Plaque
rupture and
thromboembolism play a major role in atherosclerotic acute syndrome. Experimental studies have demonstrated the potential direct anti-atherosclerotic effects of
calcium antagonists. We investigated the in vitro effect of
lercanidipine (
REC 15/2375), a third-generation, highly lipophilic
calcium antagonist on
cholesterol metabolism and
matrix metalloproteinases secretion in macrophages, two functions that predispose plaques to
rupture.
Lercanidipine (10(-6)-10(-5) M) inhibited
cholesterol esterification in macrophages and reduced cellular free and esterified
cholesterol accumulation from
acetylated LDL (63%, 62% of control P < 0.05, respectively). In addition,
lercanidipine inhibited the release of
metalloproteinases in the extracellular medium (50% and 95% inhibition
at 10(-5) M for
MMP-9 and
MMP-2, respectively). Experiments performed with
lercanidipine enantiomers or other
dihydropyridine derivatives, endowed with different lipophilicity and affinity for
calcium channels, indicated that the above effects could be related to the lipophilic, but not to the
calcium channel blocking properties of these molecules. When cells, after exposure to the
drug, were allowed to equilibrate,
lercanidipine inhibitory action could be observed at initial concentrations as low as 10(-9) M, which is the actual concentration range observed in plasma in clinical settings. In conclusion, our data indicate that
lercanidipine may exert potent anti-atherosclerotic effects by inhibiting macrophage functions involved in plaque stability.