Inhibitory action of insulin-sensitizing agents on calcium channels in smooth muscle cells from resistance arteries of guinea-pig

Abstract

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 μM and 44.9 μM 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.

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