The effect of agents interfering with soft tissue calcification and cell proliferation on calcific fibrous-fatty plaques in rabbits.

We tested agents that might suppress the formation of fibrous plaques which are the significant lesions in human atherosclerosis. Six groups of rabbits were studied for 8 weeks: one group was fed a control diet and five groups received an atherogenic diet known to produce accumulations of connective tissue in arterial lesions. One group received only the atherogenic diet and the remaining four groups were treated simultaneously with the calcification inhibitor, ethane hydroxy diphosphonate (EHDP), at two dosage levels, as well as the antimitotic agent, /V-desacetyl-A'-methylcolchicine (Colcemid), or a combination of EHDP and Colcemid, respectively. None of the drugs reduced to normal the high serum cholesterol levels induced by the diet, but all reduced the elevated serum calcium concentrations occurring in untreated rabbits on the atherqgenic diet. The lesions in the untreated group included marked accumulations of intraand extracellular lipids (chiefly cholesterol) and calcium, as well as of glycosaminoglycans, collagen, and elastin. Aortic "elastin" from these atherosclerotic rabbits had an increased content of polar amino acids, calcium, and cholesterol. Treatment with EHDP or Colcemid alone markedly inhibited these atherosclerotic processes, whereas combination therapy with both drugs completely suppressed all aspects of atherogenesis except for a few superficial lipid deposits close to the vessel lumen. The prevention of excessive deposition of arterial calcium by EHDP and also by Colcemid may play an important role in the antiatherogenic effect of these drugs.