The overall objective of these studies is to understand the role of ion channels in the plasma membrane of smooth muscle cells in esophageal peristalsis. Nitric oxide is a major neurotransmitter in esophageal peristalsis, however the smooth muscle ion channel whose activity is mediated by NO has not been identified. Preliminary data suggest that NO modifies the activity of calcium-stimulated chloride currents (recently identified by the PI) to produce its physiological effects on esophageal muscle cells. NO may also alter a novel calcium- activated K channel that the PI has described in ilial muscle cells. The PI has also demonstrate that the actions of NO donors depend on the redox state of NO produced. Important preliminary data suggest that NO* is the redox form of the endogenous nitrergic neurotransmitter.
The aim of this application is to examine the actions of sodium nitroprusside (a NO+ donor), nitrocycteine ( a NO+ donor and putative EDRF), and amine/NO adducts ( NO* donors like DNO). Functional studies will be done to study single channel currents in cell-attached and excised membrane patches. Whole cells and perforated patch currents will be studied to characterize channel currents, the actions of NO donors, and signaling pathways. Molecular expression of the channel proteins in circular muscle will be done with in situ hybridization using cDNA and sequences of published Ca- Cl and Ca small conductance K channels. The effects of NO on single cells will be relate to nitrergic neurotransmission and physiology with microelectrode, mechanical studies and measurement of esophageal motility in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031092-22
Application #
6380458
Study Section
Special Emphasis Panel (ZRG2-NTN (01))
Program Officer
Hamilton, Frank A
Project Start
1981-09-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
22
Fiscal Year
2001
Total Cost
$427,151
Indirect Cost
Name
Harvard University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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