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

Abstract

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.

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