LACIDIPINE: IN VIVO EFFECTS ON INTIMAL CAROTID THICKENING IN HYPERCHOLESTEROLAEMIC RABBITS

Targets for actual or potential pharmacological intervention In atherogenic processes are multiple and all aimed at causing existing lesions to regress, become stable, or progress more slowly, and also at preventing the formation of new lesions. Until recently, in antihypertensive trials little efforts was made to evaluate either the arterial changes or the effect of drug therapy on the arterial wall. Agents such as calcium antagonists have received increasing attention as pharmacological tools with antiatherogenic potentials. The in vivo direct antiatherogenic activity of lacidipine has been investigated on carotid rabbit intimal hyperplasia induced by perivascular stimulation of one carotid artery in hypercholesterolemic normotensive rabbits by assessing neolntimal formation. The contralateral carotid served as sham. The hypercholesterolemic diet (1.5% cholesterol) and lacidipine (1,3,10 mg/kg), mixed with food, were given daily for 8 weeks. Six weeks after dietary and drug treatment started, intimal hyperplasia was acutely induced in one carotid artery of each rabbit as described (Soma MR et al 1993). The drug treatment, at all doses, did not alter either rabbit blood pressure or plasma lipid levels. The neointimal formation was followed by measuring cross-sectional thickness of intimal (I) and medial (M) tissue of fixed arteries with light microscopy. In control animals, by 14 days after collar placement, the process of intimal myocyte proliferation was pronounced: the arteries with no collar showed an I/M tissue ratio of 0.03 ± 0.02, whereas In the carotids with collar the ratio was 20 fold higher (0.62 ± 0.04). The Intimal thickening was mostly cellular but abundant extracellular matrix and lipid depositions were present. Light microscopic observation of the sham tissue confirmed that it had no intimal thickening or cholesterol deposits. In the animals that received lacidipine neointimal formation was significantly decreased at all doses (I/M tissue ratios were 0.47 ± 0.02, 0.40 ± 0.09 and 0.32 ± 0.02, for the 1, 3, 10 mg/kg doses, respectively). Thus, the effect of the drug appeared to be dose-dependent, inhibiting by about 50% the intima media ratio at higher doses. These observations suggest a direct effect of lacidipine on smooth muscle cell migration and/or proliferation. The antiatherosclerotlc activity of lacidipine in this experimental situation is of scientific and therapeutic significance and suggests that this calcium antagonist act at an early stage of atherosclerosis. This direct antlatherosclerotic activity of lacidipine offers new therapeutic direction for such a calcium antagonist. Soma MR, Donetti E, Parolini C, Fumagalli R. Paoletti R. HMGCoA reductase inhibitors: in vivo effects on intimal carotid thickening in rabbits. Arteriosclerosis and Thrombosis 1993. 13(4): 563-570