Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities.
Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EPO) in some organs (e.g., the brain) is higher than for treatment of anemia. Notably, a dose-dependent risk of adverse effects has been associated with rhEPO administration, especially in high-risk groups, including polycythemia-hyperviscosity syndrome, hypertension, and vascular thrombosis. Of note, several clinical trials employing relatively high dosages of rhEPO in oncology patients were recently halted after an increase in mortality and morbidity, primarily because of thrombotic events. We recently identified a heteromeric EPO receptor complex that mediates tissue protection and is distinct from the homodimeric receptor responsible for the support of erythropoiesis. Moreover, we developed receptor-selective ligands that provide tools to assess which receptor isoform mediates which biological consequence of rhEPO therapy. Here, we demonstrate that rhEPO administration in the rat increases systemic blood pressure, reduces regional renal blood flow, and increases platelet counts and procoagulant activities. In contrast, carbamylated rhEPO, a heteromeric receptor-specific ligand that is fully tissue protective, increases renal blood flow, promotes sodium excretion, reduces injury-induced elevation in procoagulant activity, and does not effect platelet production. These preclinical findings suggest that nonerythropoietic tissue-protective ligands, which appear to elicit fewer adverse effects, may be especially useful in clinical settings for tissue protection.
Coleman
Thomas R
TR
The Kenneth S. Warren Institute, Warren Pharmaceuticals, Ossining, NY 10562, USA. tcoleman@kswi.org
Westenfelder
Christof
C
Tögel
Florian E
FE
Yang
Ying
Y
Hu
Zhuma
Z
Swenson
Leanne
L
Leuvenink
Henri G D
HG
Ploeg
Rutger J
RJ
d'Uscio
Livius V
LV
Katusic
Zvonimir S
ZS
Ghezzi
Pietro
P
Zanetti
Adriana
A
Kaushansky
Kenneth
K
Fox
Norma E
NE
Cerami
Anthony
A
Brines
Michael
M
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003029:Coagulants / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D051379:Mice; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D014471:Umbilical Veins
D003029:Coagulants; C488171:carbamylated erythropoietin; D004921:Erythropoietin