Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells.
We have recently demonstrated that adrenergic agents can affect hematopoiesis after syngeneic bone marrow transplantation in mice. In particular, chemical sympathectomy by 6-hydroxydopamine (6-OHDA) and/or administration of the alpha 1-adrenergic antagonist prazosin were shown to increase the concentration of blood granulocytes, platelets, and bone marrow colony-forming units-granulocyte/macrophage (CFU-GM), and to induce a granulocytic hyperplasia of the spleen. Here we show that prazosin can also enhance myelopoiesis and platelet formation in normal mice. Furthermore, noradrenaline and the alpha 1-adrenergic agonist methoxamine could directly inhibit the in vitro growth of GM-CFU. The effect of noradrenaline was counteracted by prazosin and by other alpha-adrenergic antagonists such as phentolamine and yohimbine, in the following order of potency: prazosin > phentolamine > yohimbine. In line with these results, we were able to demonstrate that 3H-prazosin binds specifically to both bone marrow cell membranes and intact bone marrow cells. Scatchard analysis of the binding to intact cells revealed the presence of two binding sites. A kd of 0.98 +/- 0.32 nM and a B max of 5 +/- 2.9 fM/2 x 10(6) cells characterized the higher affinity site, while the lower affinity site displayed a kd of 55.9 +/- 8.2 nM and a B max of 44 +/- 7.7 fM/mg protein. These saturation studies, together with competition experiments to evaluate the ability of various adrenergic compounds to displace 3H-prazosin binding, classified the higher affinity site as an alpha 1-adrenergic receptor. The remaining low affinity binding site remains to be characterized. Furthermore, separation of bone marrow cells by counterflow centrifugal elutriation (CCE) showed that the high-affinity binding is due to a lymphoid/stem cell fraction with no blasts and no GM-CFU progenitors. The low-affinity site was apparent on the rotor-off fraction, which was enriched with GM-CFU progenitor cells. These findings demonstrate that alpha-adrenergic receptors are present on bone marrow cells and participate in the regulation of hematopoiesis.
Maestroni
G J
GJ
Lab for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.
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D000818:Animals; D001792:Blood Platelets / Q000166:cytology; D001853:Bone Marrow / Q000737:chemistry* / Q000648:ultrastructure; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002498:Centrifugation / Q000379:methods; D005260:Female; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000502:physiology*; D008729:Methoxamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000032:analysis* / Q000378:metabolism / Q000502:physiology*; D014316:Tritium; D015016:Yohimbine / Q000494:pharmacology
D018340:Receptors, Adrenergic, alpha-1; D014316:Tritium; D015016:Yohimbine; D016627:Oxidopamine; D008729:Methoxamine; D011224:Prazosin; D010646:Phentolamine