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 beza®brate, agents that improve insulinresistance, on voltage-dependent Ca 2+ 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 Ca 2+ currents in a dose-dependent manner with dissociation constants of 3.0 mM and 44.9 mM and Hill coecients of 0.61 and 0.68, respectively. These two agents inhibited the 77 mM K + -induced contraction with similar potencies as those inhibiting the Ca 2+ currents. Metformin and beza®brate had no apparent eects on the Ca 2+ current or high K + -induced contraction. 3 The inhibitory action of troglitazone on Ca 2+ currents was not aected by the command potential, the holding potential, or the stimulation frequency, suggesting that its mode of the action diers from that of known organic Ca 2+ channel antagonists. 4 The inhibitory action of troglitazone on Ca 2+ currents was not aected 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 Ca 2+ channels in a dierent manner from that of organic Ca 2+ channel antagonists. This inhibitory action on Ca 2+ channels was not a common feature of insulin-sensitizing agents.

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

“…Consistent with the current observations, mice with genetic ablation of cardiac K ATP channels demonstrate increased susceptibility to lethal ventricular arrhythmias [8,11], while pharmacological K ATP openers have been shown to extend time to ventricular fibrillation and decrease incidence of ventricular fibrillation during coronary occlusion in pigs and dogs [5,6]. However, we cannot exclude the possibility that unmeasured effects of thiazolidinediones on ion channels other than K ATP [38][39][40][41] also influenced the development of ischaemic arrhythmias in the present study.…”

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

“…We suspect they may be similar to those responsible for the abovementioned thiazolidinedione-induced vasorelaxations. If so, that would include (in part) a direct inhibition of smooth muscle membrane-bound voltage-operated calcium channels, as previously established for all thiazolidinedione agents through whole-cell patch-clamp techniques (Zhang et al, 1994;Nakamura et al, 1998;Eto et al, 2001). This would be highly consistent with the ability of gemfibrozil in the present study to inhibit contractions induced solely by depolarizing smooth muscle cell membranes with a high concentration of extracellular K. Such high K only contracts smooth muscle by activating those particular channels (Kravtsov and Kwan, 1995).…”

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

“…In addition to activation of nuclear PPAR-␥ receptors, thiazolidinediones produce immediate (nontranscriptional) effects on ion channel conductances across the cell membrane of vascular smooth muscle cells (7)(8)(9). To date, however, cardiac electrophysiologic effects of thiazolidinediones have not been reported.…”