OBJECTIVE: To determine whether the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a physiological hemorcgulatory inhibitor, has a biological function in nonhematopoietic cells (rat renal interstitial fibroblasts). METHODS: Cell proliferation was measured using standard cell culture techniques and the alama blue colorimctric assay. RESULTS: OD measurement of alamar blue absorption at 48 h was significantly inhibited in fibroblasts exposed to 1 μmol AcSDKP (P<0.01). During the 48hour alamar blue absorption, only AcSDKP in concentrations of 10-7 mol/L, 10-6 mol/L, and 10-5 mol/L had significant inhibiting effects compared to cells grown in the 5% FBS RPMI 1640 media alone. The inhibition was dose dependent, and disappeared at AcSDKP concentrations higher than 10-5 mol/L or lower than 10-8 mol/L. Maximum inhibition occurred at an AcSDKP concentration of 10-6 mol/L (33% suppression). CONCLUSIONS: The inhibiting effect of AcSDKP is not limited to hematoposis cells. AcSDKP is specifically cleaved to an inactive form by the N terminal active site of angiotensin converting enzyme (ACE) and ACE inhibitors (ACEI) can increase the concentration of AcSDKP. It suggests that AcSDKP may be an endogenous modulator of renal cell proliferation and the antiproliferative action of ACEI in renal diseases may be partly mediated by AcSDKP.