Association of anxiolytic drugs diazepam and lorazepam, and the antiepileptic valproate, with heart defects--effects on cardiomyocytes in micromass (MM) and embryonic stem cell culture.

Maternal exposure to antidepressant and antiepileptic drugs has been controversially associated with embryological malformations. The underlying mechanisms are unclear. Embryonic chick heart micromass (MM) and D3 mouse embryonic stem cell (ESC) derived cardiomyocyte cultures were treated with a series of concentrations of diazepam (DZ), lorazepam (LZ) and valproic acid (VPA). It was found that DZ and LZ significantly reduced cell beating at concentrations above and including 8 μM (P<0.05), whilst not affecting cell viability and total protein up to 50 μM in both systems, indicating teratogenic rather than cytotoxic effects. At high concentrations (>50 μM), LZ also proves to be cytotoxic in MM. Exposure of the embryonic chick heart MM cultures to 100-2000 μM VPA also showed no cytotoxic effects but the contractile activity of the cultures was significantly inhibited at those concentrations (P<0.05). These experiments provide evidence that antidepressant drugs and valproate may perturb heart development.