SHORT-TERM EXPOSURE TO LOW CONCENTRATIONS OF THAPSIGARGIN INHIBITS REPLICATION OF CULTURED HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Background Central to the pathophysiology of stenosis following balloo n angioplasty and arterial bypass surgery is proliferation of vascular smooth muscle cells (VSMCs). To investigate the role of calcium (Ca2) in VSMC proliferation, the effect of thapsigargin, Ca2+ ionophore A2 3187, ionomycin, cyclopiazonic acid and di-tert-butylhydroquinone (all of which raise intracellular Ca2+ levels) on the proliferation of cul tured human VSMCs was observed. Methods Cultured VSMCs from human saph enous vein were treated with calcium-modulating drugs and proliferatio n was assessed by determining [H-3]thymidine and 5-bromo-2'-deoxyuridi ne incorporation and cell number. Results Over a 48-h exposure, thapsi gargin inhibited VSMC replication (median 50 per cent maximal inhibito ry concentration 2 nmol/l) whereas the other drugs were much less effe ctive. Short-term exposure (5, 10, 30 and 60 min) to thapsigargin elic ited a significant dose-dependent inhibition of VSMC replication where as, again, the other drugs were without significant effect. Conclusion Thapsigargin-sensitive intracellular Ca2+ pools play a key role in co ntrolling VSMC proliferation and specialized means of administering th apsigargin may constitute a possible approach to preventing stenosis.