lacidipine and Hypercholesterolemia

The in vivo antiatherogenic activity of two calcium antagonists of the dihydropyridine class (isradipine and lacidipine) was investigated in a new experimental model. The proliferative lesion induced in the rabbit carotid artery was obtained by positioning a hollow silastic collar around the vessel. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries obtained 14 days after collar placement. The effectiveness in inhibiting neointimal formation was assessed for isradipine (0.5, 1 and 4 mg kg-1 day-1) in normocholesterolemic (NC) animals and for lacidipine (1, 3, and 10 mg kg-1 day-1) in hypercholesterolemic (HC) rabbits. In NC control animals a neointimal formation was clearly detectable (I/M 0.53 +/- 0.18, n = 5). In isradipine-treated groups I/M ratios were significantly decreased (0.15 +/- 0.03, 0.12 +/- 0.02, 0.1 +/- 0.02 for the 0.5, 1 and 4 mg kg-1 day-1 doses respectively). In HC rabbits the administration of cholesterol 1% mixed with food and drug treatment started either 60 days before collar insertion (pretreated group, HC60) or on the same day (non pretreated group, HC15) of the collar placement. Only the pharmacological pretreatment was effective in reducing neointimal formation (0.47 +/- 0.02, 0.4 +/- 0.09, and 0.32 +/- 0.02 for dose 1, 3 and 10 mg kg-1 day-1 vs 1.1 +/- 0.14 in control animals). The inhibition of neointimal hyperplasia was much less evident in nonpretreated animals (0.7 +/- 0.15, 0.6 +/- 0.18 and 0.43 +/- 0.08 for dose 1, 3, and 10 mg kg-1 day-1 vs 0.72 +/- 0.2 in control animals). These results suggest a direct antiatherosclerotic effect of isradipine and lacidipine on neointimal hyperplasia induced in NC and HC pretreated rabbits independently of modulation of risk factors such as hypercholesterolemia and/or hypertension.

Topics: Animals; Arteriosclerosis; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Dose-Response Relationship, Drug; Hypercholesterolemia; Isradipine; Male; Muscle, Smooth, Vascular; Neovascularization, Pathologic; Rabbits

1. The in vivo antiatherogenic activity of the calcium antagonist, lacidipine, was investigated in two different types of atherosclerotic lesions (proliferative and fatty lesions) induced in rabbits. 2. The proliferative lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty lesions were induced by cholesterol feeding. Cholesterol (1%) and lacidipine (1, 3, and 10 mg kg-1) were given daily mixed with standard diet for 8 weeks to White New Zealand rabbits. The intimal hyperplasia (proliferative lesion) was induced 6 weeks after dietary and drug treatment started. 3. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals (n = 5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries with no collar (sham) showed an I/M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.62 +/- 0.12. In lacidipine-treated animals a significant and dose-dependent effect on proliferative lesions at all three doses tested, was observed. I/M ratios were 0.47 +/- 0.02, 0.40 +/- 0.09, 0.32 +/- 0.02 for doses 1, 3, and 10 mg kg-1 day-1, respectively (P < 0.05). 4. The fatty lesion extent was significantly reduced by lacidipine at the 10 mg kg-1 day-1 dose, although a trend was also observed with lower dosage. 5. These results suggest a direct antiatherosclerotic effect of lacidipine, independent of modulation of risk factors such as hypercholesterolaemia and/or hypertension. Furthermore, the proliferative lesions are apparently more sensitive to lacidipine than are lipid-rich lesions.

Topics: Animals; Aorta; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Hypercholesterolemia; Hyperplasia; Lipids; Male; Rabbits