Antiatherogenic activity of FR34235 (Nilvadipine), a new potent calcium antagonist. Effect on cuff-induced intimal thickening of rabbit carotid artery.

ABSTRACT

The antiatherogenic activity of FR34235 (Nilvadipine), a calcium antagonist, was examined in rabbits with carotid arteries sheathed with polyethylene cuffs, and compared with that of nifedipine, verapamil and diltiazem. The drugs were given intramuscularly in daily doses of 0.01-10 mg/kg for 3 weeks, starting on the day of cuff-placement. FR34235 dose-dependently inhibited the cuff-induced intimal thickening, and was more potent than the other calcium antagonists, whose order of potency was nifedipine, diltiazem and verapamil. In an in vitro experiment on inhibition of migration of rat aortic smooth muscle cells, using zymosan-activated air pouch exudate as a chemoattractant in modified Boyden chambers, FR34235 was also the most potent among the calcium antagonists tested. The IC50 values were 3.3 X 10(-11) M for FR34235, 1.7 X 10(-10) M for nifedipine, 6.0 X 10(-9) M for verapamil and 2.4 X 10(-7) M for diltiazem. Effects of these drugs on proliferation of rat aortic smooth muscle cells and rabbit platelet aggregation were also examined in vitro. At concentrations less than 10(-5) M, none of the drugs inhibited proliferation of the smooth muscle cells, and only verapamil inhibited collagen-induced platelet aggregation (IC50 = 9.0 X 10(-7) M). It is suggested that FR34235 should be useful for preventing and treating atherosclerosis. Inhibition of smooth muscle cell migration is thought to be its mechanism of antiatherogenic activity.