Sensitivity of Kir6.2‐SUR1 currents, in the absence and presence of sodium azide, to the K_ATP channel inhibitors, ciclazindol and englitazone

Abstract

1 Two electrode voltage clamp and single channel recordings were used to investigate the actions of various ATP-sensitive K + (K ATP ) channel inhibitors on cloned K ATP channels, expressed in Xenopus oocytes and HEK 293 cells. 2 Oocytes expressing Kir6.2 and SUR1 gave rise to inwardly rectifying K + currents following bath application of 3 mM sodium azide. Inside-out recordings from non-azide treated oocytes demonstrated the presence of K ATP channels which were activated by direct application of 3 mM azide and 0.1 mM Mg-ATP. 3 Tolbutamide inhibited azide-induced macroscopic Kir6.2-SUR1 currents, recorded from Xenopus oocytes, with an IC 50 value similar to native K ATP channels. Ciclazindol and englitazone also inhibited these currents in a concentration-dependent manner, but with relative potencies substantially less than for native K ATP channels. 4 Single channel currents recorded from inside-out patches excised from oocytes expressing Kir6.2-SUR1 currents were inhibited by tolbutamide, Mg-ATP, englitazone and ciclazindol, in the absence of azide, with potencies similar to native K ATP channels. In the presence of azide, Kir6.2-SUR1 currents were inhibited by englitazone and tolbutamide but not ciclazindol. 5 Single channel currents derived from Kir6.2D26, expressed in HEK 293 cells, were inhibited by ciclazindol and englitazone irrespective of the absence or presence of SUR1. 6 In conclusion, heterologously expressed Kir6.2 and SUR1 recapitulate the pharmacological pro®le of native pancreatic b-cell K ATP channels. However, currents induced by azide exhibit a substantially reduced sensitivity to ciclazindol. It is likely that ciclazindol and englitazone inhibit K ATP currents by interaction with the Kir6.2 subunit.

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

“…Rather, they more probably reflect direct interaction of the drugs with the sarcolemmal K ATP channel. The present study is consistent with previous demonstrations that thiazolidinediones block K ATP channels in non-cardiac cells in culture [20][21][22][23], but is the first to demonstrate an analogous effect in the heart in vivo. During low-flow ischaemia and reperfusion, when a minority of pigs develop ventricular fibrillation, we observed no significant effect of thiazolidinedione treatment on the incidence of ventricular fibrillation.…”

“…Thus, the present findings suggest that thiazolidinediones interact with either Kir6.2 or SUR2A subunits, but not with Kir6.1 or SUR2B. An interaction of thiazolidinediones with Kir6.2 is supported by studies in cell culture [22,23] and would contrast with the actions of sulfonylurea K ATP blockers, which interact with SUR subunits.…”

“…Another possibility is that they exert direct adverse cardiac effects. Other compounds in the class, including troglitazone and englitazone, block K ATP channels in a variety of non-cardiac cells in vitro [20][21][22][23]; however, it is not known whether thiazolidinediones exert similar effects in the heart.…”

Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

“…However, no direct evidence based on voltage clamp analysis is available to exclude the contribution of other ion currents. Furthermore, rosiglitazone was shown to block a wide variety of non-cardiac ion channels, including neuronal Ca 2+ channels, epithelial Na + channels, ATP-sensitive K + channels, delayed rectifier K + channels and L-type Ca 2+ channels in aortic smooth muscle cells (Knock et al, 1999;Mishra and Aaronson, 1999;McKay et al, 2000;Pancani et al, 2009;Pavlov et al, 2009). In contrast to the lack of data on cardiac cells with rosiglitazone, another thiazolidinedione derivative troglitazone was shown to effectively block L-type Ca 2+ current (ICa) in ventricular myocytes of guinea pigs (Nakajima et al, 1999;Katoh et al, 2000) and rats (Arikawa et al, 2002;, while in rabbit ventricular cells Na + , Ca 2+ and K + currents were suppressed by the drug (Ikeda and Watanabe, 1998).…”

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty

“…In vitro studies indicate that TZDs block voltage-gated potassium channels and L-type calcium channels in isolated ventricular cardiomyocytes ( 25,180 ) and block ATP-sensitive potassium current in channels from cardiac and noncardiac cells (181)(182)(183)(184)(185). Because these effects are immediate, they suggest nontranscriptional effects of the drugs rather than classical effects via nuclear PPAR-␥ .…”