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

1.血管张力增加的发病机制。(1)采用RTPCR和fura-2微荧光技术，研究了原代培养大鼠主动脉平滑肌细胞血管紧张素（AT） II（1型）和内皮素（ET） A受体mrna表达水平与生理反应性（[Ca]i）的关系。结果发现，ATII、PKC和PKA调节了ATII受体mRNA的表达，且mRNA水平的升高伴随着生理反应性的提高；(2)cAMP诱导了ETA受体mRNA的上调，增加了对ET-1的反应性。(3)利用fura-2前表面荧光法和猪冠状动脉条带，我们发现ET-3主要通过细胞外空间的Ca内流增加[Ca]i诱导血管收缩，并且在ET-1和ET-3的血管收缩反应中，钙敏感性功能的时间依赖性调节机制明显。新型血管扩张剂的研制。(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器[Ca]i的变化和钙敏感性。抑制细胞外空间的钙内流和细胞内储存的钙释放在降低[Ca]i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敏感的k通道的打开。(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k通道，并通过释放内皮细胞中的EDRF来放松平滑肌。LP-805诱导的EDRF不仅通过降低[Ca]i使平滑肌松弛，而且通过降低平滑肌细胞收缩器的Ca敏感性使平滑肌松弛。

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.