IN-VIVO AND IN-VITRO PRESSOR EFFECTS OF ERYTHROPOIETIN IN RATS

Hypertension (HTN) is a common complication of recombinant erythropoie tin (EPO) therapy, but the mechanism of the EPO-associated HTN is unce rtain. In the present study we examined the effects of EPO and the veh icle alone on rat caudal artery contractile response and basal and thr ombin-stimulated platelet cytosolic Ca2+ concentration ([Ca2+](i)) in vitro and on blood pressure (BP) and heart rate in vivo. At high conce ntrations (200 U/ml) EPO caused a small but consistent contraction in the caudal artery rings (P < 0.01) without affecting the response to e ither angiotensin II (ANG II) or the alpha(1)-agonist methoxamine. Inc ubation with EPO significantly increased basal platelet [Ca2+](i) (P < 0.01) and augmented the thrombin-induced rise of [Ca2+](i) in Ca2+-fr ee medium (P < 0.05). Long-term EPO administration led to a significan t elevation of BP within 2 wk regardless of whether the hematocrit was allowed to rise or was kept constant by dietary iron deficiency. In c ontrast, single intravenous administration of high-dose EPO (400 and 5 ,000 U/kg), estimated to yield plasma concentrations comparable with t hose employed in vitro, failed to either alter BP or modify the BP res ponse to ANG II during a 60-min observation period. This was associate d with a significant rise in plasma guanosine 3',5'-cyclic monophospha te but no discernible change in plasma atrial natriuretic peptide, sug gesting enhanced nitric oxide (NO) release. Thus, at high concentratio ns, EPO appears to possess a fast-acting presser effect in vitro but n ot in vivo. The observed discrepancy may be due to enhanced NO release with EPO administration in vivo. However, HTN does occur with repeate d EPO administration in a time-dependent and hematocrit-independent ma nner. This suggests that expression of the hypertensive effect of EPO in vivo involves a gradual conditioning process.