Roles of central digitalis-like factor in stress and cardiovascular diseases

中枢洋地黄样因子在应激和心血管疾病中的作用

• 批准号: 07457164
• 负责人: GOTO Atsuo
• 金额: $ 4.8万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457164/
• 关键词: stress; ouabain; central nervous system; sodium; hypertension; cardiovascular diseases; risk factor; sympathetic neruous system; stress ストレス; ウアバイン; 交感神経系; ストレス; ホルモン

#1 We destroyed rat central catecholamine (CA) neurons with intracerebroventricular injection of 6-hydroxydopamine and found that hypothamic ouabainlike compound (OLC) content and plasma OLC level were markedly decreased in accordance with reduced brain norepinephrin content. OLC may be closely related to central CA neurons. #2 We tested the hypothesis that OLC may participate in a homeostatic response to acute stress. Adrenal and plasma OLC levels increased in response to acute swim stress. OLC may function as a stress hormone. #3 An expansion of body fluid volume may induce the release of humoral factors, which could increase systemic vasular resistance and cause volume-dependent, forms of hupertension. Acute volume expansion could induce a similar enhanced vascular Ca2+ channel activity to that seen in hypertension, suggestin a possible contribution of circulating OLC.#4 We determined the plasma aldosterone concentration during sodium depletion in rats immunized against ouabain and … More found decreased aldosterone concentration in these rats. Endogenous OLC may play an important role in the regulation of aldosterone secretion and/or production. #5 We measured plasma and urine levels of OLC to evaluate its role in the hypertensive mechanisms in a 64-year-old male patient with ectopic adrenocorticotrophin (ACTH) syndrome due to jung cancer. The maximum plasma level was 40-fold the normal subject's range. Plasma and urine levels of OLC correlated with systolic blood pressure (BP) and diastolic BP.OLC with biological activity could account for this mineralocorticoid-type hypertension. The contribution of OLC to ACTH-induced hypertension was suggested also in rats. #6 We measured office BO,ambulatory BP (ABP) and plasma electrolytes in 82 essential hypertensive patients and found that in essential hypertensives plasma K concentration is inversely related to ABP including daytime and nighttime BOs.K may be a factor determining the whole day BP in essential hypertension. #7 We investigated the potential roles of circulating OLC in the regulation of Na and K distribution between the cells and the extracellular fluid. Consistent lower plasma K levels and steeper Na and K gradients were observed in rats immunized against ouabain. K handling in response to hypertonic NaCl load was altered and lower plasma K level was maintained in these rats. Chronic administration of PST-2238, a newly developed antiouabain agent, significantley lowered plasma K levels in rats with subtotal nephrectomy. OLC may determine the internal Na Nd K distribution and the transmembrane cation gradients in vivo. #8 We injected intraperitoneally hypertonic NaCl solution to rats and found the elevation of OLC levels in plasma, pituitary and adrenal in response to hypertonic NaCl load. OLC may play an important role in the elimination of excess body Na with hypernatremia. Less

#1我们用侧脑室注射6-羟基多巴胺破坏大鼠中央儿茶酚胺（CA）神经元，发现下丘脑哇巴因样化合物（OLC）含量和血浆OLC水平显著降低，与脑去甲肾上腺素含量降低一致。OLC可能与中枢CA神经元密切相关。#2我们测试了OLC可能参与对急性应激的稳态反应的假设。肾上腺和血浆OLC水平增加急性游泳应激反应。OLC可能作为一种应激激素发挥作用。#3体液体积的扩张可能会引起体液因子的释放，这可能会增加全身血管阻力并导致体积依赖性的高血压。急性容量扩张可诱导类似的血管Ca 2+通道活性增强，与高血压中所见相似，这可能是循环OLC的贡献。4.我们测定了哇巴因免疫大鼠在钠耗竭过程中的血浆醛固酮浓度， ...更多信息 发现这些大鼠的醛固酮浓度降低。内源性OLC可能在调节醛固酮分泌和/或产生中起重要作用。#5我们测量了OLC的血浆和尿液水平，以评估其在一名64岁男性患者的高血压机制中的作用，该患者患有因荣格癌症引起的异位促肾上腺皮质激素（ACTH）综合征。最大血浆水平是正常受试者范围的40倍。血、尿OLC水平与收缩压、舒张压相关，具有生物活性的OLC可能是这种盐皮质激素型高血压的原因。OLC的贡献ACTH诱导的高血压大鼠也建议。#6我们测量了82例原发性高血压患者的诊室BO、动态血压（ABP）和血浆电解质，发现原发性高血压患者的血浆K浓度与ABP（包括日间和夜间BO）呈负相关。K可能是决定原发性高血压患者全天BP的一个因素。#7我们研究了循环OLC在调节细胞和细胞外液之间的Na和K分布中的潜在作用。一致较低的血浆K水平和陡峭的Na和K梯度，观察到对哇巴因免疫的大鼠。高渗氯化钠负荷的钾处理被改变，维持在这些大鼠较低的血浆钾水平。PST-2238是一种新研制的抗哇巴因药物，长期给药可显著降低肾大部切除大鼠血浆K水平。OLC可以决定体内Na、Nd、K的内部分布和跨膜阳离子梯度。#8我们向大鼠腹腔内注射高渗NaCl溶液，发现血浆、垂体和肾上腺中的OLC水平响应于高渗NaCl负荷而升高。OLC可能在高钠血症时体内钠的排出中起重要作用。少

项目成果

Goto, A.: "Role of ouabainlike conpound in the regulation of transmenbrane sodium and potassium gradionts in rats." Hypertension. 30. 753-758 (1997)

Goto, A.：“哇巴因样化合物在调节大鼠跨膜钠和钾梯度中的作用。”

Goto A,Yamada K.: "An approach to the development of novel antihypertensive drugs : potential role of sodium pump inhibitors" Trend Pharmacol Sci. 19 (in press). (1998)

Goto A，Yamada K.：“新型抗高血压药物的开发方法：钠泵抑制剂的潜在作用”Trend Pharmacol Sci。

K. Yamada: "Modulation of the levels of ouabainlike compound by central catecholainine, heurons in rats" FEBS lett. 360. 67-69 (1995)

K. Yamada：“大鼠体内儿茶素、神经元对哇巴因样化合物水平的调节”FEBS lett。

後藤 淳郎: "内因性ウアバイン様物質,別刷・医栄のあゆみ 内分泌代謝疾患" 医歯薬出版, 3 (1997)

Atsushi Goto：“内源性哇巴因样物质，重印，IE的内分泌和代谢疾病史”石药出版，3（1997）

Yamada K,Goto A,Omata M.: "Modulation of the levels of ouabain-like compound by central catecholamine neurons in rats" FEBS Lett. 360. 67-69 (1995)

Yamada K，Goto A，Omata M.：“大鼠中枢儿茶酚胺神经元对哇巴因样化合物水平的调节”FEBS Lett。