Received for publication May 24, 2005.
Revised July 12, 2005.
Accepted for publication July 12, 2005.

Calcium channel blocker inhibits Western-type diet-evoked atherosclerosis development in ApoE-deficient mice

Abstract

Calcium channel blockers (CCBs) slow the progression of atherosclerosis. The purpose of the present experiments was to examine the action of lacidipine in a condition that accelerates the development of atherosclerosis in order to test the hypothesis that that the protective action of lacidipine in atherosclerosis is unrelated to the reduction of blood pressure. Male ApoE-deficient mice (6weeks old) were exposed either to normal chow (ND) or to Western-type diet (WD, Adjusted Calories Diet containing 42 % from fat) for 8 weeks. Western-type diet induced a reduction of NO-mediated, endothelium-dependent relaxation to acetylcholine (Max relaxation % = 55.8 ± 2 for ND and 46.6 ± 2 for WD, n=8, p< 0.05). Dose-relaxation curves to S-nitroso-N-acetylpenicillamine (SNAP) a NO donor were also significantly rightward shifted (n=7, ANOVA, p<0.01) in WD compared to ND arteries. Chronic treatment of WD mice with lacidipine (1 and 3 mg/kg/day) increased significantly the acetylcholine-evoked relaxation (to 76.6 ± 3.5 %, n=6, ANOVA, p<0.001) and prevented the loss of responsiveness to SNAP in mice exposed to WD. Plasma renin activity (PRA) and endothelin-1 (ET-1) plasma levels as well as TBARS levels in kidneys were significantly lower in WD mice treated with lacidipine than in untreated ones. In mice exposed to WD lacidipine reduced extension of atherosclerotic lesions, renal injury and increase in blood pressure. Experimental data indicate that inhibition of Western-type diet-evoked alterations is related to both antioxidant and vasoactive properties of lacidipine.

Key words: ApoE-deficient mice, atherosclerosis, calcium antagonist, calcium channel blocker, lacidipine, vasorelaxation