Acute effects of recombinant human erythropoietin on plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients

Background. The pathogenesis of rHuEpo-induced hypertension in haemodialysis (HD) patients still remains uncertain. Endothelin-1 (ET-1) is produced from proendothelin-1 (proET-1) by an endothelin-converting enzyme. 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 activity of endothelin-converting enzyme (ECE) has been proposed as an important factor in the pathophysiology of various hypertensive diseases. However there is no report on whether a change in the rate of conversion of proET-1 to ET-1 may be involved in the pathogenesis of rHuEpo-induced hypertension. The purpose of this study was to ascertain the potential 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 of 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 group (10 HD patients). Results. Plasma erythropoietin levels reached maximal 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 (14.7 +/- 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 in 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 interdialysis hypertension following a single i.v. injection of rHuEpo, the molar ratio of ET-1 over proET-1 (ET-1/proET-1) was significantly higher than in patients without hypertension. In addition, the increase in ET-1 levels was significantly greater in patients with interdialysis hypertension, while changes in proET-1 level were similar in both hypertensive 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. Differences 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.