Antiatherogenic properties of calcium antagonists

A generalized accumulation of cholesterol, calcium and matrix materials (collagen, elastin and proteoglycans) occurs in an age-dependent manner in major arteries. Human atherogenesis is a disease of arteries characterized by a focal accumulation of fibrous matrix elements, lipids and calcium at lesion sites. Studies in cholesterol-fed animal models have indicated that calcium competitors and chelating agents can reduce calcium, lipid and matrix accumulation in arterial lesions and reduce the extent of lesion formation. These agents generally alter soft and hard tissue calcium pools or have deleterious side-effect profiles. Antiatherogenic studies with calcium antagonists (which have been shown to be safe in human clinical studies) have created confusion because of conflicting results. It is apparent, however, that high doses of calcium antagonists can significantly decrease atherogenic lesion development in cholesterol-fed rabbits. The antiatherogenic effects of calcium antagonists may be the result of changes in intracellular calcium pools within smooth muscle cells, which may lead to alterations in cellular metabolic activity or may be due to activities not related to calcium channel effects. Several mechanisms involving regulation of lipoprotein receptor synthesis, lipoprotein uptake or degradation, cholesterol ester hydrolytic activity and arterial matrix synthesis are discussed as potential sites of activity for calcium antagonists. A dihydropyridine channel antagonist, PN 200-110 (isradipine), has been shown to be a very potent antiatherogenic agent in the rabbit and also to be a potent inhibitor of smooth muscle cell matrix synthesis.