Effect of lercanidipine and its (R)-enantiomer on atherosclerotic lesions induced in hypercholesterolemic rabbits.
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. 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. 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. 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.
Soma
M R
MR
Institute of Pharmacological Sciences, University of Milan, Italy.
Natali
M
M
Donetti
E
E
Baetta
R
R
Farina
P
P
Leonardi
A
A
Comparato
C
C
Barberi
L
L
Catapano
A L
AL
D000818:Animals; D001158:Arteries / Q000378:metabolism; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000627:therapeutic use*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004095:Dihydropyridines / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D006965:Hyperplasia / Q000188:drug therapy; D008264:Macrophages / Q000378:metabolism; D008297:Male; D011817:Rabbits
D002121:Calcium Channel Blockers; D002791:Cholesterol, Dietary; D004095:Dihydropyridines; C060343:lercanidipine