EFFECTS OF RAPAMYCIN ON GROWTH FACTOR-STIMULATED VASCULAR SMOOTH-MUSCLE CELL-DNA SYNTHESIS - INHIBITION OF BASIC FIBROBLAST GROWTH-FACTOR AND PLATELET-DERIVED GROWTH-FACTOR ACTION AND ANTAGONISM OF RAPAMYCIN BY FK506

Rapamycin (RPM) is a potent and effective immunosuppressant which we h ave shown previously to inhibit intimal thickening in rat allograft an d balloon-injured arteries. In this report, we have examined the effec ts of RPM on growth factor-induced vascular smooth muscle cell (VSMC) DNA synthesis. RPM potently inhibited platelet-derived growth factor ( PDGF) (IC50=5x10(-9) M) and basic fibroblast growth factor (bFGF) (IC5 0=8x10(-10) M)-induced VSMC DNA synthesis. In contrast, only the highe st concentrations of FK506 and CsA significantly altered PDGF- or bFGF -induced VSMC DNA synthesis. Addition of RPM (10(-9) M) at as late as 46 hr after growth factor addition still effectively suppressed bFGF- or PDGF-induced DNA synthesis by 76% and 54%, respectively. The extent of the antagonism of RPM's inhibition of bFGF-induced VSMC DNA synthe sis by FK506 was inversely proportional to RPM concentration and direc tly proportional to FK506 concentration.