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

Abstract

BACKGROUND:

Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis.

METHODS AND RESULTS:

RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg. kg-1. d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically 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 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (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/medial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05).

CONCLUSIONS:

RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.

• Authors: G Bilder, T Wentz, R Leadley, D Amin, L Byan, B O'Conner, S Needle, H Galczenski, J Bostwick, C Kasiewski, M Myers, A Spada, L Merkel, C Ly, P Persons, K Page, M Perrone, C Dunwiddie
• Journal: Circulation (Circulation) Vol. 99 Issue 25 Pg. 3292-9 (Jun 29 1999) ISSN: 1524-4539 [Electronic] United States
• PMID: 10385505 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Quinoxalines
• RPR 101511A
• Thiophenes
• Protein-Tyrosine Kinases
• Receptors, Platelet-Derived Growth Factor

Topics

• Administration, Oral
• Angioplasty, Balloon, Coronary
• Animals
• Coronary Disease (prevention & control, therapy)
• Enzyme Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinoxalines (pharmacology)
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Recurrence
• Swine
• Thiophenes (pharmacology)
• Time Factors
• Tunica Intima (metabolism)
• Tunica Media (metabolism)