Bode-Böger S M, Böger R H, Kuhn M, Radermacher J, Frölich J C
Institute of Clinical Pharmacology, Hannover Medical School, Germany.
J Cardiovasc Pharmacol. 1992;20 Suppl 12:S25-8. doi: 10.1097/00005344-199204002-00009.
Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoietin (rhEPO). We investigated the effect of rhEPO on the vascular tone of rabbit aorta. rhEPO had no direct vasoconstrictor effect, but it enhanced norepinephrine (NE)-induced contractions of rabbit aortic rings. Relaxations to acetylcholine (ACh, 1 microM) were unaltered in the presence or absence of rhEPO, indicating that the endothelium-dependent NO pathway was not affected by rhEPO. In rings of human renal artery and rabbit aorta, rhEPO (200 U/ml) increased the synthesis of constrictor prostanoids. The cyclooxygenase inhibitors indomethacin and aspirin abolished the increase in prostanoid production. However, they did not completely suppress the rhEPO-induced enhancement of NE contractions in rabbit aorta. We further investigated the effect of rhEPO on prostanoid and endothelin-1 synthesis in cultured human endothelial cells. Endothelial cells from human umbilical veins (HUVEC) were isolated and cultured. After incubation with rhEPO, the formation of prostaglandin (PG) I2 (analyzed as its stable metabolite 6-keto-PGF1 alpha), PGF2 alpha, PGE2, thromboxane (Tx) B2, and of endothelin-1 (ET-1) was measured by radioimmunoassay (RIA). rhEPO (200 U/ml) increased the formation of PGF2 alpha and TxB2 and decreased the formation of PGI2 in HUVEC. The release of ET-1 was increased by nearly 90% in the presence of rhEPO (200 U/ml). We conclude that a shift in the balance of constrictor and relaxing prostanoids as well as an increased synthesis of ET-1 may contribute to the hypertensive side effect of rhEPO therapy. ET-1 may at least in part be responsible for the unexpectedly low inhibitory effect of indomethacin on rhEPO-enhanced contractions of rabbit aorta.
高血压是接受重组人促红细胞生成素（rhEPO）治疗的肾性贫血患者出现的主要副作用。我们研究了rhEPO对兔主动脉血管张力的影响。rhEPO没有直接的血管收缩作用，但它增强了去甲肾上腺素（NE）诱导的兔主动脉环收缩。在有或没有rhEPO的情况下，对乙酰胆碱（ACh，1微摩尔）的舒张反应没有改变，这表明内皮依赖性一氧化氮途径不受rhEPO影响。在人肾动脉环和兔主动脉环中，rhEPO（200单位/毫升）增加了缩血管前列腺素的合成。环氧化酶抑制剂吲哚美辛和阿司匹林消除了前列腺素生成的增加。然而，它们并没有完全抑制rhEPO诱导的兔主动脉中NE收缩增强。我们进一步研究了rhEPO对培养的人内皮细胞中前列腺素和内皮素-1合成的影响。分离并培养人脐静脉内皮细胞（HUVEC）。用rhEPO孵育后，通过放射免疫测定（RIA）测量前列腺素（PG）I2（以其稳定代谢物6-酮-PGF1α分析）、PGF2α、PGE2、血栓素（Tx）B2和内皮素-1（ET-1）的形成。rhEPO（200单位/毫升）增加了HUVEC中PGF2α和TxB2的形成，并减少了PGI2的形成。在rhEPO（200单位/毫升）存在的情况下，ET-1的释放增加了近90%。我们得出结论，缩血管和舒张性前列腺素平衡的改变以及ET-1合成的增加可能导致rhEPO治疗的高血压副作用。ET-1可能至少部分负责吲哚美辛对rhEPO增强的兔主动脉收缩的意外低抑制作用。
