RECOMBINANT-HUMAN-ERYTHROPOIETIN ENHANCES VASOCONSTRICTOR TONE VIA ENDOTHELIN-1 AND CONSTRICTOR PROSTANOIDS

Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoieti n (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 P GF(2 alpha) and TXB(2) was investigated in arterial rings incubated wi th rHuEPO. Endothelial cells from human umbilical veins (HUVECs) were isolated and cultured in flasks (37 degrees C, 5% CO2). After incubati on with rHuEPO, the formations of prostacyclin (as its stable metaboli te 6-keto-PGF(1 alpha)), PGF(2 alpha), PGE(2), thromboxane (TX) B-2 an d of ET-1 were measured by radioimmunoassays. rHuEPO had no direct vas oconstrictor 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, in dicating that endothelial vasoactive factors might be involved. Relaxa tions to acetylcholine (ACh, 1 mu M) were unaltered in the presence or absence of rHuEPO, suggesting that the endothelial NO-cGMP pathway wa s not impaired by rHuEPO. Incubation with rHuEPO (20 to 200 U/ml) incr eased the release of the vasoconstrictor mediators ET-1, PGF(2 alpha) and TXB(2), and decreased prostacyclin formation in isolated rabbit ar terial 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 responsivenes s to noradrenalin induced by rHuEPO in rabbit carotid artery, but simu ltaneous administration of rHuEPO with both antagonists completely abo lished the force increment. In conclusion, these studies show that a d ose-dependent shift in the balance of constrictor and relaxing prostan oids as well as an increased synthesis of ET-1 induced by rHuEPO lead to the enhanced vascular responsiveness to noradrenalin in isolated ra bbit arteries. The increased vascular responsiveness to noradrenalin, which is in line with clinical observations, may contribute to the hyp ertensive side effect associated with rHuEPO therapy in patients with chronic renal failure.