EFFECTS OF PIOGLITAZONE ON CALCIUM CHANNELS IN VASCULAR SMOOTH-MUSCLE

Pioglitazone, an insulin-sensitizing, antidiabetic agent, has blood pressure-lowering effects in insulin-resistant hypertensive rats and attenuates growth factor-induced increases of intracellular Ca2+ in rat aortic vascular smooth muscle cells. To determine whether modulation of voltage-dependent Ca2+ channels plays a role in this association, we investigated the effects of pioglitazone on voltage-dependent current in cultured rat aortic (a7r5) and freshly dissociated rat tail artery vascular smooth muscle cells. Both cell types were studied with whole-cell patch-clamp techniques. Current through L-type Ca2+ channels was elicited with a voltage ramp in the presence of Ba2+ substituted for Ca2+. T-type Ca2+ current was studied using a two-pulse protocol that enabled the isolation of transient current. In a7r5 vascular smooth muscle cells, 2-minute application of pioglitazone (5 and 10 mu mol/L) reduced L-type current by 7.9 +/- 1.0% (n=8) (mean +/- SEM, number of cells) and 14.5 +/- 3.0% (n=9) (P<.01, two-tailed paired t test), respectively. In contrast, 2-minute application of pioglitazone had no significant effect on T-type Ca2+ current. In freshly dissociated tail artery vascular smooth muscle cells, 2-minute application of 10 mu mol/L pioglitazone had an insignificant effect (4.8 +/- 5.6% reduction); however, 25 mu mol/L pioglitazone reduced L-type current by 27.3 +/- 7.2% (n=5) (P<.01). Two-minute application of 0.1% or 0.2% dimethyl sulfoxide (vehicle) alone had no significant effects on currents in either type of vascular smooth muscle cell. The blood pressure-lowering and growth-inhibiting effects of pioglitazone may be in part due to inhibition of inward Ca2+ current through L-type channels in vascular smooth muscle.