| Project/Area Number |
11670710
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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 |
Circulatory organs internal medicine
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| Research Institution | JIKEI UNIVERSITY SCHOOL OF MEDICINE |
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Principal Investigator |
SEKI Shingo Division of cardiology, Department of Internal Medicine, Jikei University School of Medicine Lecturer, 医学部, 講師 (70179323)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | calcium / Dahl rat / hypertrophy / heart failure / sodium-calcium exchanger / hypertrophy |
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| Research Abstract |
Objectives: The mechanisms responsible for the transition from cardiac hypertrophy to failure are poorly understood. Changes in intracellular Ca^<2+> handling were dynamically investigated in a wholeheart experimental model of pressure-overload hypertrophy and failure. Methods: We used 18 (hypertrophy) and 22-24 (failure) week-old male Dahl salt-sensitive rats (DS) and DahI salt-resistant rats (DR) fed a high-salt diet for 12 weeks. We monitored fura-2 fluorescence ratio, an index of the cytoplasmic Ca^<2+> concentration ([Ca24]i) using a Ca^<2+> analyzer in a retrograde perfused heart. Left ventricular pressure and electrocardiogram were simultaneously recorded. Ca^<2+> handling was assessed by exposing the hearts to 2 min of low-Na^<+> (70 mM) perfusion to increase [Ca^<2+>]i (n=6). The hearts were then stimulated at 2.5 to 5 Hz to determine the Ca^<2+>-force-frequency relationship (n=4). Resulls: Blood pressure was higher, and heart weight-to-body weight ratio was greater in hypertrophic DS than in DR. We confirmed the increase in [Ca24]i was dependent on Na^+/Ca^<2+> exchanger by assessing the effect of exchanger inhibitor KB-R7943 on [Ca^<2+>]i. The time-to-peak transient was prolonged in hypertrophic DS compared with that in DR during normal beating. During low-Na^+ exposure with and without 10 mM caffeine pretreatment (inhibition of SR), the time-to-peak diastolic [Ca^<2+>]i and the decaytime from peak [Ca^<2+>]i were prolonged in hypertrophic and failing DS compared with DR. The forcefrequency relationship was initially positive in DR but was negative at all times in hypertrophic DS. Elevation of diastolic [Ca^<2+>]i was greater in hypertrophic DS than in DR with increased stimulation. Conclusions: These results suggest that slowing of cellular Ca2^<2+> mobilization and removal is related to impaired Ca^<2+> handling in late-phase cardiac hypertrophy. Activity of the Na^+/Ca^<2+> exchanger and the SR may both be affected.
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