Calcium antagonists retard extracellular matrix production in connective tissue equivalent

Hypertrophic and keloid scars are characterized by the overproduction of extracellular matrix collagen and proteoglycans. Because cellular secretion of macromolecules is known to be a calcium-dependent process, we have examined the effect of calcium antagonists on the rate of incorporation of [3H]proline into protein and Na235SO4 into sulfated glycosaminoglycans. Experiments were carried out in vitro using uniaxially oriented mammalian fibroblast-populated collagen matrices which exhibit many histoarchitectural features of scar matrix. We observed that nifedipine and verapamil in sufficient concentrations inhibited the incorporation of proline into extracellular matrix protein. The concentration range studied was 1 to 100 microM. Cobalt chloride (200 microM) had a similar effect on proline incorporation, but enhanced the incorporation of sulfate into extracellular matrix glycosaminoglycans. We conclude that cellular calcium metabolism appears to regulate extracellular matrix production and that hypertrophic disorders of wound healing may respond to therapy with calcium antagonist drugs.