Calcium antagonists as anti-atherosclerotic agents

Abstract

Hypercholesterolaemia and hypertension are two major risk factors for atherosclerosis. Each contributes to the progression of plaque, which can eventually occlude arteries leading to myocardial infarction (MI), stroke and peripheral vascular damage. Both elevated blood pressure and high plasma cholesterol can now be controlled with anti-hypertensives and medicines such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, but no treatments are available that act specifically to reduce or reverse the progression of plaque. Calcium entry blockers (CEBs) are potent anti-hypertensives. However, the rationale for the use of a CEB to interfere with the mechanisms of plaque formation is also strong. It can be hypothesised that CEBs should potentially be able to reduce cholesterol deposition, cellular proliferation and migration and increased cellular matrix, since all of these processes involve calcium. However, CEBs are a heterogeneous class, differing in terms of structure, potency, vascular selectivity and duration of action. In addition, some possess additional properties such as anti-oxidant activity. The newer, third generation dihydropyridines, such as lacidipine, which combine potent CEB activity with long duration of action and anti-oxidant activity, offer the best hope of demonstrating anti-atherosclerotic effects in man. Animal data have confirmed that CEBs are able to reduce plaque progression, though to differing extents. Few so far have been assessed in man. Of those tested, results have not been encouraging. However, the ongoing trials with longer-acting compounds, such as lacidipine (ELSA), are of longer duration and are using B-mode ultrasonography monitoring to afford more precise measurements of atherosclerotic plaque progression. Thus, more consistent daily cover by the CEB should be expected, and the longer monitoring period and the more sensitive measurement should afford an improved chance of demonstrating clinical efficacy.