Differential sensitivities of the vascular K(ATP) channel to various PPAR activators.

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⁺ (K(ATP)) 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 K(ATP) channel blockers targeting at the K(ir)6.1 subunit. Structural comparison of these PPAR agonists may shed insight into the critical chemical groups for the channel inhibition. K(ir)6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell voltage clamp. The K(ir)6.1/SUR2B channel was strongly inhibited by several PPAR(γ) agonists with potencies similar to, or higher than, that of Rosiglitazone, while other PPAR(γ) agonists barely inhibited the channel. The K(ir)6.1/SUR2B channel was also inhibited by PPAR(α) and PPAR(β/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 PPAR(γ) agonists with weak K(ATP) channel inhibition may be potential candidates as therapeutical agents, and those with strong channel inhibition may be used as selective K(ATP) channel blockers. The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects.