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 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.