Troglitazone and pioglitazone attenuate agonist-dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells

1 The effects of troglitazone and pioglitazone on agonist-induced Ca2+ mobilization and cell proliferation were studied using fluorescent Ca2+ indicator fura-2 AM and incorporation of [H-3]-thymidine in rat aortic smooth muscle cells. The patch clamp techniques were also employed. 2 Vasopressin and platelet-derived growth factor-BE (PDGF) caused a transient elevation in [Ca2+](i) by Ca2+ mobilization from intracellular stores, followed by a sustained rise due to Ca2+ entry. Nicardipine partly inhibited the sustained phase, but La3+ completely abolished it. 3 Troglitazone and pioglitazone did not significantly affect the transient rise elicited by these agonists, but preferentially inhibited the sustained phase of [Ca2+](i). 4 Under voltage clamp conditions, troglitazone and pioglitazone inhibited voltage-dependent L-type Ca2+ 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 mu M, respectively. On the other hand, nifedipine and nicardipine did not inhibit I-cat. 5 Vasopressin and PDGF increased incorporation of [H-3]-thymidine, and nifedipine and nicardipine partly suppressed it. However, the inhibitory effects of La3+ and exclusion of extracellular Ca2+ were more potent than the Ca2+ blocking agents. Troglitazone and pioglitazone also inhibited it concentration-dependently. 6 These results suggest that troglitazone and pioglitazone preferentially inhibited agonist (vasopressin and PDGF)-induced Ca2+ 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.