Investigation of erythropoietin induced hypertension with special reference to nitric oxide

自从重组人促红细胞生成素被引入治疗肾性贫血以来，高血压的发展或加重仍然是该疗法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。既往研究表明，其主要原因之一可能是外周血管阻力增加，其主要原因是血液粘度、内皮素、自主神经系统、外周血氧分压和血管内皮细胞功能障碍的增加。提示高血压的遗传易感性可能与促红细胞生成素引起高血压的病因有关。最近，Caravaca等人在回顾性研究中报道了抗血小板聚集药物，如双唑、噻氯匹定、双嘧达莫和阿司匹林等，可预防红细胞生成素治疗的高血压的发生。他们还在…观察到更多关于促红细胞生成素治疗降低血压和增加外周血管阻力的前瞻性研究。在本课题中，我们观察了抗血小板药物潘生丁和噻氯匹定对体外培养的大鼠VSMC产生IL-1β的刺激作用。对于潘生丁，该化合物通过抑制磷酸二酯酶而增强IL-1β诱导的NO的产生，导致培养的大鼠血管平滑肌细胞内cAMP含量增加。另一方面，噻氯匹定通过刺激腺苷环化酶增加IL-1β诱导的NO产生，导致细胞内cAMP含量增加，但抗血小板聚集药物是否能刺激NO的产生，以及增加的NO产生是否可以预防促红细胞生成素引起的高血压，仍有待临床研究。较少

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