Physiological studies suggest that dopaminergic mechanisms are important in the regulation of gastrointestinal motility. However, little is known about dopamine receptors in the gastrointestinal (GI) tract. In man dopamine inhibits motility in the upper gut, but stimulates motility in the colon. These contrasting effects on motor activity suggest the presence of heterogenous populations of dopaminergic receptors in the GI tract. Our preliminary studies indicate that the inhibitory effect of dopamine is mediated via two mechanisms: (a) DA1 receptors on smooth muscle cells mediating muscle relaxation, and (b) a second type of dopamine receptor located on postganglionic cholinergic neurons which inhibits the release of acetylcholine. In contrast, the stimulatory effect of dopamine appears to be mediated by DA2 receptors on presynapatic postganglionic sympathetic neurons which inhibit the release of norepinephrine. We propose to demonstrate the operation of the above pathways in different regions of the gut and test the hypothesis that the dual action of dopamine on gastrointestinal motility reflects regional differences in the distribution of peripheral DA1 and DA2 receptors. To investigate the mechanisms through which dopamine acts in different regions of the GI tract, pharmacological studies will be performed on innervated and denervated muscle strips obtained from the stomach, intestine and colon of guinea pig and man. Specific DA1 and DA2 agonists and antagonists will be used at varying concentrations to construct Schild plots to characterize dopamine receptor subtypes. Specific dopamine receptors on smooth muscle will be identified and characterized using isolated smooth muscle cells to establish binding and biological action of dopamine. We also propose to demonstrate the role of dopamine mediating GI motility via postganglionic sympathetic and cholinergic neurons. Specific dopamine agonists and antagonists will be used to determine the dopamine receptor subtypes which regulate the release of 3H-acetylcholine and 3H-norepinephrine from muscle strips obtained from different regions of the gut. These studies will demonstrate the participation of both myogenic and neural mechanisms responsible for dopaminergic modulation of gastrointestinal motility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035783-03
Application #
3234033
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1986-05-01
Project End
1990-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Lien, Han-Chung; Sun, Wei Ming; Chen, Yen-Hsueh et al. (2003) Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. Am J Physiol Gastrointest Liver Physiol 284:G481-9
Gonlachanvit, Sutep; Chen, Yen Hsueh; Hasler, William L et al. (2003) Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins. J Pharmacol Exp Ther 307:1098-103
Bjornsson, Einar S; Chey, William D; Hooper, Forrest et al. (2002) Impaired gastrocolonic response and peristaltic reflex in slow-transit constipation: role of 5-HT(3) pathways. Am J Physiol Gastrointest Liver Physiol 283:G400-7
Sun, W M; Hasler, W L; Lien, H C et al. (2001) Nizatidine enhances the gastrocolonic response and the colonic peristaltic reflex in humans. J Pharmacol Exp Ther 299:159-63
Jednak, M A; Shadigian, E M; Kim, M S et al. (1999) Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy. Am J Physiol 277:G855-61
Bjornsson, E S; Chey, W D; Ladabaum, U et al. (1998) Differential 5-HT3 mediation of human gastrocolonic response and colonic peristaltic reflex. Am J Physiol 275:G498-505
Gorelick, A B; Koshy, S S; Hooper, F G et al. (1998) Differential effects of amitriptyline on perception of somatic and visceral stimulation in healthy humans. Am J Physiol 275:G460-6
Kim, M S; Chey, W D; Owyang, C et al. (1997) Role of plasma vasopressin as a mediator of nausea and gastric slow wave dysrhythmias in motion sickness. Am J Physiol 272:G853-62
Hasler, W L; Soudah, H C; Owyang, C (1996) Mechanisms by which octreotide ameliorates symptoms in the dumping syndrome. J Pharmacol Exp Ther 277:1359-65
Walsh, J W; Hasler, W L; Nugent, C E et al. (1996) Progesterone and estrogen are potential mediators of gastric slow-wave dysrhythmias in nausea of pregnancy. Am J Physiol 270:G506-14

Showing the most recent 10 out of 32 publications