Investigation of the mechanism ofthe tolerance of organic nitrate and Escape from the tolerance
| Project/Area Number |
14572096
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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 |
医薬分子機能学
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| Research Institution | Osaka City University |
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Principal Investigator |
TAKEMURA Shigekatsu Osaka City University, Graduate School of Medicine, Research Assistant, 大学院・医学研究科, 助手 (00322363)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Organic nitrate / Tolerance of Nitrate / Cytochrome P450 / Free Radical / Nitric Oxide / Thiols / Iron Metabolism |
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| Research Abstract |
The mechanism of organic nitrate tolerance is poorly defined. We studied the rat P450-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified P450 isoforms relationship between P450 expression and nitrate tolerance following continuous infusion of organic nitrates in rats. The hypotensive effect of an nitroglycerin (NTG) bolus injection was abolished in rats which had been previously provided a continuous 48 hr infusion of NTG This effect was accompanied by a gradual but marked decrease in plasma and urinary nitrate levels following a peak at 18-24 hr. Nitrate tolerance was reversible ; the decline in the hypotensive effect and P450 levels observed after two days of continuous infusion was followed by restoration to control levels two days after cessation of the infusion. Similarly, the hypotensive action disappeared in P450-depleted, and -inhibited rats. At 48 hr after infusion, NTG-induced NO generation of the vessels increased in acetone (a P450 inducer)-pretreated rats. The appearance and disappearance of P450 paralleled the conversion of organic nitrates to NO. Our observations indicate that nitrate tolerance is in large part the result of decreased P450 expression and activity. Interventions that maintain or increase P450 activity may be a strategy to provide relief from ischemic conditions in humans.
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Report
(3 results)
Research Products
(29 results)
