2003 Fiscal Year Final Research Report Summary
Roles of c-kit in development and pathophysiology of smooth muscle
| Project/Area Number |
13670091
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Kumamoto University |
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Principal Investigator |
TOKUTOMI Yoshiko KUMAMOTO University, Grad.Sch.Med.Sci., Instructor, 大学院・医学薬学研究部, 助手 (90253723)
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| Co-Investigator(Kenkyū-buntansha) |
TOKUTOMI Naofumi KUMAMOTO University, Grad.Sch.Med.Sci., Associate Professor, 大学院・医学薬学研究部, 助教授 (30227582)
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| Project Period (FY) |
2001 – 2003
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| Keywords | smooth muscle / c-kit / mouse / contraction / intracellular Ca^<2+> / pacemaker / α_1-acid glycoprotein |
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| Research Abstract |
Drug-induced contraction of gastrointestinal tracts seems to depend upon the extent of their rhythmic contraction that is driven by the activity of gastrointestinal pacemaker cells. In BALB/c mice chronically administered with a neutralizing anti-c-Kit monoclonal antibody (ACK2), rhythmic contraction of gastrointestinal tract was impaired and contractile responses to drugs., including acetylcholine, prostaglandin F_<2α> and bradykinin were anomalously augmented. Histochemical analysis of the c-kit positive cells in the gastrointestinal tract revealed the decreased number of c-kit positive cells in the ACK2-treated animals, which lead to the impaired rhythmic contraction. Since the intestinal c-kit positive cells in primary culture developed Ca^<2+>-dependent rhythmic Cl^-current, the rhythmic current is supposed to be an origin of gastrointestinal pacemakers. The extent of anomaly in drug-induced contraction correlated with the extent of impairment in rhythmic contraction. The anomalou
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s drug-induced contraction in the preparation from ACK2-treated animals, which is accompanied by the impaired rhythmic contraction, was mimicked when the gastrointestinal segments from control animals were superfused with a low temperature organ bath solution at 25℃. These results suggest that rhythmic discharge of excitation of smooth muscle cells, which is triggered by rhythmic excitatory input from c-kit cells, regulates the extent of drug-induced contraction.
We have demonstrated that human α_1-acid glycoprotein produces a transient relaxation in the mouse aorta precontracted with phenylephrine. It is more likely that the α_1-acid glycoprotein-induced relaxation is due to block of Ca^<2+>-entry through VDCC or NSCC in the smooth muscle cells rather than activation of endothelial NO pathway. The transient relaxation induced by α_1-acid glycoprotein might occur as prolonged relaxation in the peripheral blood vessel, which may result in improvement of the blood circulation at tissue with inflammation. Less
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