Troglitazone and pioglitazone attenuate agonist‐dependent Ca 2+ mobilization and cell proliferation in vascular smooth muscle cells

The effects of troglitazone and pioglitazone on agonist‐induced Ca 2+ mobilization and cell proliferation were studied using fluorescent Ca 2+ indicator fura‐2 AM and incorporation of [ 3 H]‐thymidine in rat aortic smooth muscle cells. The patch clamp techniques were also employed. Vasopressin and platelet‐derived growth factor‐BB (PDGF) caused a transient elevation in [Ca 2+ ] i by Ca 2+ mobilization from intracellular stores, followed by a sustained rise due to Ca 2+ entry. Nicardipine partly inhibited the sustained phase, but La 3+ completely abolished it. Troglitazone and pioglitazone did not significantly affect the transient rise elicited by these agonists, but preferentially inhibited the sustained phase of [Ca 2+ ] i . Under voltage clamp conditions, troglitazone and pioglitazone inhibited voltage‐dependent L‐type Ca 2+ current (I Ca·L ). They also inhibited nonselective cation channels (I cat ) elicited by vasopressin in a concentration‐dependent manner. The half maximal inhibitory concentrations of troglitazone on I Ca·L and I cat were 4.6 and 5.7 μ M , respectively. On the other hand, nifedipine and nicardipine did not inhibit I cat . Vasopressin and PDGF increased incorporation of [ 3 H]‐thymidine, and nifedipine and nicardipine partly suppressed it. However, the inhibitory effects of La 3+ and exclusion of extracellular Ca 2+ were more potent than the Ca 2+ blocking agents. Troglitazone and pioglitazone also inhibited it concentration‐dependently. These results suggest that troglitazone and pioglitazone preferentially inhibited agonist (vasopressin and PDGF)‐induced Ca 2+ entry and proliferation in rat vascular smooth muscle cells, where the inhibitory effects of thiazolidinediones on I Ca·L and I cat might be partly involved. Thus, thiazolidinediones may exert hypotensive and antiatherosclerotic effects.British Journal of Pharmacology (1999) 128 , 673–683; doi: 10.1038/sj.bjp.0702818