Differential sensitivities of the vascular KATP channel to various PPAR activators

Abstract

Several agonists of the peroxisome proliferator-activated receptors (PPARs) are currently used for the treatment of metabolic disorders including diabetes. We have recently shown that one of them, Rosiglitazone, inhibits the vascular ATP-sensitive K+ (KATP) channel and compromises the coronary vasodilation by the β-adrenoceptor agonist. Here, we show evidence for the channel inhibition by various PPAR agonists, information that may be useful for finding new therapeutical agents with less cardiovascular side-effects and more selective KATP channel blockers targeting at the Kir6.1 subunit. Structural comparison of these PPAR agonists may shed insight into the critical chemical groups for the channel inhibition.Kir6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell voltage clamp. The Kir6.1/SUR2B channel was strongly inhibited by several PPARγ agonists with potencies similar to, or higher than, that of Rosiglitazone, while other PPARγ agonists barely inhibited the channel. The Kir6.1/SUR2B channel was also inhibited by PPARα and PPARβ/δ agonists with intermediate potencies. The structure necessary for the channel inhibition appears to include the thiazole linked to an aromatic or furan ring. Additions of side groups such as small aliphatic chain increased the potency for channel inhibition, while additions of aromatic rings reduced it. These results indicate that the PPARγ agonists with weak KATP channel inhibition may be potential candidates as therapeutical agents, and those with strong channel inhibition may be used as selective KATP channel blockers. The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects.