Higher erythropoietin secretion in response to cobaltous chloride in post-hypoxic than in hypertransfused polycythemic mice.
BACKGROUND
We have shown previously that both erythrocyte production rate (EPR) and plasma erythropoietin (EPO) levels in response to hypoxia or to compounds able to stimulate EPO secretion are very much higher in post-hypoxic (PH) than in hypertransfused (HT) polycythemic mice with similar levels of hematocrit. Since it has been demonstrated that cobalt (Co) treatment rises renal EPO-mRNA and increases plasma EPO levels, the present study was conducted to determine whether there is a difference between PH and HT mice in relation to the erythropoietic response to Co and whether the stimulatory effect of Co on EPO secretion can be blunted by polycythemia.


METHODS
Adult female mice of the CF-1 strain were made polycythemic by either exposing them to 270 h of discontinuous hypoxia (18 h/d) in a hypobaric chamber maintained at 456 hPA (PH mice) or by injecting them with 0.8 ml of washed packed red cells on two consecutive days (HT mice). Measurement of the erythrocyte production rate (EPR) was made by RBC-59Fe uptake. Plasma EPO concentration was determined by RIA. Cobalt chloride (CoC12) was dissolved in saline and injected in doses of 4 and 8 umoles/mouse. Recombinant human EPO (HEMAX 4000, Bio Sidus SA, Argentina) was dissolved in PBS + albumin to the desired concentration.


RESULTS
By comparison with the corresponding dose-regression line for rHu-EPO, it was estimated that the responses (EPR) (measured as RBC-59Fe incorporation) of PH mice to sc injections of 4 and 8 umoles of CoC12 were equivalent to 95 and 145 mU of rHu-EPO, respectively. The response of HT mice to 4 umoles of the drug was not detectable. At the upper dose level, the response was equivalent to 52 mU of rHuEPO. Plasma immunoreactive EPO (iEPO) titers 12 h after COC12 (8 umoles) were not significantly different between normocythemic and PH mice. The observed values were significantly higher than those found in HT mice.


CONCLUSIONS
These findings demonstrate that EPO production in response to COC12 is depressed by polycythemia when induced by transfusion but not when induced by chronic exposure to hypobaric hypoxia. They also confirm, but not explain the nature of the conditioning effect of exposure to hypoxia which makes the mechanism controlling EPO secretion either more sensitive to EPO-secreting stimuli or unable to recognize the polycythemic state.
Alippi
R M
RM
Càtedra de Fisiologia, Facultad de Odontologia, Universidad de Buenos Aires, Republica Argentina.
Boyer
P
P
Leal
T
T
Barcelò
A C
AC
Martinez
M P
MP
Bozzini
C E
CE
D000818:Animals; D001803:Blood Transfusion; D003035:Cobalt / Q000494:pharmacology*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006400:Hematocrit; D006801:Humans; D000860:Hypoxia / Q000097:blood* / Q000150:complications; D051379:Mice; D011086:Polycythemia / Q000097:blood* / Q000209:etiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012636:Secretory Rate; D013268:Stimulation, Chemical
D011994:Recombinant Proteins; D004921:Erythropoietin; D003035:Cobalt; C018021:cobaltous chloride