INHIBITION OF PROTEIN-SYNTHESIS AND ANTIPROLIFERATIVE EFFECT OF THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR TRANDOLAPRILAT IN RAT VASCULAR SMOOTH-MUSCLE CELLS

Objective: To investigate the effect of the angiotensin converting enz yme (ACE) inhibitor trandolaprilat on vascular smooth muscle cell grow th, and to analyse its mechanism of action. Design: Aortic vascular sm ooth muscle cells (VSMC) from Wistar-Kyoto rats were cultured, and cel l proliferation was analysed using a cell synchrony technique. Methods : Proliferative activity was assessed by [H-3]-thymidine uptake and do ubling time. Protein synthesis was assessed by [H-3]-leucine incorpora tion. Actin formation was measured using sodium dodecylsulphate-polyac rylamide slab gel electrophoresis and a densitometric assay. The effec t of trandolaprilat on translational protein synthesis was also examin ed using the cell-free protein synthesis system of reticulocyte lysate and messenger RNA from VSMC. Results- Trandolaprilat decreased [H-3]- thymidine uptake and increased the doubling time of randomly cycling V SMC. The cell synchrony study revealed that this antiproliferative eff ect was due to increased transition time from S to G2-M. Decreased cel l cycle progression during G2-M was reflected by inhibition of cellula r protein synthesis during this period. Cellular protein in randomly c ycling VSMC was also decreased by trandolaprilat. This decreased prote in synthesis was probably produced by inhibition of RNA translation. C onclusions. The ACE inhibitor trandolaprilat reduces VSMC proliferatio n by lengthening the G2-M phase of the cell cycle, and produces a decr ease in cellular protein content. This effect is probably mediated by inhibition of protein synthesis at the translational level.