Rosiglitazone selectively inhibits K_ATP channels by acting on the K_IR6 subunit

Abstract

BACKGROUND AND PURPOSERosiglitazone is an anti-diabetic drug acting as an insulin sensitizer. We recently found that rosiglitazone also inhibits the vascular isoform of ATP-sensitive K + channels and compromises vasodilatory effects of b-adrenoceptor activation and pinacidil. As its potency for the channel inhibition is in the micromolar range, rosiglitazone may be used as an effective KATP channel inhibitor for research and therapeutic purposes. Therefore, we performed experiments to determine whether other isoforms of KATP channels are also sensitive to rosiglitazone and what their sensitivities are. EXPERIMENTAL APPROACHKIR6.1/SUR2B, KIR6.2/SUR1, KIR6.2/SUR2A, KIR6.2/SUR2B and KIR6.2DC36 channels were expressed in HEK293 cells and were studied using patch-clamp techniques. KEY RESULTSRosiglitazone inhibited all isoforms of KATP channels in excised patches and in the whole-cell configuration. Its IC50 was 10 mmol·L -1 for the KIR6.1/SUR2B channel and~45 mmol·L -1 for KIR6.2/SURx channels. Rosiglitazone also inhibited KIR6.2DC36 channels in the absence of the sulphonylurea receptor (SUR) subunit, with potency (IC50 = 45 mmol·L -1 ) almost identical to that for KIR6.2/SURx channels. Single-channel kinetic analysis showed that the channel inhibition was mediated by augmentation of the long-lasting closures without affecting the channel open state and unitary conductance. In contrast, rosiglitazone had no effect on KIR1.1, KIR2.1 and KIR4.1 channels, suggesting that the channel inhibitory effect is selective for KIR6.x channels. CONCLUSIONS AND IMPLICATIONSThese results suggest a novel KATP channel inhibitor that acts on the pore-forming KIR6.x subunit, affecting the channel gating. LINKED ARTICLEThis article is commented on by Dart, pp. 23-25 of this issue. To view this commentary visit http://dx

Lipophilicity predicts the ability of nonsulphonylurea drugs to block pancreatic beta‐cell KATP channels and stimulate insulin secretion; statins as a test case

“…However, many other structurally diverse drugs can also block K ATP as an “off target”; where inadvertent block of the pancreatic beta‐cell K ATP channel can lead to the adverse effects of hyperinsulinaemia and hypoglycaemia seen in the clinic, for example following over dosage with quinolones in the treatment of malaria . Indeed, most studies that have investigated the ability of nonsulphonylurea drugs to block beta‐cell K ATP channel activity and stimulate insulin secretion have arisen from clinical reports of adverse hypoglycaemic episodes during their acute usage; as reported for thiazolidinediones, quinolones, fluoroquinolones and pheniramines . Although no obvious common structural chemical moieties underlie the “off target” action of these drugs, they do all share the common property of lipophilicity.…”

Differential sensitivities of the vascular KATP channel to various PPAR activators

“…We have previous shown that Pioglitazone inhibits the K ir 6.1/SUR2B channel only modestly [8]. Similarly, the channel was inhibited weakly by Ciglitazone, Troglitazone and AS605240 (Fig.…”

“…We have recently shown that Rosiglitazone acts on the vascular wall by selective inhibition of the ATP-sensitive K + (K ATP ) channel that is composed of K ir 6.1/SUR2B and expressed in vascular smooth muscle (VSM)[8] This isoform of K ATP channels is targeted by various endogenous vasodilators and vasoconstrictors that work on the K ATP channel via protein phosphorylations by PKA and PKC, respectively [9-13]. The channel inhibition by therapeutical concentrations of Rosiglitazone may compromise the activity-dependent vasodilation, consistent with the ischemic coronary side-effect of Rosiglitazone found in its users[14].…”

“…Unlike sulfonylureas, Rosiglitazone inhibits the vascular K ATP channel by acting on the pore-forming K ir 6 subunit and has no inhibitory effect on K ir 1.1, K ir 2.1 and K ir 4.1 channels [8,14]. Thus, the demonstration of more potent glitazones may have impact on the therapeutical design for several cardiovascular diseases such as hypertension and shock as well as the development of pharmacological tools targeting at the K ir 6.1 subunit of the K ATP channels for research purposes.…”

Computational identification of novel Kir6 channel inhibitors

“…acts 83 predominantly on the pore-forming Kir6.x subunits and not on the SUR subunits. Further analysis of 84 single KATP channels suggests that the drug suppresses channel activity by extending long-lasting 85 channel closures, most likely via modulating the gating mechanism(Yu et al, 2012). 86Kir6 inhibitors such as RSG, which block channels at clinically relevant doses, could provide a good 87 starting point towards development of novel, specific inhibitors, suitable for developing drugs towards 88 treatment of Cantú syndrome.…”