LISINOPRIL, AN ANGIOTENSIN-I-CONVERTING-ENZYME INHIBITOR, PREVENTS ENTRY OF MURINE HEMATOPOIETIC STEM-CELLS INTO THE CELL-CYCLE AFTER IRRADIATION IN-VIVO

The hemoregulatory peptide N-Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been shown in vivo to inhibit the cycling of murine hematopoietic stem cell s triggered into S-phase by either cytotoxic drug administration or ir radiation. This prop erty, further confirmed using in vitro models, de monstrates that the peptide has an in vivo protective effect on the he matopoietic system. AcSDKP has been shown to be a physiological substr ate of angiotensin I-converting enzyme (ACE), which catabolizes the pe ptide through a dipeptidasic activity. Thus, oral administration of AC E inhibitor to humans has led to an increase in the plasma AcSDKP conc entration. In the present paper, we report on the in vivo effect of li sinopril, an ACE inhibitor, on the proliferative status of murine hema topoietic stem cells triggered into S-phase by irradiation. Administra tion of lisinopril (10 mg/kg) 1 hour after irradiation led to a 90 to 100% inhibition of murine plasma ACE activity as observed during the f irst 4 hours postirradiation. This inhibition was correlated with a 60 0% increase in the endogenous plasma AcSDKP level and a total suppress ion at 24 hours of entry of the hematopoietic stem cell into the cell cycle. We discuss the possible role of ACE in the regulation of hemato poietic stem cell proliferation through control of the AcSDKP concentr ation.