DIRECT ANTIATHEROGENIC ACTIVITY OF ISRADIPINE AND LACIDIPINE ON NEOINTIMAL LESIONS INDUCED BY PERIVASCULAR MANIPULATION IN RABBITS

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 rab bit carotid artery was obtained by positioning a hollow silastic colla r around the vessel. The neointimal formation was determined by measur ing cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries obtained 14 days after collar placement. The effectiven ess 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 hypercholesterolem ic (HC) rabbits. In NC control animals a neointimal formation was clea rly 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 3 mg kg(-1) day(-1) doses respectively), In H C rabbits the administration of cholesterol 1% mixed with food and dru g treatment started either 60 days before collar insertion (pretreated group, HC60) or on the same day (non pretreated group, HC15) of the c ollar placement, Only the pharmacological pretreatment was effective i n 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 a nimals). The inhibition of neointimal hyperplasia was much less eviden t in nonpretreated animals (0.7+/- 0.15, 0.6+/-0.18 and 0.43+/-0.08 fo r 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 isradi pine and lacidipine on neointimal hyperplasia induced in NC and HC pre treated rabbits independently of modulation of risk factors such as hy percholesterolemia and/or hypertension. (C) 1997 The Italian Pharmacol ogical Society.