Bode-Böger S M, Böger R H, Kuhn M, Radermacher J, Frölich J C
Institute of Clinical Pharmacology, Hannover Medical School, Germany.
Kidney Int. 1996 Oct;50(4):1255-61. doi: 10.1038/ki.1996.435.
Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoietin (rHuEPO). We investigated the effect of rHuEPO on the vascular tone of isolated rabbit aorta and carotid artery under isometric conditions. The production of prostacyclin and the vasoconstrictor prostanoids PGF2 alpha and TXB2 was investigated in arterial rings incubated with rHuEPO. Endothelial cells from human umbilical veins (HUVECs) were isolated and cultured in flasks (37 degrees C, 5% CO2). After incubation with rHuEPO, the formations of prostacyclin (as its stable metabolite 6-keto-PGF1 alpha), PGF2 alpha, PGE2, thromboxane (TX) B2 and of ET-1 were measured by radioimmunoassays. rHuEPO had no direct vasoconstrictor effect, but it enhanced noradrenalin-induced contractions. This effect was more prominent in rings with intact endothelium than in rings from which the endothelium had been mechanically removed, indicating that endothelial vasoactive factors might be involved. Relaxations to acetylcholine (ACh, 1 microM) were unaltered in the presence or absence of rHuEPO, suggesting that the endothelial NO-cGMP pathway was not impaired by rHuEPO. Incubation with rHuEPO (20 to 200 U/ml) increased the release of the vasoconstrictor mediators ET-1, PGF2 alpha and TXB2, and decreased prostacyclin formation in isolated rabbit arterial rings and in HUVECs, respectively. The cyclooxygenase inhibitor indomethacin abolished the rHuEPO-induced increase in vasoconstrictor prostanoid production. ET-1 formation by HUVECs was also increased by rHuEPO in a dose-dependent manner (maximal effect +90% by rHuEPO 200 U/ml, P < 0.05). Indomethacin and the selective ETA receptor antagonist BQ123 each partly inhibited the enhancement of vascular responsiveness to noradrenalin induced by rHuEPO in rabbit carotid artery, but simultaneous administration of rHuEPO with both antagonists completely abolished the force increment. In conclusion, these studies show that a dose-dependent shift in the balance of constrictor and relaxing prostanoids as well as an increased synthesis of ET-1 induced by rHuEPO lead to the enhanced vascular responsiveness to noradrenalin in isolated rabbit arteries. The increased vascular responsiveness to noradrenalin, which is in line with clinical observations, may contribute to the hypertensive side effect associated with rHuEPO therapy in patients with chronic renal failure.
高血压是接受重组人促红细胞生成素（rHuEPO）治疗的肾性贫血患者出现的主要副作用。我们在等长条件下研究了rHuEPO对离体兔主动脉和颈动脉血管张力的影响。在与rHuEPO一起孵育的动脉环中研究了前列环素以及血管收缩性前列腺素PGF2α和TXB2的生成。从人脐静脉分离内皮细胞（HUVECs）并在培养瓶中培养（37℃，5%二氧化碳）。用rHuEPO孵育后，通过放射免疫测定法测量前列环素（作为其稳定代谢产物6-酮-PGF1α）、PGF2α、PGE2、血栓素（TX）B2和ET-1的生成。rHuEPO没有直接的血管收缩作用，但它增强了去甲肾上腺素诱导的收缩。这种作用在具有完整内皮的血管环中比在机械去除内皮的血管环中更明显，表明内皮血管活性因子可能参与其中。在有或没有rHuEPO的情况下，对乙酰胆碱（ACh，1μM）的舒张反应没有改变，这表明rHuEPO没有损害内皮NO-cGMP途径。用rHuEPO（20至200U/ml）孵育分别增加了离体兔动脉环和HUVECs中血管收缩介质ET-1、PGF2α和TXB2的释放，并减少了前列环素的生成。环氧合酶抑制剂吲哚美辛消除了rHuEPO诱导的血管收缩性前列腺素生成增加。rHuEPO也以剂量依赖性方式增加了HUVECs中ET-1的生成（rHuEPO 200U/ml时最大效应增加90%，P<0.05）。吲哚美辛和选择性ETA受体拮抗剂BQ123各自部分抑制了rHuEPO诱导的兔颈动脉对去甲肾上腺素血管反应性的增强，但rHuEPO与两种拮抗剂同时给药完全消除了力量增加。总之，这些研究表明，rHuEPO诱导的收缩性和舒张性前列腺素平衡的剂量依赖性转变以及ET-1合成增加导致离体兔动脉对去甲肾上腺素的血管反应性增强。对去甲肾上腺素血管反应性的增加与临床观察结果一致，可能导致慢性肾衰竭患者rHuEPO治疗相关的高血压副作用。
