Norepinephrine protects mice from acute lethal doses of carboplatin

We demonstrated in previous studies that adrenergic agents may affect hematopoiesis via high- and low-affinity alpha1-adrenoceptors present on bone marrow (BM) cells [1-3]. Here we show that norepinephrine administration in mice rescued hematopoiesis from the toxic effect of the non-cell cycle specific chemotherapeutic agent, carboplatin. Protection of granulocyte/macrophage colony-forming units (GM-CFUs) was already apparent only a few hours after carboplatin and norepinephrine administration. On day 3, hematopoietic rescue was reflected by higher leukocyte and platelet counts. At its most effective dose (3 mg/kg, subcutaneously injected), norepinephrine protected 77% of the mice previously injected intravenously with 200 mg/kg of carboplatin (LD 100: 170 mg/kg). Simultaneous administration of the alpha1-adrenoceptor antagonist prazosin reduced the percentage of surviving mice to 30%, indicating that alpha1-adrenoceptors mediated most of the norepinephrine-induced hematopoietic rescue. Consistently, prazosin administration also reduced blood counts and GM-CFUs. In vitro, norepinephrine (1 microM) rescued GM-CFUs in BM cells, although this effect was counteracted by low concentrations (0.1-10 nM) of prazosin. Our findings indicate a previously undescribed novel mechanism of hematopoietic regulation and may find application in preventing the myeloablative effect of anticancer treatments.