Influence of bisphosphonate on the negative erythropoietic effects of uranyl nitrate

Uranium salts, such as uranyl nitrate, induce severe renal dysfunction and tubular necrosis and a significant impairment of both oxygen dependent erythropoietin production and response to recombinant human erythropoietin. All effects are transient and reach maximal severity on the 7th day post injection. We investigated the effects of ethane 1-hydroxy-1, 1-bisphosphonate, which counteracts the inhibitory effect of uranyl nitrate on bone formation, on the negative erythropoietic effects of uranyl nitrate. Adult female Wistar rats received 1 mg/kg body weight of uranyl acetate by the i.v. route. Ethane 1-hydroxy-1,1-bisphosphonate was injected simultaneously at a dose of 7.5 mg/kg by the same route. Seven days after drug injections, plasma erythropoietin was estimated after hypobaric hypoxemia or cobalt chloride administration. The response to exogenous erythropoietin was also measured in uranyl nitrate- and/or ethane 1-hydroxy-1,1-bisphosphonate-injected rats made polycythemic by transfusion. The erythroid response was quantitated in terms of red blood cell 59iron uptake. Ethane 1-hydroxy-1, 1-bisphosphonate counteracted the effect of uranyl nitrate on oxygen-dependent and cobalt-dependent erythropoietin production, but did not correct the right shift of the dose-response relationship for exogenous erythropoietin induced by uranyl nitrate in the polycythemic rat.