Investigation of erythropoietin induced hypertension with special reference to nitric oxide

促红细胞生成素诱发的高血压的研究，特别是一氧化氮

• 批准号: 06671146
• 负责人: KUSANO Eiji
• 金额: $ 1.09万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06671146/
• 关键词: hemodialysis; erythropoietin; hypertension; nitric oxide; nitric oxide synthase; cultured smooth muscle cell; cytokine; 一酸化窒素; 一酸化窒素合成酵素; 培養血管内皮細胞; SHR; WKY

Since the introduction of recombinant human erythropoietin to renal anemia, the development or aggravation of hypertension remains one of the most common and serious complications of this therapy. The precise mechanism in the development of hypertension are still not clear. Previous studies suggested that one of the major causes may be the increase of periphral vascular resistance, which derived from the increase of blood viscosity, endothelin, autonomic nervous system, peripheral oxygen tension and vascular endothelial dysfunction. It is also suggested that genetic predisposition to hypertension may relate to the etiology of erythropoietin induced hypertension. However, no conclusive results were so far obtained to explain for this type of hypertension.Recentrly, Caravaca et al reported anti-platelet aggregation drugs such as ditazole, ticlopidine, dipyridamole and aspirin prevented the development of hypertension treated with erytropoetin in retrospective study. They also observed in … More prospective study that antiplatelet drugs reduced blood pressure and periphral vascular resistance increased by erythropoietin treatment. They did not mention about the mechanism for this effect of antiplatelet aggregation drugs.In the present project, we observed antiplatelet drug, dipyridamole and ticlopidine, stimulated IL-1beta induced NO production in rat VSMC in culture. AS for dipyridamole, this compound enhanced the interleukin-1beta-induced NO production via inhibition of phosphodiesterase resulting in an increase of intracellular cAMP content in cultured rat vascular smooth muscle cells. On the other hand, ticlopidine enhanced the interleukin-1beta-induced NO production via stimulation of adenylate cyclase resulting in an increase of intracellular cAMP content.However, the clinical studies are needed to determine whether NO production could be stimulated by anti-platelet aggregation drugs, and whether the increased NO production might prevent erythropoietin induced hypertension in HD patients. Less

自从将重组人促红细胞生成素引入肾性贫血以来，高血压的发展或加重仍然是这种治疗最常见和最严重的并发症之一。高血压发生发展的确切机制尚不清楚。以往的研究认为，其主要原因之一可能是外周血管阻力增加，其来源于血液粘度、内皮素、自主神经系统、外周氧分压升高和血管内皮功能障碍。高血压的遗传易感性可能与促红细胞生成素诱导的高血压的病因有关。Caravaca等最近在回顾性研究中报道了抗血小板聚集药物如地他唑、噻氯匹定、双嘧达莫和阿司匹林可预防红细胞增多症治疗后高血压的发生。他们还观察到， ...更多信息 前瞻性研究表明，抗血小板药物降低血压和外周血管阻力增加促红细胞生成素治疗。本课题观察了抗血小板药物双嘧达莫和噻氯匹定对体外培养的大鼠VSMC产生NO的刺激作用。与双嘧达莫一样，该化合物通过抑制磷酸二酯酶，导致培养的大鼠血管平滑肌细胞内cAMP含量增加，从而增强白细胞介素-1 β诱导的NO产生。噻氯匹定可通过刺激腺苷酸环化酶而增加白细胞介素1 β诱导的NO产生，从而增加细胞内cAMP含量，但抗血小板聚集药物是否能刺激NO产生，以及NO产生的增加是否能预防红细胞生成素诱导的HD患者高血压，尚需临床研究证实。少

项目成果

Kusano, E., Iimura, O., Ikeda, U., Shimada, K., Asano, Y.: "Atrial natriuretic peptide enhances IL-1b stimulated nitric oxide production in cultured rat vascular smooth muscle cells." J.Am.Soc.Nephrol.7 (9). 1566 (1996)

Kusano, E.、Iimura, O.、Ikeda, U.、Shimada, K.、Asano, Y.：“心房钠尿肽增强培养的大鼠血管平滑肌细胞中 IL-1b 刺激的一氧化氮的产生。”

Iimura,O.et al.: "Dipyridamole enhances interleukin-1β stimilated nitric oxide production by cultured rat vascular smooth muscle cells." Europ.J.Pharmacol.296. 319-326 (1996)

Iimura, O. 等人：“双嘧达莫增强了培养的大鼠血管平滑肌细胞中白介素 1β 刺激的一氧化氮的产生。”Europ.J.Pharmacol.296 (1996)。

Kusano,E.et al.: "Argineine vasopressin inhibits interleukin-1β stimulated nitrix oxide and cGarp production via V1 receptor incultuned rat vascular smocth muscle cells." J.Hypertens.(in press). (1997)

Kusano, E. 等人：“精氨酸加压素通过 V1 受体培养的大鼠血管平滑肌细胞抑制白介素 1β 刺激的一氧化氮和 cGarp 的产生。”（出版中）。

草野英二他: "エリスロポエチンの昇圧機序-抗血小板薬の影響-" 第3回エリスロポエチン研究会proceedings. 103-107 (1995)

Eiji Kusano 等人：“促红细胞生成素升压机制 - 抗血小板药物的作用”第 3 届促红细胞生成素研究组论文集 103-107 (1995)。

Kusano,E.: "Nitric oxide in blood pressure regulation with special reference to patients undergoing nemodialysis" Clin.Exp.Nephrol.(in press). (1997)

Kusano,E.：“一氧化氮在血压调节中的作用，特别是针对接受血液透析的患者”Clin.Exp.Nephrol.（出版中）。