Pathophysiology and therapeutic strategy of coronary vasospasm of microvessels using a novel porcine model.
| Project/Area Number |
15590762
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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 | Fukushima Medical University |
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Principal Investigator |
ISHIBASHI Toshiyuki Fukushima Medical University, School of Medicine, Assistant Professor, 医学部, 助教授 (00223024)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Yukiko Fukushima Medical University, School of Medicine, Assistant Professor, 医学部, 教授 (90004712)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Coronary microcirculation / coronary vasospasm / endothelial injury / endothelin / RhoA / ヘンドセリン / 攣縮 / アセチルコリン |
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| Research Abstract |
Balloon endothelial denudation (ED) was carried out in the epicardial left anterior descending coronary artery (LAD) every 2 weeks, for a total of four times, in 12 pigs. Changes in the denuded site diameter and LAD blood flow caused by acetylcholine (ACh) or serotonin were assessed before each denudation and at 8 weeks. Blood pressure, electrocardiogram (ECG) from the LAD area and LAD blood flow were monitored continuously in conscious and unrestrained pigs. Spontaneous ECG ST depression with a decrease in LAD blood flow appeared at around 2 weeks. In accordance with this, 0.05 μg/kg ACh induced similar ECG and LAD blood flow changes without denuded site narrowing at 8 weeks, suggesting microvascular spasm (Coron Artery Dis 2004 ; 15 : 137-145). In addition, repeated endothelial denudation significantly increased the basal level of plasma concentration of endothelin-1 (ET-1) in coronary sinus at 8weeks compared with control group p<0.01). ET-1 concentration in coronary sinus 1 minute after ACh injection was further augmented in ED group at 4, 6 and 8 weeks compared with the basal level (p<0.01, each). Repeated ED increased the production of reactive oxygen species (ROS) detected by ascorbyl free radical (AFR) and dihydroethidium staining, whereas it was almost prevented by ET-1 type A receptor (ET_A) antagonist. ED induced the decrease of eNOS expression in the microvessels and the downregulation was attenuated in ED+ET_A group. Histological analysis revealed that ET_A antagonist suppressed the downstream vascular remodeling induced by repeated ED. ET-1 plays a crucial role for coronary microvascular spasm and the blockade of ET-1 may be beneficial for treating coronary vasospasm. Furthermore, we found a rapid activation pathway of RhoA which plays an important role in endothelial dysfunction (J Biol Chem 2005 ; 280 : 10182-10188). It remains to elucidate whether this rapid RhoA activation associates with endothelial dysfunction of coronary vasospasm.
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Report
(3 results)
Research Products
(12 results)
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[Journal Article] Thrombin-induced rapid geranylgeranylation of RhoA as an essential process for RhoA activation in endothelial cells.2005
Author(s)
Hiroshi Ohkawara, Toshiyuki Ishibashi, Takayuki Sakamoto, Koichi Sugimoto, Kenji Nagata, Keiko Yokoyama, Nobuo Sakamoto, Masashi Kamioka, Isao Matsuoka, Shigetomo Fukuhara, Naotoshi Sugimoto, Yoh Takuwa, Yukio Maruyama.
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Journal Title
Journal of Biological Chemistry 280 (11)
Pages: 10182-10188
Description
「研究成果報告書概要(欧文)」より
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