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.