Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonists Restore Impaired Vasorelaxation via ATP-Sensitive K⁺ Channels by High Glucose

Abstract

The present study was designed to examine whether in the human artery, synthetic peroxisome proliferator-activated receptor (PPAR)-␥ agonists restore vasorelaxation as well as hyperpolarization via ATP-sensitive K ϩ channels impaired by the high concentration of D-glucose and whether the restoration may be mediated by the antioxidant capacity of these agents. The isometric force and membrane potential of human omental arteries without endothelium were recorded. The production rate of superoxide was evaluated using a superoxide-generating system with xanthine-xanthine oxidase in the absence of smooth muscle cells. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. Addition of D-glucose (20 mM) but not L-glucose (20 mM) reduced this vasorelaxation and hyperpolarization. Synthetic PPAR-␥ agonists (troglitazone and rosiglitazone) and/or an inhibitor of superoxide generation (4,5-dihydroxy-1,3-benzene-disulfonic acid, Tiron), but not a PPAR-␣ agonist (fenofibrate), restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Troglitazone and rosiglitazone, but not fenofibrate, decreased the production rate of superoxide without affecting uric acid generation. These findings suggest that synthetic PPAR-␥ agonists recover the function of ATP-sensitive K ϩ channels reduced by the high concentration of glucose in human vascular smooth muscle cells and that the effect of these agonists may be mediated in part by their antioxidant capacity.

Beneficial Effect of Propofol on Arterial Adenosine Triphosphate-sensitive K+Channel Function Impaired by Thromboxane

“…It is of importance to note that increased oxidative stress seen in some pathophysiological conditions induces malfunction of ATP-sensitive K ϩ channels in vascular smooth muscle cells. 8,9 A superoxide inhibitor Tiron and a nonselective NADPH oxidase inhibitor apocynin (which also acts as a superoxide inhibitor), but not a hydrogen peroxide scavenger catalase, recovered ATP-sensitive K ϩ channel function in the current study, indicating that superoxide via NADPH oxidase is a most likely source of the K ϩ channel inhibition in blood vessels induced by thromboxane A 2 . 8,18 Vascular smooth muscle cells contain several superoxide-producing pathways, among which NADPH oxidase is predominant.…”

“…Accumulating findings demonstrated that adenosine triphosphate (ATP)-sensitive K ϩ channels make significant contributions in the regulation of vascular smooth muscle tone under normal physiologic as well as pathophysiological conditions, 7 whereas increased oxidative stress reportedly induces malfunction of these channels. 8,9 However, it has been unknown whether thromboxane A 2 impairs the K ϩ channel function via increased production of superoxide in blood vessels.…”

Effect of rosiglitazone in sodium arsenite-induced experimental vascular endothelial dysfunction

“…Growing body of evidence suggested that opening of ATP sensitive K + channels activates eNOS in order to generate NO and thus regulates vasorelaxation (Jindal et al, 2008;Grossini et al, 2009). It is interesting to note from a recent study in which it has been suggested that PPARγ agonist rosiglitazone causes vasorelaxation through an activation of ATP sensitive K + channel (Kinoshita et al, 2006). Hence, it is possible that sodium-arsenite may down-regulate ATP sensitive K + channel, and thereby deactivating eNOS as evident by reduced NO level observed in the present study.…”

Naringin protects cardiomyocytes against hyperglycemia-induced injuries in vitro and in vivo

“…In addition, accumulating evidence has revealed that DM has been associated with dysfunction of the cardiovascular K ATP channels (Weintraub 2003). Hyperglycemia and DM impair vasodilation mediated by K ATP channels in human vascular smooth muscle cells (Miura et al 2003, Kinoshita et al 2004, Kinoshita et al 2006. Furthermore, a recent study shows that diabetes reduces mitoK ATP expression and function.…”