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.
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