1998 Fiscal Year Final Research Report Summary
Involvement of LDL cholestetol in the diabetes-induced cascular dysfunction)
| Project/Area Number |
09670110
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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 | Hosei University |
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Principal Investigator |
KAMATA Katsuo Hoshi University, Inst.Med., 医薬品化学研究所, 助教授 (40121496)
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| Co-Investigator(Kenkyū-buntansha) |
SUENAGA Hiroshi Hoshi University, Inst.Med.Chem., Research Assistant, 医薬品化学研究所, 助手 (70277698)
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| Project Period (FY) |
1997 – 1998
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| Keywords | diabetes / streptozotocin / LDL cholesterol / Ca^<2+> / superoxide dismutase / superoxide anion / endothelin-1 / prostanoid |
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| Research Abstract |
I have investigated possible involvement of LDL cholesterol and endothelin-1 on an impaired endothelium-dependent relaxation of the vessels from streptozotocin (STZ)-induced diabetic rats and mice.
1) Streptozotocin increases plasma glucose levels. The low concentration of insulin and the high plasma glucose concentration then increase the concentration of plasma LDL cholesterol, and the increased LDL concentration may cause down-regulation of the expression of LDL.Long-term, a high plasma glucose concentration also reduces the expression of Mn2^<+-> superoxide dismutase mRNA and the activity of superoxide dismutase in the aorta. The decreased superoxide dismutase may inactivate NO and oxidize LDL, leading to the accumulation of oxidized LDL which may impair the activity of the endothelium, thereby resulting in the observed endothelial dysfunction.
2) I have demonstrated a weaker ACh-induced influx of Ca2^<2+> into the aortic endothelium of STZ-induced diabetic mice and that the decrease
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d influx of Ca2^<2+> can be restored to normal by the chronic administration of cholestyramine. LPC reduced the influx of Ca2^+ into the endothelium and 0a2^+ release from storage in aortae from normal mice, suggesting that LPC may affect Ca2^+ mobilization in the endothelium.
3) I found marked increases not only in plasma glucose but also in the plasma ET-1 level in STZ-induced diabetic rats. The decreased contractile response and the increased vasodilator response of the mesenteric arterial bed to ET-1 seen in diabetic rats may be due pnmarily to a desensitization of ETA receptors, though ET8 receptor are also desensitized. This desensitization may be a consequence of the elevation in the plasma endothelin-1 level seen in STZ-induced diabetic rats.
4) The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was impaired in mesenteric arterial beds from diabetic rats.An increased production of PGI_2 and decreased formation of TXA_2 may be responsible for the attenuation of the methoxamine-induced mesenteric vasoconstriction seen in diabetic rats. On the basis of the present resuhs, we propose that changes in prostanoid turnover in the diabetic state may be partly responsible for the lower blood pressure seen in our diabetic rats. Less
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