Effect of erythropoietin on blood pressure and on the vascular endothelial ET-1/ETB receptor system.
BACKGROUND
Recombinant human erythropoietin (rhEPO) increases blood pressure (BP) and the vascular production of endothelin-1 in renal failure rats. This study was designed to investigate the effect of rhEPO on BP and on the ET-1/ET(B)R system in rats with normal renal function. To further characterize the effect of rhEPO on the ET-1/ET(B)R system, we also studied heterozygous (+/-) ET(B)R knockout (KO) mice.


METHODS
The animals received either the vehicle or rhEPO (100 U/kg subcutaneously three times per week). ET(B)R(+/-) mice were compared with ET(A)R(+/-) and wild-type (WT) mice. In rats, the ET(B)R mRNA expression was assessed in blood vessels as well as the vascular ET(B)R density using immunohistochemistry. In mice, ET-1 concentration was measured in the thoracic aorta.


RESULTS
RhEPO administration increased hematocrit levels in all treated animals. This therapy had no effect on BP in normal rats, but it did increase vascular and renal cortex ET(B)R mRNA expression. Immunohistochemistry confirmed that the ET(B)R density was increased in blood vessel endothelium in these normal rats. In contrast, rhEPO increased BP in ET(B)R(+/-) mice and this pressor effect was associated with higher ET-1 concentrations in the thoracic aorta.


CONCLUSIONS
RhEPO exerts a pleotropic effect on the endothelial ET-1/ET(B)R system. The increase in endothelial ET(B)R expression may contribute to maintaining normal BP during rhEPO administration in normal animals. Conversely, conditions with deficient ET(B)R expression, such as in ET(B)R(+/-) mice, may lead to hypertension while receiving the same therapy.
Rodrigue
Marie-Eve
ME
Centre Hospitalier Universitaire de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Québec, Canada.
Brochu
Isabelle
I
D' orléans-Juste
Pedro
P
Larivièrea
Richard
R
Lebel
Marcel
M
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry; D001794:Blood Pressure / Q000187:drug effects*; D019332:Endothelin-1 / Q000032:analysis*; D004730:Endothelium, Vascular / Q000737:chemistry*; D004921:Erythropoietin / Q000494:pharmacology*; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000737:chemistry; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D044022:Receptor, Endothelin A / Q000032:analysis; D044023:Receptor, Endothelin B / Q000032:analysis* / Q000235:genetics; D011994:Recombinant Proteins
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D004921:Erythropoietin