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 alpha(1)-adrenoceptors presen t on bone marrow (BM) cells [1-3]. Here we show that norepinephrine ad ministration in mice rescued hematopoiesis from the toxic effect of th e non-cell-cycle specific chemotherapeutic agent, carboplatin. Protect ion of granulocyte/macrophage colony-forming units (GM-CFUs) was alrea dy apparent only a few hours after carboplatin and nore pinephrine adm inistration. On day 3, hematopoietic rescue was reflected by higher le ukocyte and platelet counts. At its most effective dose (3 mg/kg, subc utaneously injected), norepinephrine protected 77% of the mice previou sly injected intravenously with 200 mg/kg of carboplatin (LD 100: 170 mg/kg). Simultaneous administration of the al-adrenoceptor antagonist prazosin reduced the percentage of surviving mice to 30%, indicating t hat al-adrenoceptors mediated most of the norepinephrine-induced hemat opoietic rescue. Consistently, prazosin administration also reduced bl ood counts and GM-CFUs. In vitro, norepinephrine (1 mu M) rescued GM-C FUs in BM cells, although this effect was counteracted by low concentr ations (0.1-10 nM) of prazosin. Our findings indicate a previously und escribed novel mechanism of hematopoietic regulation and may find appl ication in preventing the myeloablative effect of anticancer treatment s.