BLOCKADE OF DNA-SYNTHESIS INDUCED BY PLATELET-DERIVED GROWTH-FACTOR BY TRANILAST, AN INHIBITOR OF CALCIUM-ENTRY, IN VASCULAR SMOOTH-MUSCLE CELLS

The present study was conducted to establish a pharmacological method of controlling growth of vascular smooth muscle cells (VSMC) by blocki ng calcium entry, In cultured rat VSMC, 1 nM platelet-derived growth f actor (PDGF) induced a biphasic elevation of cytoplasmic free calcium concentration, ([Ca2+](c)). The second sustained phase of [Ca2+](c) wa s dependent on extracellular calcium, At lower concentrations, PDGF in duced oscillatory changes in [Ca2+](c,) and reduction of extracellular calcium attenuated the oscillation, An antiallergic compound, tranila st, abolished the sustained phase of [Ca2+](c) induced by 1 nM PDGF. T ranilast also inhibited the oscillatory changes in [Ca2+](c) induced b y 200 pM PDGF, In addition, PDGF-induced calcium influx in the late G( 1) phase, as assessed by measuring the initial uptake of Ca-45, was in hibited by tranilast in a concentration-dependent manner. Tranilast al so inhibited PDGF-augmented DNA synthesis; the ID50 for the inhibition of DNA synthesis was nearly identical to that for calcium influx. Alt hough tranilast blocked PDGF-induced calcium entry, it did not affect PDGF-mediated autophosphorylation of the PDGF receptor, activation of phosphatidylinositol 3-kinase, activation of Ras or mitogen-activated protein kinase. Similarly, PDGF-induced elevation of diacylglycerol wa s not affected by tranilast. These results suggest that the antiallerg ic drug tranilast inhibits PDGF-induced DNA synthesis by blocking PDGF -medialed calcium entry. Tranilast may be of use in controlling PDGF-i nduced DNA synthesis in VSMC.