EFFECT OF SR-33805 ON ARTERIAL SMOOTH-MUSCLE CELL-PROLIFERATION AND NEOINTIMA FORMATION FOLLOWING VASCULAR INJURY

The possible activity of SR 33805 ylamio-propoxyl]-4-benzenesulfonyl]- 2-isopropyl-3- methyl-1-indole), a novel Ca2+ channel blocker, in earl y atherogenesis was investigated. In vitro, SR 33805 strongly inhibite d fetal calf serum-induced proliferation of cultured human aortic smoo th muscle cells with an IC50 value of 0.3 +/- 0.1 mu M (n = 3). In thi s respect, SR 33805 was several fold more active than the reference co mpounds: diltiazem, verapamil, nifedipine and fantofarone. SR 33805 wa s also a potent inhibitor of platelet-derived growth factor- or basic fibroblast growth factor-induced proliferation of human smooth muscle cells. SR33805 inhibited serum-stimulated Ca-45(2+) uptake in these ce lls, with an IC50 value of 47 +/- 18 nM. The effect of SR 33805 on int imal smooth muscle hyperplasia in rabbit carotid arteries subjected to air-drying endothelial injury was then investigated. After a 16-day t reatment, SR 33805 (6.0 mg/kg/day p.o.) inhibited the development of i ntimal thickening. Under the same experimental conditions, nifedipine, verapamil, diltiazem (2 x 6 mg/kg/day p.o. - 16 days) and fantofarone (12 mg/kg/day p.o. - 16 days) were inactive. These results show that SR 33805, a novel and potent Ca2+ channel blocker, can reduce myointim al thickening following endothelial injury.