| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
1) Streptozotocin increases plasma glucose levels. Relationships between the plasma ET-1 level and the levels of other plasma constituents (glucose, cholesterol, and triglyceride) were found in 10-week streptozotocin (STZ)-induced diabetic rats. In contrast, at one week after the STZ injection only plasma ET-1 and glucose levels were elevated, suggesting that the hyperglycemia but not cholesterol might trigger the excess production of ET-1.
2) We investigated the effects of chronic pravastatin treatment on the impaired endothelium-dependent relaxation seen in aortae from established STZ-induced diabetic rats. The enhanced level of malondialdehyde (MDA)-modified LDL seen in STZ-induced diabetic rats was normalized by pravastatin treatment. LDL isolated from diabetic rats, but not those from pravastatin-treated diabetics, showed enhanced the susceptibility to oxidation, but incubation in vitro with pravastatin had no effect on LDL oxidation. Following incubation of control aortae for 6 hr
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with LDL (0.1mg protein mL-1) isolated from diabetic rats, the endothelium-dependent relaxation to acetylcholine was impaired, but LDL isolated from control or pravastatin-treated rats had no such effect. This inhibitory effect of diabetic LDL was prevented by superoxide dismutase (SOD), a superoxide scavenger. These results suggest that pravastatin preserves endothelial function in aortae from STZ-induced diabetic rats without lowering plasma cholesterol, and its effect may be due to decreased LDL oxidation.
3) Aortae from diabetic rats, but not those from high-insulin-treated diabetic rats, showed an impaired endothelium-dependent in response to acetylcholine (ACh) by comparison with untreated controls.In the combined presence of the nitric oxide inhibitor NG-nitro-L-arginine and the cyclo-oxygenase inhibitor indomethacin, NA-induced contractility was significantly greater in aortae from high-insulin-treated diabetic rats than in those from controls or untreated diabetic rats. An increased expression of the mRNA for the α_<1D> and α_<1B> adrenergic receptors was found in aortae from high-insulin-treated diabetic rats. These results demonstrate that in rats with established STZ-induced diabetes, high-insulin treatment prevents the development of an impaired endothelium-dependent relaxation in the aorta, and that such treatment enhances NA-induced contractility. This enhancement may be related to an upregulation in the expression of the mRNA for the α_<1B> or α_<1D> adrenergic receptor that is secondary to the hyperinsulinaemia. Less
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