Effect of angiotensin II and angiotensin(1-7) on hematopoietic recovery after intravenous chemotherapy.

Abstract

Previous studies have shown that angiotensin peptides stimulate the proliferation of hematopoietic progenitors in vitro, promote survival after exposure to lethal irradiation as well as accelerate the recovery of white blood cells (WBC), i.e., lymphocytes, monocytes and neutrophils, and platelets. These changes in the level of formed elements in the blood after irradiation was thought to be due to increases in the numbers of bone marrow progenitors including myeloid, erythroid and megakaryocyte progenitors by the action of angiotensin peptides. In view of these findings, the effect of angiotensin peptides on recovery after chemotherapy was assessed. The effect of angiotensin II (AII) and angiotensin(1-7) (A1-7) on the recovery of WBC and platelets in the blood, as well as the number of myeloid, erythroid and megakaryocyte progenitors in the bone marrow and the number of myeloid progenitors in the blood after intravenous administration of chemotherapeutic drugs was assessed in a mouse model. RESULTS. In initial studies, subcutaneous administration of 10 or 100 microg/kg per day of AII starting either 2 days before or 2 days after intravenous administration of 5-fluorouracil (5FU) accelerated WBC recovery (return to baseline between 7 and 14 days). Further, consistent with previous observations, the number of myeloid progenitors in the bone marrow and blood was increased after systemic administration of angiotensin peptides. The comparability of A(1-7) and AII in their effect on hematopoietic recovery after chemotherapy was shown in subsequent studies. Daily administration of both AII and A(1-7) increased platelet numbers in the peripheral blood and myeloid, erythroid and megakaryocyte progenitors in the bone marrow. As 5FU is not a stem cell toxin, these studies were repeated with administration of A(1-7) initiated before or after intravenous cyclophosphamide. Following treatment with A(1-7) before cyclophosphamide the numbers of circulating WBC initially increased and then decreased starting on day 14. Following treatment with A(1-7) 2 days after cyclophosphamide the numbers of WBC and the numbers of myeloid progenitors increased in the peripheral blood and bone marrow. These findings suggest that angiotensin peptides accelerate hematopoietic recovery in multiple cellular lineages after chemotherapy, perhaps through an increase in the number of early hematopoietic progenitors.