1990 Fiscal Year Final Research Report Summary
Molecular Mechanism and its Clinical Significance of Abnormalities in Voltage-Sensitive Calcium Channel in the Diabetic Heart.
| Project/Area Number |
01570357
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
内科学一般
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| Research Institution | Third Department of Medicine, Shiga University of Medical Science |
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Principal Investigator |
KASHIWAGI Atsunori Shiga University of Medical Science, the Third Department of Medicine, Assistant Professor, 医学部, 講師 (20127210)
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| Project Period (FY) |
1989 – 1990
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| Keywords | Diabetes Mellitus, / Diabetic Myocardiopathy, / Protein Kinase C / Voltage-Sensitive Calcium Channel, / Calcium Channel Blocker / Intracellular Free Calcium, / Energy-Disperse X-Ray Microanalysis / Abnormal Regulation of Intracellular Calcium |
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| Research Abstract |
Voltage operated calcium channel (VOCC) and intracellular calcium deposition were evaluated in cardiac muscle isolated from diabetic rats in order to identify calcium over-loading in diabetic cardiac myocytes. (1) Intramitochondrial calcium deposition in diabetic ventricular myocytes : collaboration with Dr Mizuhira of the Shionogi research laboratory, intracelluar calcium deposition was measured using the oxalate-pyroantimonate precipitation method , the microwave fixation method and energy-disperse X-ray microanalysis on electron microscope. Intramitochondrial calcium content in the diabetic group increased by 48% as compared with the control and the increase was marked in abnormally swollen mitochondria with disintegrated cristae which were marked in diabetic cardiac muscle. (2) Abnormalities in cardiac membrane VOCC in diabetes : Cardiac plasma membrane VOCC was measured using [3H]PN220-110, a dihydropyridine calcium channel blocker. An increase in the maximum binding site of [3H]P
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N200-110 was found in 6-wk-diabetic rats and the increase reached to 64% above the control in 10-wk-diabetic rats without any change in Kd for the binding. The [3H]PN200-110 binding to cardiac membrane fraction isolated from diabetic rats was less sensitive to verapamil effect. (3) Abnormalities in skeletal muscle membrane VOCC and intracellular calcium deposition : Using energy-disperse X-ray microanalysis, the increases in both intra-mitochondria and sarcoplasmic reticular calcium content were shown in soleus muscle obtained from diabetic rats. Furthermore, tissue calcium content which was measured by atomic absorption analysis also significantly increased in soleus muscle in diabetic rats as compared to the control. The maximum [3H]PN200-110 binding to skeletal muscle membrane fraction in the diabetic group significantly increased by 91% above the control without any change in the affinity of the binding. (4) The effect of calcium channel blocker on protein kinase C (PKC) activity in diabetic cardiac muscle : Both membrane-bound and soluble PKC activities in diabetic cardic muscle increased by 41 and 94% above the control, respectively. The increase in PKC in diabetic cardiac muscle was completely normalized by in vivo verapamil treatment. These results indicate that intracelluar calcium overloading in cardiac muscle may be associated with diabetic myocardiopathy. Less
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