Captopril inhibitsin vitroandin vivothe proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.