SODIUM PUMP INHIBITORS IN BLOOD PRESSURE REGULATION

工作概要 钠敏感型高血压的起源仍然是 明确了 钠敏感性高血压的实验模型已经 在实验室动物中产生，其特征在于 可抑制钠转运的内源性洋地黄样因子（EDLF） 穿过血管平滑肌 我们实验室之前的研究表明， 表明卡登素（哇巴因样化合物或OLC）和 蟾蜍二烯内酯（一种海蟾毒配基样化合物或MBG）可以被刺激 在大型动物中，通过盐水血浆体积扩张和急性 增加pCO 2。 这些研究还表明，α 1和α 3 血管平滑肌和神经末梢Na/K ATP酶亚型 大鼠组织，分别被发现有不同的敏感性， 各种EDLF。在本年度，盐水的不同影响 扩容对大鼠脑皮质和血浆OLC和MBG的影响 分析了 在生理盐水输注期间，血浆MBG水平升高， 血浆OLC降低。 同时，下丘脑和脑中的OLC 皮质MBG增加，而中枢神经系统MBG无变化。这些 研究结果表明，MBG和OLC都参与了调节， 循环液量，但OLC具有其主导作用， 中枢神经系统，而MBG负责抑制中枢神经系统， 血管平滑肌中Na/K ATP酶的α-1亚型。 第二 一项研究调查了六周高血压的单独和综合影响， 钠饮食和社会隔离对大鼠尿MBG的影响。 高钠饮食 在隔离的大鼠中，尿MBG增加两倍，收缩压升高 在整个研究期间，虽然组饲养动物的钠负荷 或隔离与正常钠饮食没有影响尿MBG或 血压.对血管平滑肌Na/K泵无长期影响 在任何条件下观察到活性。 这项研究表明，高 钠摄入对循环蟾蜍双烯雌酚EDLF产生持续影响， 但这种作用本身不足以抑制血管Na/K泵 长期的活动。 未来的研究将侧重于以下方面的作用： OLC和MBG在Dahl高血压Na/K泵活性中的作用， 对高钠饮食的遗传敏感性 此外， 长期MBG给药对血压、OLC、MBG和Na/K泵的影响 活动将被调查。

SUMMARY OF WORK The origins of sodium sensitive forms of hypertension remain to be clarified. Experimental models of sodium sensitive hypertension have been created in laboratory animals that are characterized by elevations in endogenous digitalis-like factors (EDLF) that can inhibit sodium transport across vascular smooth muscle. Previous studies in our laboratory have shown that both a cardenolide (a ouabain-like compund or OLC) and a bufodienolide ( a marinobufagenin-like compound or MBG) can be stimulated acutely in large animals by expansion of saline plasma volume and by acute increases in pCO2. These studies have also shown that alpha-1 and alpha-3 isoforms of Na/K ATPase in vascular smooth muscle and nerve endings of rat tissues, respectively, are found to have different sensitivites to various EDLF. During the current year, the differential effects of saline volume expansion on OLC and MBG in brain cortex and blood plasma of rats were analyzed. During saline infusion, plasma levels of MBG increased while plasma OLC decreased. Concurrently, OLC in hypothalamus and brain cortex increased, but central nervous system MBG did not change. These findings indicate that MBG and OLC are both involved in the regulation of circulating fluid volume, but OLC has its predominant effect in the central nervous system, while MBG is responsible for inhibition of the alpha-1 isoform of the Na/K ATPase in vascular smooth muscle. A second study investigated the separate and combined effects of six weeks of high sodium diet and social isolation on urinary MBG in rats. High sodium diet in isolated rats tripled urinary MBG and increased systolic blood pressure throughout the study period, while sodium loading of group-housed animals or isolation with normal sodium diet had no effects on urinary MBG or blood pressure. No long term effects on vascular smooth muscle Na/K pump activity were observed under any condition. This study shows that high sodium intake produce sustained effects on circulating bufodienolide EDLF, but that this effect alone is not sufficient to inhibit vascular Na/K pump activity over the long term. Future research will focus on the role of OLC and MBG in Na/K pump activity in Dahl hypertension, which involves a genetic sensitivity to high sodium diet. In addition, the effects of chronic MBG administration on blood pressure, OLC, MBG and Na/K pump activity will be investigated.