Restenosis following angioplasty in the swine coronary artery is inhibitedby an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A

Background-Platelet-derived growth factor (PDGF), a purported mediator of a rterial response to injury, stimulates proliferation, chemotaxis, and matri x production by activation of its membrane receptor tyrosine kinase. Becaus e these activities underlie restenosis, inhibition of the PDGF-receptor tyr osine kinase (PDGFr-TK) is postulated to decrease restenosis,; Methods and Results-RPR101511A is a novel compound which selectively and po tently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent prol iferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluat e the effect of RPR101511A (30 mg.kg(-1).d(-1) BID for 28 days following PT CA) on coronary restenosis, PTCA was performed in hypercholesterolemic mini pigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angi ographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98+/-0.09 versus 2.01+/-0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30+/-0.06 versus 2.52+/-0.13). At termination, there was an average 59% loss of gain in the vehicle-treated group but no loss of gain with RPR10151 1A (2.16+/-0.05 versus 2.59+/-0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/m edial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05). Conclusions-RPR101511A, which acts by inhibition of the PBGFr-TK, completel y prevented angiographic loss of gain following PTCA and significantly redu ced histological intimal hyperplasia.