Effect of lercanidipine and its (R)-enantiomer on atherosclerotic lesions induced in hypercholesterolemic rabbits

1 The in vivo antiatherogenic activity of the calcium antagonist lercanidip ine and its (R)-enantiomer was investigated in two different types of ather osclerotic lesions (hyperplastic and fatty-streak lesions) in rabbits. 2 Lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) as well as its (R)-enant iomer at 3 mg kg(-1) week(-1) were given by subcutaneous injection for 10 w eeks to White New Zealand rabbits, with cholesterol feeding beginning at we ek 2. The hyperplastic lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty streak lesions were i nduced by cholesterol feeding. In untreated animals (n = 5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arter ies without collar showed a intima/media (I/M) ratio of 0.03+/-0.02, wherea s in carotids with a collar the ratio was 2+/-0.42. In lercanidipine-treate d animals a significant and dose-dependent effect on intimal hyperplasia wa s observed. I/M ratios were 0.73+/-0.4, 0.42+/-0.1, 0.32+/-0.1 for 0.3, 1, and 3 mg kg(-1) week(-1), respectively (P<0.05). The lercanidipine enantiom er (3 mg kg(-1) week(-1)) was as effective as the racemate (0.41+/-0.11). P roliferation of-smooth muscle cells, assessed by incorporation of BrdU into DNA, was reduced by about 50%, 70%, 85%, and 80% by lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) and its (R)-enantiomer, respectively. 3 The area of fatty-streaks in the aorta (n=11-15) was significantly reduce d by lercanidipine (3 mg kg(-1) week(-1), 16% vs 27%, P<0.05), a trend was observed also with lower doses. When different segments of the aorta were c onsidered (arch, thoracic, abdominal) a significant and dose-dependent effe ct in the thoracic and abdominal aorta was observed also at lower doses. Th e (R)-enantiomer was as effective as lercanidipine. 4 These results suggest a direct antiatherosclerotic effect of lercanidipin e, independent of modulation of risk factors such as hypercholesterolemia a nd/or hypertension as demonstrated by the absence of stereoselectivity.