TOLERANCE DEVELOPMENT TO ANTIMITOGENIC ACTIONS OF PROSTACYCLIN BUT NOT OF PROSTAGLANDIN E-1 IN CORONARY-ARTERY SMOOTH-MUSCLE CELLS

This study compares the antimitogenic effects of iloprost and prostagl andin E-1 on platelet-derived growth factor-BE stimulated DNA synthesi s ([H-3]thymidine incorporation) in bovine coronary artery smooth musc le cells. When added 20-24 h after stimulation with platelet-derived g rowth factor-BB (20 ng/ml), both iloprost and prostaglandin E-1, conce ntration-dependently (IC50 3-5 nM) inhibited DNA synthesis. However, w hen added together with the growth factor (0-24 h), the inhibition of DNA synthesis by iloprost was markedly attenuated, indicating toleranc e development. In contrast, no tolerance to antimitogenic effects of p rostaglandin E-1 or forskolin were observed. When added to iloprost-to lerant cells, both prostaglandin E-1 and forskolin, still inhibited DN A synthesis. There was no evidence for transcriptional down-regulation of prostacyclin receptor gene by iloprost. The data demonstrate a tol erance development to antimitogenic actions of prostacyclin but not of prostaglandin E-1 and suggest that the receptors. mediating the antip roliferative actions of these prostaglandins, may be different. (C) 19 98 Elsevier Science B.V.