In vivo and in vitro pressor effects of erythropoietin in rats.
Vaziri, N. D., X. J. Zhou, J. Smith, F. Oveisi, K. Baldwin, R E.
Purdy.
Departments of Medicine, Pharmacology and Physiology, University of
California, Irvine, Irvine, California
APStracts 2:0121F, 1995.
Hypertension (HTN) is a common complication of recombinant
erythropoietin (EPO) therapy but the mechanism of the EPO-associated
HTN is uncertain. In the present study we examined the effects of EPO
and the vehicle alone on rat caudal artery contractile response and
basal and thrombin-stimulated platelet [Ca++]i in vitro and on blood
pressure (BP) and heart rate in vivo. At high concentrations (200
U/ml) EPO caused a small but consistent contraction in the caudal
artery rings (p <0.01) without affecting the response to either
angiotensin II (AII), or 1-agonist, methoxamine. Incubation with EPO
significantly increased basal platelet cytosolic [Ca++]i (p
<0.01) and augmented the thrombin-induced rise of [Ca++]i in
Ca++-free medium (p <0.05). Long-term EPO administration led to
a significant elevation of BP within two weeks whether the hematocrit
was allowed to rise or kept constant by dietary iron deficiency. In
contrast, single IV administration of high-dose EPO (400 and 5000
U/kg) estimated to yield plasma concentrations comparable with those
employed in vitro failed to either alter BP or modify the BP response
to AII during a 60-minute observation period. This was associated
with a significant rise in plasma cGMP but no discernible change in
plasma ANP, suggesting enhanced nitric oxide (NO) release. Thus, at
high concentrations EPO appears to possess a fast-acting pressor
effect in vitro but not in vivo. The observed discrepancy may be due
to enhanced nitric oxide release with EPO administration in vivo.
However, HTN does occur with repeated EPO administration in a time
-dependent and hematocrit-independent manner. This suggests that
expression of the hypertensive effect of EPO in vivo involves a
gradual conditioning process.
Received 23 May 1994; accepted in final form 26 June 1995.
APS Manuscript Number F170-4.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 July 1995.