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.
Maestroni
G J
GJ
Center for Experimental Pathology, Istituto Cantonale diPatologia, Locarno, Switzerland.
Togni
M
M
Covacci
V
V
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells; D016190:Carboplatin / Q000633:toxicity*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D016190:Carboplatin; D009638:Norepinephrine; D011224:Prazosin