CHOLESTEROL, CALCIUM AND ATHEROSCLEROSIS - IS THERE A ROLE FOR CALCIUM-CHANNEL BLOCKERS IN ATHEROPROTECTION

It is well known that the atherogenic dyslipidemias of either elevated serum LDL or reduced HDL levels correlate with the degree and severit y of atherosclerosis. However, how this leads to atherogenesis is poor ly understood. A role for cellular oxidative stress mediated by oxidiz ed LDL has gained widespread acceptance, but this pathway is unlikely to be the sole atherogenic signal. Recent evidence obtained from arter ial smooth muscle cells (SMC) and endothelial cells (EC) is consistent with another pathway that may explain, in part, the early alterations contributing to the initiation of cellular atherogenic modification. This pathway involves enrichment of the cell plasma membrane with chol esterol. In SMC, in vitro (cell culture) and in vivo (cholesterol feed ing) experiments demonstrate that cholesterol enrichment of the SMC me mbrane occurs rapidly and is associated with an increase in membrane b ilayer width, calcium permeability, and cell proliferation. Removal of excess membrane cholesterol with human HDL restores these alterations , suggesting that this membrane structural 'defect' mediates these cha nges in cell function. In vitro, the increased calcium permeability is inhibitable by calcium channel blockers (CCBs), but in vivo, a calciu m 'leak' pathway develops that is virtually uninhibitable. It is not s urprising that the literature on the application of CCBs for atheropro tection is not wholly convincing. However, with the advent of the new third generation of CCBs, new hope arises. One of the first CCBs of th is generation is amlodipine (Norvasc), a charged dihydropyridine that has a remarkable pharmacologic profile. First, it is markedly lipophil ic allowing it to partition readily into cell membranes. Second, in th e membrane it has the ability to re-order, or restore, the 'swollen' m embrane bilayer back to normal in atherosclerotic SMC. Third, it has p otent antioxidant properties. Fourth, it appears to inhibit the expres sion of a variety of genes implicated in atherogenesis. Fifth, it is a CCB. Amlodipine has demonstrated atheroprotection in both rabbit and subhuman primate models of this disease. We propose that cellular alte rations induced by enrichment of the cell membrane with cholesterol, w hich appears to modulate SMC to the atherosclerotic phenotype, are inh ibitable by amlodipine through a combination of its varied pharmacolog ic properties. The potential for atheroprotection with amlodipine is c urrently being investigated in a human trial (PREVENT trial) and the r esults of this trial will determine the relevance of the preclinical f indings to humans. (C) 1997 Elsevier Science Ireland Ltd.