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

1 The in vivo antiatherogenic activity of the calcium antagonist lercanidipine and its (R)‐enantiomer was investigated in two different types of atherosclerotic 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)‐enantiomer at 3 mg kg −1 week −1 were given by subcutaneous injection for 10 weeks to White New Zealand rabbits, with cholesterol feeding beginning at week 2. The hyperplastic lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty streak lesions were induced by cholesterol feeding. In untreated animals ( n =5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries without collar showed a intima/media (I/M) ratio of 0.03±0.02, whereas in carotids with a collar the ratio was 2±0.42. In lercanidipine‐treated animals a significant and dose‐dependent effect on intimal hyperplasia was 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 enantiomer (3 mg kg −1 week −1 ) was as effective as the racemate (0.41±0.11). Proliferation 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 reduced 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 considered (arch, thoracic, abdominal) a significant and dose‐dependent effect in the thoracic and abdominal aorta was observed also at lower doses. The (R)‐enantiomer was as effective as lercanidipine. 4 These results suggest a direct antiatherosclerotic effect of lercanidipine, independent of modulation of risk factors such as hypercholesterolemia and/or hypertension as demonstrated by the absence of stereoselectivity.British Journal of Pharmacology (1998) 125 , 1471–1476; doi: 10.1038/sj.bjp.0702221