Inhibitory action of insulin-sensitizing agents on calcium channels in smooth muscle cells from resistance arteries of guinea-pig.
1. The actions of troglitazone, pioglitazone, metformin and bezafibrate, agents that improve insulin-resistance, on voltage-dependent Ca2+ channels in arterial smooth muscle cells were examined by use of the conventional and nystatin-perforated whole-cell clamp methods. Single cells were freshly isolated from resistance mesenteric arteries of guinea-pigs. The actions of these agents on 77 mM K+-induced contraction of the isolated arteries were also examined with the use of isometric tension recording. 2. The thiazolidinedione derivatives, troglitazone and pioglitazone, inhibited whole-cell Ca2+ currents in a dose-dependent manner with dissociation constants of 3.0 microM and 44.9 microM and Hill coefficients of 0.61 and 0.68, respectively. These two agents inhibited the 77 mM K+-induced contraction with similar potencies as those inhibiting the Ca2+ currents. Metformin and bezafibrate had no apparent effects on the Ca2+ current or high K+-induced contraction. 3. The inhibitory action of troglitazone on Ca2+ currents was not affected by the command potential, the holding potential, or the stimulation frequency, suggesting that its mode of the action differs from that of known organic Ca2+ channel antagonists. 4. The inhibitory action of troglitazone on Ca2+ currents was not affected by the addition of insulin to, or the removal of glucose from, the solutions. 5. In conclusion, the thiazolidinedione derivatives directly inhibited the voltage-dependent Ca2+ channels in a different manner from that of organic Ca2+ channel antagonists. This inhibitory action on Ca2+ channels was not a common feature of insulin-sensitizing agents.
Nakamura
Y
Y
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Ohya
Y
Y
Onaka
U
U
Fujii
K
K
Abe
I
I
Fujishima
M
M
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007333:Insulin Resistance; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques
D015220:Calcium Channels; D007004:Hypoglycemic Agents