PERINDOPRIL STIMULATES CULTURED MESANGIAL CELL ACTIVATION VIA BRADYKININ ACCUMULATION

Angiotensin I converting enzyme inhibitors have become important drugs for the treatment of hypertension, preventing angiotensin II generati on. We have studied the effect of an angiotensin I converting enzyme i nhibitor, perindopril, on mesangial cell contraction and proliferation , and a possible role of bradykinin as a mediator of the observed effe cts of perindopril. Perindopril(10(-5) M) and bradykinin (10(-7) M) in duced decreases in planar cell surface area, that were time-dependent. Preincubation with the bradykinin B2 receptor antagonist D-Arg[Hyp(3) ,D-Phe(7)]bradykinin (10(-5) M) significantly blunted the contractile response to perindopril and bradykinin. Both perindopril and bradykini n induced an increased [H-3-]thymidine incorporation into DNA and the number of viable cells. These effects were reduced significantly by br adykinin B2 receptor antagonist D-Arg[Hyp(3),D-Phe(7)]bradykinin. Kall ikrein activity was detected in cultured mesangial cells. The addition of perindopril to wells containing mesangial cells induced a 7 times increase in bradykinin concentration in culture medium. Low but signif icant amounts of bradykinin were detected in wells containing only cul ture medium and 10% fetal calf serum. The presence of kallikrein (0.1 U/ml) induced an increase in bradykinin in the culture medium. In conc lusion, perindopril induces mesangial cell contraction and proliferati on, effects that could be mediated by an increase in bradykinin concen tration in the culture medium.