Direct Antiatherogenic Activity of Isradipine and Lacidipine on Neointimal Lesions Induced by Perivascular Manipulation in Rabbits

Abstract

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.

The Effects of Calcium Channel Blockers are not Related to their Chemical Structure in the Collar Model of the Rabbit

“…18 However, the effects of CCBs on intimal thickening, an early stage of atherosclerosis, seem to be contradictory. 11,12,19,20 During the last decade, our laboratory has investigated the effects of several CCBs on the formation of intimal thickening in the collar model. 11,12,21 Nicardipine, a CCB of the dihydropyridine class, has been shown to inhibit the formation of intimal thickening in this animal model.…”

Lacidipine Inhibits Adhesion Molecule and Oxidase Expression Independent of Blood Pressure Reduction in Angiotensin-Induced Vascular Injury

“…13,16 Others have also demonstrated that dihydropyridines affect directly cell infiltration and macrophage activation in vivo. [27][28][29] We have recently shown that dihydropyridines also lead to downregulation of ICAM-1 and VCAM and influence endothelial cell permeability. 30,31 We also demonstrated that monocyte infiltration was reduced by lacidipine.…”

Calcium-channel modulators for cardiovascular disease

“…A variety of animal models have been used to determine whether CCBs exert an inhibitory effect on atherosclerotic lesion formation. These models include the cholesterol-fed rabbit, in which the lesions resemble the fatty streak stage of atherosclerotic lesion development in humans [154][155][156]. Diet-induced atherosclerosis in monkeys is also used and, in this case, the lesions resemble those found in humans, both in pathology and distribution.…”