Pathological role of endothelin ET_B receptors

内皮素ET_B受体的病理作用

• 批准号: 12670098
• 负责人: MATSUMURA Yasuo
• 金额: $ 2.18万
• 依托单位: Osaka University of pharmaceutical Sciences, Assistant
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670098/
• 关键词: endothelin-1; ET_B receptor; hypertension; renal failure; 腎障害

We evaluated the pathological role of ET_B receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting-lethal (sl) rat which carries a naturally occurring deletion in ET_B receptor gene. When homozygous (sl/sl) and wild-type (+/+) rats were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than wild-type rats. Chronic treatment with ABT-627, an ET_A receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histologial damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous, compared with wild-type rats. Renal and vaslcular injuries were significantly improved by ABT-627. In DOCA-salt-induced hypertension. Enhanced ET-1 production and ET_A-mediated actions are responsible for the increased susceptivity to DOCA-salt hypertention and tissue injuries in ET_B receptor-defici … More ent ratsUsing same animals, we also evaluated the role of endothelin ET\B-receptor-mediated action in the development and maintenance of ischemic acute renal failure (ARF). Animals were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histological damage were markedly and equally observed both in homozygous and wild-type groups, and these renal njury gradually recovered. When the ischemia/reperfusion-induced renal injury was examined at 7 days after the reperfusion, the recovery in homozygous ARF rats obviously delayed compared with the cases in wild-type animals. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ET_B-receptor-mediated actoins do not play an important role in the development of ischemic ARF, but may be involoved in the recovery process from the ischemia/reperfusion-induced renal injury Less

本研究利用ET_B受体基因自然缺失的斑点致死（sl）大鼠模型，探讨了ET_B受体在DOCA盐诱导的高血压、心血管肥大和肾损害中的病理作用。当用DOCA-盐处理纯合子（sl/sl）和野生型（+/+）大鼠时，纯合子大鼠比野生型大鼠表现出更早和更高的收缩压升高。长期应用ET_A受体拮抗剂ABT-627可完全抑制DOCA盐诱导的高血压。肾功能不全和组织学损害更严重的纯合子比野生型大鼠。与野生型大鼠相比，在纯合子中观察到显著的血管肥大。ABT-627显著改善了肾和血管损伤。在DOCA-盐诱导的高血压中。ET-1产生增加和ET_A介导的作用是ET_B受体缺陷性高血压患者对DOCA盐高血压耐受性增加和组织损伤的原因。 ...更多信息 本实验还观察了内皮素受体介导的内皮素B在缺血性急性肾功能衰竭（ARF）发生和维持中的作用。通过夹闭肾蒂45分钟，然后再灌注，使动物经受缺血性ARF。再灌注后24 h，野生型组和纯合子组肾小球功能和组织学损害均明显减轻，并逐渐恢复。在再灌注后7天检查缺血/再灌注诱导的肾损伤时，与野生型动物相比，纯合子ARF大鼠的恢复明显延迟。缺血/再灌注后肾内皮素-1含量的增加在纯合子大鼠比野生型大鼠更显着。因此，ET_B受体介导的肌动蛋白在缺血性ARF的发生发展中不起重要作用，但可能参与缺血/再灌注肾损伤的恢复过程。

项目成果

松村靖夫: "エンドセリン受容体拮抗薬と内皮機能"血圧. 8. 67-74 (2001)

Yasuo Matsumura：“内皮素受体拮抗剂和内皮功能”血压。8. 67-74 (2001)

西田昌広: "Role of Endothelia ET_B receptor in the pathogenesis of ischemic acute renal failure"J. Cardiovasc. Pharmacol. (印刷中). (2002)

Masahiro Nishida：“内皮细胞 ET_B 受体在缺血性急性肾衰竭发病机制中的作用”J. Cardiovasc（正在出版）。

松村靖夫: "Exaggerated vascular and renal pathology in deoxycorticosterone acetate-salt, endothelin-B receptor-deficient rats"Circulation. 102. 2765-2773 (2000)

Yasuo Matsumura：“醋酸脱氧皮质酮盐、内皮素 B 受体缺陷大鼠的血管和肾脏病理学夸大”循环。 102. 2765-2773 (2000)

MATSUMURA Yasuo, KURO Toshihiko, KOBAYASHI Yutaka, KONISHI Fumiko, TAKAOKA Masanori, WESSALE Jerry L., OPGENORTH Terry j., GARIEPY Cheryl E. and YANAGISAWA Masashi: "Increased susceptivity to deoxycorticosterone acetate-salt-induce hypertension in endothe

MATSUMURA​​ Yasuo、KURO Toshihiko、KOBAYASHI Yutaka、KONISHI Fumiko、TAKAOKA Masanori、WESSALE Jerry L.、OPGENORTH Terry j.、GARIEPY Cheryl E. 和 YANAGISAWA Masashi：“内皮细胞对醋酸脱氧皮质酮盐的敏感性增加可诱发高血压

松村靖夫: "Enhanced blood pressure sensitivity to DOCA-salt treatment in endothelin ET_B receptor-deficient rats"Br. J. Pharmacol. 129. 1060-1062 (2000)

Yasuo Matsumura：“内皮素 ET_B 受体缺陷大鼠对 DOCA 盐治疗的血压敏感性增强”Br. J. Pharmacol. 129. 1060-1062 (2000)