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 mumol/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 mumol/L pioglitazone had an insignificant effect (4.8 +/- 5.6% reduction); however, 25 mumol/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Physiology, Wayne State University, School of Medicine, Detroit, MI.
F
F
Zhang
J R
JR
Sowers
J L
JL
Ram
P R
PR
Standley
J D
JD
Peuler
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D015220:Calcium Channels; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077205:Pioglitazone; D004121:Dimethyl Sulfoxide