide levels and acetylcholinesterase activity.

Based upon previous morphologic studies, we hypothesized that the development of acquired megacolon was associated with abnormalities of enteric neurotransmitter concentrations and enzymatic activities. Specimens were obtained at surgery from patients with normal descending-sigmoid colon (n = 13) and patients with sigmoid megacolon (n = 6; defined by radiologic measurement). Radioimmunoassays were used to measure the non-adrenergic, non-cholinergic inhibitory neuropeptide, vasoactive intestinal peptide, and the non-adrenergic, non-cholinergic excitatory neuropeptide, substance P, while spectrophotometric assays were used to quantitate acetylcholinesterase activity and choline acetyltransferase activity. There were significantly decreased concentrations of vasoactive intestinal peptide and decreased acetylcholinesterase activity in muscularis externa from patients with acquired megacolon. In megacolon, vasoactive intestinal peptide-containing nerve fibers appeared to be diminished in circular and longitudinal smooth muscle, and immunostaining of nerve cell bodies in the plexus submucosus externus appeared diminished. These results suggest the hypothesis that production of vasoactive intestinal peptide is altered allowing secondary colonic hypertrophy to develop from prolonged cholinergic nerve-mediated contractions of circular smooth muscle. As a corollary to this hypothesis, colonic dilatation might result from prolonged contraction of longitudinal smooth muscle.

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.

Characterization of neuropeptides extracted from canine intestine.

Quantitative determination of neuropeptides in biologic tissues by radioimmunoassay requires both an efficient extraction of neuropeptides as well as maintenance of immunochemical reactivity. Vasoactive intestinal peptide, substance P, and met5-enkephalin were chosen for this study because they are neuropeptides which appear to be involved in multiple physiologic systems. Since all three neuropeptides have a methionine residue within their amino acid sequence, oxidation of methionine to methionine-sulfoxide during the extraction process could diminish their immunochemical reactivity. Multiple factors that might be important in extracting these neuropeptides from canine intestine, including pH of the solvent, tissue homogenization, heating, and addition of enzyme inhibitors, were examined. Concentrations of vasoactive intestinal peptide-like immunoreactivity and substance P-like immunoreactivity were significantly higher in acidic solvents, and tissue homogenization appeared to increase the concentrations of these two neuropeptides. Substance P-like immunoreactivity was increased by heating after tissue homogenization, suggesting heat-induced denaturation of tissue enzymes liberated by homogenization. Separation of acidic tissue extracts by high performance liquid chromatography followed by radioimmunoassay for all three neuropeptides revealed minor acid-induced oxidation of substance P. These results should be useful for planning the extraction of these three neuropeptides from other tissues.

Effects of fractionated doses of ionizing radiation on colonic motor activity.

The colonic motor effects of fractionated irradiation were studied in five conscious dogs. Seven colonic and two ileal strain gauge transducers were implanted. After control recordings, an abdominal dose of 250 cGy was administered three times a week on alternate days for three successive weeks (total dose 2,250 cGy). Recordings were then continued for 3 wk after the completion of radiation. Colonic giant migrating contractions (GMCs) occurred at a frequency of 0.15 +/- 0.05 contractions/h in the control state. Only one of these contractions (8.3%) originated in the small bowel and propagated into the colon. Abdominal field irradiation significantly increased the incidence of colonic GMCs to 0.51 +/- 0.11 contractions/h (P < 0.05). Fifty-four percent of GMCs originated in the small intestine. GMCs during the radiation schedule were associated with explosive diarrhea on seven occasions. Irradiation did not alter the frequency of colonic migrating motor complexes, but the mean duration of contractile states decreased in the middle and distal colon. Diarrhea occurred as early as the second dose of radiation. Pathological changes in the colon were correlated with motor activity. Both small intestinal and colonic GMCs reverted to control frequencies after cessation of radiation exposure. Abdominal irradiation significantly altered the contractile activity of the colon. These changes are associated with abdominal cramping and diarrhea.

Fractionated doses of ionizing radiation alter postprandial small intestinal motor activity.

We investigated the effects of total abdominal fractionated irradiation on postprandial small intestinal motor activity in five dogs. Five strain-gauge transducers were attached to the seromuscular layer of the duodenum, jejunum, and ileum of each dog to record circular muscle contractions. Radiation (250 cGy) was administered three times a week on alternate days for three successive weeks (total dose, 2250 cGy). Postprandial 4-hr recordings were made once each week during radiation and at one and three weeks following completion of radiation. Duodenal mean amplitude and area under contractions did not change during or following the radiation schedule, but the mean frequency and duration of duodenal contractions decreased during the radiation schedule. Both parameters returned to baseline values postirradiation. Jejunal mean duration, amplitude, area, and frequency of contractions decreased during radiation; mean amplitude and area returned to baseline values postirradiation but not the duration and frequency of contractions. All parameters of ileal contractions decreased during radiation, and all but area and amplitudes remained depressed postirradiation. Significantly decreased strength and frequency of contractions, particularly in the jejunum and ileum occur during and following irradiation. These changes may potentially alter transit time.

Gastrointestinal motor effects of erythromycin.

We studied the small intestinal motor effects of oral and intravenous (iv) erythromycin in 10 conscious dogs. After control recordings with placebo, oral or iv erythromycin was given at 40% of the migrating motor complex (MMC) cycle. Recordings were made after administration until normal contractile activity had returned or 12 h postdrug administration. Low doses initiated a premature MMC. High doses, however, prolonged the MMC cycle length. Erythromycin reduced the MMC propagation velocity at all doses. Both oral and iv erythromycin induced amyogenesia. During this pattern, electrical control activity was obliterated in the proximal and destabilized in the distal small intestine. Erythromycin also increased the incidence of retrograde giant contractions (RGCs) and vomiting. These effects occurred within the first 2 h after oral and within the first 30 min after iv administration. The incidence of giant migrating contractions (GMCs) increased significantly from 5 to 12 h but not from 0 to 5 h after administration. The distance of origination of GMCs from the ileocolonic junction was significantly increased from 5 to 12 h. The amplitude ratio, duration, and velocity of migration of GMCs induced after erythromycin were similar to control values. Clusters of coordinated antral and duodenal contractions also occurred early after administration. Our findings suggest that erythromycin has multiple motor effects on the stomach and small intestine. Diarrhea, abdominal cramping, and vomiting associated with erythromycin may be related to increased incidence of GMCs and RGCs. Erythromycin has a biphasic effect on MMC cycle length, initiating premature MMCs at low doses and prolonging their cycle length at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)