Shawn C. Leming

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 mucosalsubmucosal (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.

GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs

Background  GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated.

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.