Vaziri N D, Zhou X J, Naqvi F, Smith J, Oveisi F, Wang Z Q, Purdy R E
Department of Medicine, University of California, Irvine 92717, USA.
Am J Physiol. 1996 Jul;271(1 Pt 1):E113-22. doi: 10.1152/ajpendo.1996.271.1.E113.
We studied the mechanism of erythropoietin (EPO)-induced hypertension (HTN) in rats with chronic renal failure (CRF). After partial nephrectomy, rats were randomized into four groups. Group A received EPO, 150 U/kg, two times weekly for 6 wk to prevent anemia; group B received placebo injections and became anemic; group C received EPO but was kept anemic by dietary iron deficiency; and group D received placebo and regular transfusions to match hematocrit (Hct) in group A. Blood pressure (BP), Hct, platelet cytosolic calcium ([Ca2+]i) and magnesium concentration, and pressor and vasodilatory responses were determined. By design, Hct in groups A and D were comparable and significantly greater (P < 0.01) than in groups B and C. Despite divergent Hct values, the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy. EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals. EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization, angiotensin II or alpha 1-agonist, methoxamine in vitro, or the pressor response to angiotensin II in vivo. However, EPO therapy impaired the hypotensive response to nitric oxide (NO) donors, sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine, and reversed the CRF-induced upregulation of guanosine 3',5'-cyclic monophosphate production by thoracic aorta in vitro. Thus EPO-induced HTN in CRF rats is Hct independent and is associated with and perhaps causally related to increased basal and stimulated [Ca2+]i and impaired vasodilatory response to NO.
我们研究了促红细胞生成素（EPO）诱导的慢性肾功能衰竭（CRF）大鼠高血压（HTN）的机制。部分肾切除术后，将大鼠随机分为四组。A组每周两次接受150 U/kg的EPO，共6周以预防贫血；B组接受安慰剂注射并出现贫血；C组接受EPO，但通过饮食缺铁使其保持贫血状态；D组接受安慰剂并定期输血以使血细胞比容（Hct）与A组匹配。测定血压（BP）、Hct、血小板胞浆钙（[Ca2+]i）和镁浓度以及升压和血管舒张反应。根据设计，A组和D组的Hct具有可比性，且显著高于（P < 0.01）B组和C组。尽管Hct值不同，但与安慰剂治疗组B和D相比，EPO治疗组A和C的血压显著升高。无论EPO治疗是在肾切除术后立即开始还是在4周后开始，均会发生高血压。EPO治疗增强了CRF动物基础[Ca2+]i的升高，并恢复了凝血酶介导的血小板[Ca2+]i的缺陷性升高。EPO治疗在体外对68 mM K(+)诱导的去极化、血管紧张素II或α1激动剂甲氧明引起的尾动脉收缩，或体内对血管紧张素II的升压反应均无影响。然而，EPO治疗损害了对一氧化氮（NO）供体硝普钠和S-亚硝基-N-乙酰-D,L-青霉胺的降压反应，并逆转了CRF诱导的体外胸主动脉鸟苷3',5'-环磷酸生成的上调。因此，CRF大鼠中EPO诱导的高血压与Hct无关，并且与基础和刺激的[Ca2+]i增加以及对NO的血管舒张反应受损有关，甚至可能存在因果关系。
