Dose-Response Relationship between Norepinephrine and Erythropoiesis: Evidence for a Critical Threshold

Abstract

Severe traumatic injury elicits a neuroendocrine response that activates the sympathetic nervous system. Our previous work suggests that norepinephrine (NE) influences the bone marrow (BM) erythropoietic response. However, the dose-response relationship between NE and erythropoiesis remains unclear. Two days following chemical sympathectomy with 6-hydroxydopamine (6-OHDA) or injection with saline vehicle (SHAM), male Sprague-Dawley rats were infused continuously with either saline (NS) or increasing doses of NE for 5 d via osmotic pumps. Erythropoiesis was assessed by growth of erythroid progenitor colonies (BFU-E and CFU-E for early and late progenitors, respectively). Following chemical sympathectomy with 6-OHDA, both BFU-E and CFU-E growth is inhibited (42%∗ and 43%∗ versus 100% SHAM, ∗P < 0.05). SHAM rats with continuous infusion of exogenous NE show a clear dose-response inhibition of both BFU-E and CFU-E colony growth. In the 6-OHDA rats, continuous infusion of NE restored BFU-E and CFU-E growth at 10(-8) g/h and 10(-9) g/h, respectively. Erythroid precursor colony growth is inhibited in sympathectomized rats. In addition, supraphysiologic doses of exogenous NE inhibit normal erythropoiesis in a dose-dependent fashion. Following chemical sympathectomy with 6-OHDA, exogenous NE restores erythropoiesis in a narrow window. Therefore, NE has a complex interaction within the BM and the elevation of NE following traumatic injury impacts BM erythropoietic function.