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THE PATHOGENESIS OF AN INCREASE IN VASCULAR TONUS : THE DEVELOPMENT OF NEW VASODILATORS.

血管紧张度增加的发病机制：新血管扩张剂的开发。

基本信息

批准号：
04454268
负责人：
KANAIDE Hideo
金额：
$ 4.1万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

1.THE PATHOGENESIS OF AN INCREASE IN VASCULAR TONUS.(1) Using RTPCR and fura-2 microfluorometry, the relationships between the levels of the expression of angiotensin (AT) II (type 1) and endothelin (ET) A receptor mRNAs and the physiological responsiveness ([Ca]i) were investigated in rat aortic smooth muscle cells in primary culture. It was found that ATII,PKC and PKA regulate the expression of ATII receptor mRNA,and the increase in mRNA level is accompanied by an increase in physiological responsiveness, and (2) cAMP induces an up-regulation of ETA receptor mRNA and increases the responsiveness to ET-1. (3) Using fura-2-front-surface fluorometry and porcine coronary arterial strips, we found that ET-3 induces vasoconstriction by increasing [Ca]i mainly through Ca-influx from the extracellular space, and that distinct mechanisms of time-dependent modulation of the Ca-sensitivity function in the vasoconstrictor responses to ET-1 and ET-3.THE DEVELOPMENT OF NEW VASODILATORS.(1) It was found that the main action of papaverine and nicorandil is to decrease changes in [Ca]i and Ca-sensitivity of the contractile apparatus of vascular smooth muscle. Inhibition of both Ca-influx from the extracellular space and Ca-release from the intracellular store plays a major role in the decrease of [Ca]i. (2) In case of nicorandil, the decrease of [Ca]i is due in part to opening of ATP-sensitive K-channels. (3) In rabbit femoral arteries, it was found that LP-805 relaxs smooth musle mainly by activating ATP-sensitive K-channels of smooth muscle cells, and by releasing EDRF from endothelial cells. EDRF induced by LP-805 relaxs smooth muscle not only by decreasing [Ca]i but also decreasing Ca-sensitivity of the contractile apparatus of smooth muscle cells.

1.血管紧张性增高的发病机制(1)应用RT-PCR和Fura-2荧光显微分析技术，研究了血管紧张素（AT）Ⅱ（1型）和内皮素（ET）A受体mRNA表达水平与主动脉平滑肌细胞生理反应性（[Ca]i）的关系。发现ATII、PKC和PKA调节ATII受体mRNA的表达，ATII受体mRNA水平的增加伴随着生理反应性的增强;（2）cAMP诱导ETA受体mRNA的上调，增强对ET-1的反应性。(3)用Fura-2荧光法和猪冠状动脉条研究发现，ET-3主要通过细胞外Ca内流增加[Ca]i引起血管收缩，并发现ET-1和ET-3对血管收缩反应中Ca敏感性的时间依赖性调节机制不同。(1)发现罂粟碱和尼可地尔的主要作用是降低血管平滑肌收缩装置的[Ca]i和Ca敏感性的变化。细胞外Ca内流和细胞内Ca释放的抑制在[Ca]i的降低中起主要作用。(2)在尼可地尔的情况下，[Ca]i的降低部分是由于ATP敏感性K通道的开放。(3)在兔股动脉中，发现LP-805主要通过激活平滑肌细胞的ATP敏感性K通道和从内皮细胞释放EDRF来松弛平滑肌。LP-805诱导的EDRF不仅通过降低[Ca]i而且通过降低平滑肌细胞收缩装置的Ca敏感性来松弛平滑肌。