ACUTE EFFECTS OF RECOMBINANT-HUMAN-ERYTHROPOIETIN ON PLASMA-LEVELS OFPROENDOTHELIN-1 AND ENDOTHELIN-1 IN HEMODIALYSIS-PATIENTS

Background. The pathogenesis of rHuEpo-induced hypertension in haemodi alysis (HD) patients still remains uncertain. Endothelin-1 (ET-1) is p roduced from proendothelin-1 (proET-1) by an endothelin-converting enz yme. Since proET-1 is known to have approximately 1/100 the potency of ET-1 for contracting an isolated blood vessel, the change in the acti vity of endothelin-converting enzyme (ECE) has been proposed as an imp ortant factor in the pathophysiology of various hypertensive diseases. However there is no report on whether a change in the rate of convers ion of proET-1 to ET-1 may be involved in the pathogenesis of rHuEpo-i nduced hypertension. The purpose of this study was to ascertain the po tential role of ECE in the development of rHuEpo-induced hypertension. Methods. The levels of plasma erythropoietin, proET-1, ET-1, and mean arterial blood pressure (MAP) were measured following a single dose o f rHuEpo (100 U/kg) in HD patients with 24-h ambulatory blood pressure monitoring. Different routes of administration (19 intravenous group, 10 subcutaneous group) were compared to a placebo-injected control gr oup (10 HD patients). Results. Plasma erythropoietin levels reached ma ximal value 5 min after i.v. injection of rHuEpo (13.1 +/- 2.4 vs 2780 .9 +/- 290.1 mU/ml, P < 0.01), whereas it was 6 h in the s.c. group (1 4.7 +/- 3.8 vs 38.9 +/- 17.7 mU/ml, P < 0.05). A significant increase in MAP was noted 30 min after rHuEpo injection, which lasted for 3 h i n the i.v. group. However, no significant changes in MAP were noted in patients given rHuEpo subcutaneously. Both the plasma concentrations of proET-1 and ET-1 started to increase from 10 min after i.v. rHuEpo administration, with the proET-1 reaching a peak level at 30 min (13.5 +/- 7.4 vs 21.6 +/- 3.8 pg/ml, P < 0.05) and the ET-1 at 1 h (4.2 +/- 2.6 vs 9.9 +/- 4.8 pg/ml, P < 0.05). In patients with significant int erdialysis hypertension following a single i.v. injection of rHuEpo, t he molar ratio of ET-1 over proET-1 (ET-1/proET-1) was significantly h igher than in patients without hypertension. In addition, the increase in ET-1 levels was significantly greater in patients with interdialys is hypertension, while changes in proET-1 level were similar in both h ypertensive and non-hypertensive groups. Changes in interdialysis MAP (Delta IDMAP) was significantly correlated with Delta ET-1 during the interdialysis period, but not with Delta proET-1. Conclusion. Differen ces in ET-1/proET-1 ratio in relation to changes in MAP after a single intravenous administration of rHuEpo suggest a potential role for ECE in the pathogenesis of rHuEpo-induced hypertension.