title: Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation.
abstract: OBJECTIVE
  Angiotensin (1-7) [A(1-7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1-7). In this study, the ability of A(1-7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury.
  
  
  METHODS
  Mice were exposed to TBI (doses of 2-7 Gray [Gy]) of cesium 137 gamma rays, followed by treatment with A(1-7), typical doses were 100-1000 μg/kg given once or once daily for a specified number of days depending on the study. Animals are injected subcutaneously via the nape of the neck with 0.1 ml drug in saline. The recovery of blood and bone marrow cells was determined. Effects of TBI and A(1-7) on survival and bleeding time was also evaluated.
  
  
  RESULTS
  Daily administration of A(1-7) after radiation exposure improved survival (from 60% to 92-97%) and reduced bleeding time at day 30 after TBI. Further, A(1-7) increased early mixed progenitors (3- to 5-fold), megakaryocyte (2- to 3-fold), myeloid (3- to 6-fold) and erythroid (2- to 5-fold) progenitors in the bone marrow and reduced radiation-induced thrombocytopenia (RIT) (up to 2-fold). Reduction in the number of treatments to 3 per week also improved bone marrow recovery and reduced RIT. As emergency responder and healthcare systems in case of nuclear accident or/and terrorist attack may be overwhelmed, the consequence of delayed initiation of treatment was ascertained. Treatment with A(1-7) can be delayed up to 5 days and still be effective in the reduction of RIT or acceleration of bone marrow recovery.
  
  
  CONCLUSIONS
  The data presented in this paper indicate that A(1-7) reduces the consequences of critical radiation exposure and can be initiated well after initial exposure with maximal effects on early responding hematopoietic progenitors when treatment is initiated 2 days after exposure and 5 days after exposure for the later responding progenitors and reduced thrombocytopenia. There was some effect of A(1-7) even when given days after radiation exposure.
authors.affiliation: School of Pharmacy, University of Southern California, Los Angeles, California, USA. krodgers@usc.edu
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Rodgers
authors.forename: Theresa
authors.initials: T
authors.lastname: Espinoza
authors.forename: Norma
authors.initials: N
authors.lastname: Roda
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Meeks
authors.forename: Colin
authors.initials: C
authors.lastname: Hill
authors.forename: Stan G
authors.initials: SG
authors.lastname: Louie
authors.forename: Gere S
authors.initials: GS
authors.lastname: Dizerega
mesh_terms: D000740:Anemia / Q000209:etiology / Q000517:prevention & control; D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D007970:Leukopenia / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000502:physiology; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D010446:Peptide Fragments; D011837:Radiation-Protective Agents; D000803:Angiotensin I; C118790:angiotensin I (1-7)