U-61, 431F, A STABLE PROSTACYCLIN ANALOG, INHIBITS THE PROLIFERATION OF BOVINE VASCULAR SMOOTH-MUSCLE CELLS WITH LITTLE ANTIPROLIFERATIVE EFFECT ON ENDOTHELIAL-CELLS

The effects of U-61, 431F, ciprostene, a stable prostacyclin analogue, were examined on the proliferation of cultured quiescent bovine aortic endothelial cells (EC) and smooth muscle cells (SMC). After stimulation with 5% fetal calf serum, U-61, 431F suppressed both the DNA systhesis and proliferation of SMC dose-dependently at the concentration of 3 approximately 100-mu-M, but had no effect on either of them in EC at a concentration of up to 30-mu-M. The inhibitory effect on DNA synthesis was greater in SMC than in EC at 3 approximately 50-mu-M. When SMC were stimulated with platelet-derived growth factor (PDGF) for 2 hrs followed by a 22-hr incubation with insulin, U-61, 431F (1 approximately 50-mu-M) administered at the time of PDGF stimulation did not inhibit DNA synthesis. SMC initiated and terminated DNA synthesis at about 15-18 h and 24 h after stimulation with serum, respectively. Inhibition of DNA synthesis in serum-stimulated SMC as a function of the addition time of U-61, 431F reduced at 3-12 h after the stimulation. U-61, 431F raised the cyclic AMP (cAMP) content in SMC. Moreover, a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and a more specific cAMP phosphodiesterase inhibitor, Ro 20-1724, augmented the inhibition of DNA synthesis in SMC concomitant with further elevation of cAMP level. These results suggest that U-61, 431F inhibits DNA synthesis of SMC acting in the progression stage rather than in the competence stage, with little antiproliferative effect on EC. cAMP may play an important role in its antiproliferative action in SMC.