Relationship between endothelin and organ dysfunction in SIRS

SIRS中内皮素与器官功能障碍的关系

• 批准号: 09671543
• 负责人: MITAKA Chieko
• 金额: $ 1.15万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671543/
• 关键词: Endotoxic shock; Endothelin; Endothelin receptor antagonist; Hemodynamics; Renal blood flow; Renal function; NO synthase inhibitor; Post operation of abdominal aortic aneurysm; エンドトキシンシッョク; L-カナヴァニン; 呼吸機能障害; 低酸素症; 臓器障害; エンドセリン受容体桔抗薬; 敗血症性ショッ

1) Clinical studyEndothelin-1 (ET-1) release during operation correlated (r=0.678) with bleeding volume during operation in patients with abdominal aortic aneurysm. In two patients with rapture of abdominal aortic aneurysm, elevated plasma ET-1 levels gradually decreased in survivor, whereas elevated ET-1 levels remained high in non-survivor. These findings suggest that plasma ET-1 levels reflect the degree of surgical stress and vascular injury.2) Study of canine endotoxic shock modelLPS (250 ng/kg/min for 2 hr) induced hypotension, metabolic acidosis, hypoxemia, and renal dysfunction in anesthetized dogs. Plasma ET-1 levels increased and positively correlated with MAP, MPAP, PCWP, and CV'P in dogs with endotoxic shock. Pretreatment of nonselective ETィイD2AィエD2/ETィイD2BィエD2 receptor antagonist, TAK-044 (5 mg/kg), prevented LPS-induced metabolic acidosis, hypoxemia, and renal dysfunction. Therefore, TAK-044 is a useful agent to prevent acute renal failure during endotoxic shock. In addition, selective inducible NO synthase inhibitor, L-canavanine (10 mg/kg/hr for 5 hr), further increased plasma ET-1 levels, which were associated with decrease in DOィイD22ィエD2I and lactic acidosis. These findings suggest that ET-1 plays a compensatory role against vasodilation during endotoxic shock , but excessive ET-1 may decrease organ blood flow and induce organ dysfunction.

1)临床研究腹主动脉瘤患者术中内皮素-1（ET-1）释放与术中出血量相关（r=0.678）。在两例腹主动脉瘤破裂患者中，存活者血浆ET-1水平升高逐渐下降，而死亡者血浆ET-1水平仍升高。2）犬内毒素休克模型的研究LPS（250 ng/kg/min，2 h）诱导麻醉犬低血压、代谢性酸中毒、低氧血症和肾功能不全。内毒素休克犬血浆ET-1水平升高，并与MAP、MPAP、PCWP、CV’P呈正相关。非选择性ET受体D2 A拮抗剂D2/ET受体D2 B拮抗剂D2受体拮抗剂TAK-044（5 mg/kg）预处理可预防LPS诱导的代谢性酸中毒、低氧血症和肾功能不全。因此，TAK-044是预防内毒素休克期间急性肾衰竭的有效药物。此外，选择性诱导型NO合酶抑制剂L-刀豆氨酸（10 mg/kg/hr，持续5 hr）进一步升高血浆ET-1水平，这与DO升高D22、DO降低D2 I和乳酸酸中毒有关。提示ET-1对内毒素休克时的血管舒张起代偿作用，但过量的ET-1可使器官血流量减少，引起器官功能障碍。

项目成果

三高千恵子 他: "エンドトキセミアにおける選択的誘導型NO合成酵素(iNOS)阻害薬、L-カナヴァニンの血行動態、血中エンドセリン濃度に及ぼす影響"日本救急医学会雑誌. 10・9. 546 (1999)

Chieko Mitaka 等人：“L-刀豆氨酸（一种选择性诱导型 NO 合酶 (iNOS) 抑制剂）对内毒素血症中血流动力学和血液内皮素浓度的影响”，日本急性医学会杂志 10/9。

Chieko Mitaka, Takashi Nagura, Yukio Tsunoda, Keisuke Amaha: "Relationship between plasma endothelin-1 concentrations and number of organ dysfunction in critically ill patients."J Jan Soc Intensive Care Med. 1. 33-38 (1997)

Chieko Mitaka、Takashi Nagura、Yukio Tsunoda、Keisuke Amaha：“重症患者血浆内皮素-1 浓度与器官功能障碍数量之间的关系。”J Jan Soc 重症监护医学杂志。

Chieko Mitaka, Yukio Hirata, Kuninori Yokoyama, Takashi Nagura, Yukio Tsunoda, Keisuke Amaha: "Improvement of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist."Crit Care Med. 27. 146-153 (1999)

Chieko Mitaka、Yukio Hirata、Kuninori Yokoyama、Takashi Nagura、Yukio Tsunoda、Keisuke Amaha：“通过非选择性内皮素受体拮抗剂改善内毒素血症犬的肾功能障碍。” Crit Care Med。

三高千恵子他: "外科的侵襲下におけるエンドセリン-1の臨床的意義"日本臨床麻酔学会誌. 18. 18-20 (1998)

Chieko Mitaka 等：“手术侵袭下内皮素-1 的临床意义”日本临床麻醉学会杂志 18. 18-20 (1998)。

Chieko Mitaka, et al.: "Pathologic Role of Endothelin-1 in Septic Shock" J Cardiovasc Pharmac. 31. S233-S235 (1998)

Chieko Mitaka 等人：“内皮素 1 在感染性休克中的病理作用”J Cardiovasc Pharmac。