Effect of SR 33805 on arterial smooth muscle cell proliferation and neointima formation following vascular injury.
The possible activity of SR 33805 ([[N-[dimethoxy-3,4-phenethyl]-N- methylamino-propoxyl]-4-benzenesulfonyl]-2-isopropyl-3-methyl-1-in dole), a novel Ca2+ channel blocker, in early atherogenesis was investigated. In vitro, SR 33805 strongly inhibited fetal calf serum-induced proliferation of cultured human aortic smooth muscle cells with an IC50 value of 0.3 +/- 0.1 microM (n = 3). In this respect, SR 33805 was several fold more active than the reference compounds: diltiazem, verapamil, nifedipine and fantofarone. SR 33805 was also a potent inhibitor of platelet-derived growth factor- or basic fibroblast growth factor-induced proliferation of human smooth muscle cells. SR 33805 inhibited serum-stimulated 45Ca2+ uptake in these cells, with an IC50 value of 47 +/- 18 nM. The effect of SR 33805 on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to air-drying endothelial injury was then investigated. After a 16-day treatment, SR 33805 (6.0 mg/kg/day p.o.) inhibited the development of intimal 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 myointimal thickening following endothelial injury.
Dol
F
F
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Schaeffer
P
P
Lamarche
I
I
Mares
A M
AM
Chatelain
P
P
Herbert
J M
JM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries; D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011817:Rabbits; D013450:Sulfones / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D007211:Indoles; D013450:Sulfones; D016222:Fibroblast Growth Factor 2; C084255:SR 33805; D004815:Epidermal Growth Factor; D002118:Calcium