Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K ⁺ Channels in Human Omental Artery

Abstract

Objective-The present study was designed to examine in the human omental artery whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K ϩ channels in the vascular smooth muscle and whether this inhibitory effect is mediated by the production of superoxide. Methods and Results-Human omental arteries without endothelium were suspended for isometric force recording.Changes in membrane potentials were recorded and production of superoxide was evaluated. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. D-glucose (10 to 20 mmol/L) but not L-glucose (20 mmol/L) reduced these vasorelaxation and hyperpolarization. Tiron and diphenyleneiodonium, but not catalase, restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Calphostin C and Gö6976 simultaneously recovered these vasorelaxation and hyperpolarization in arteries treated with D-glucose. Phorbol 12-myristate 13 acetate (PMA) inhibited the vasorelaxation and hyperpolarization, which are recovered by calphostin C as well as Gö6976. D-glucose and PMA, but not L-glucose, significantly increased superoxide production from the arteries, whereas such increased production was reversed by Tiron. Key Words: ATP-sensitive K ϩ channels Ⅲ high glucose Ⅲ human artery Ⅲ protein kinase C Ⅲ superoxide I ncreasing evidence suggests that ATP-sensitive K ϩ channels play important roles in physiological and pathophysiological vasodilation. 1 Previous studies on the diabetic animal models suggest that hyperglycemia impairs the activity of ATP-sensitive K ϩ channels in the vascular smooth muscle cells. 2,3 Although a recent study on coronary arterioles from the diabetic patients has documented the reduction of vasorelaxation mediated by ATP-sensitive K ϩ channels, 4 the acute effect of high glucose on the activity of K ϩ channels has not been studied in the human blood vessels. Conclusions-TheseStudies using several diabetic animal models indicate that superoxide reduces the activity of ATP-sensitive K ϩ channels in the vascular smooth muscle cells. 5 However, the evidence showing that hyperglycemia-induced formation of reactive oxygen species modulates the activity of ATP-sensitive K ϩ channels is scarce. Recent studies on the rat as well as the rabbit demonstrated that protein kinase C activation inhibits ATP-sensitive K ϩ channels expressed on vascular smooth muscle cells. 6,7 In animal models, hyperglycemia is reportedly capable of increasing the activity of protein kinase C, whereas this has not been well-documented in the human vasculature. 8 In addition, it is unclear whether in the human blood vessels the activation of protein kinase C via acute exposure of high glucose may induce increased production of superoxide, resulting in the inhibitory effect on the function of K ϩ channels. Therefore, the present study was designed to examine in the human omental artery, whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K ϩ channels, and wh...

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

“…In humans as well as animals, diabetes mellitus impairs the activity of ATP-sensitive K ϩ channels in vascular smooth muscle cells, resulting in decreased vasodilation mediated by these channels (Mayhan and Faraci, 1993;Zimmermann et al, 1997;Miura et al, 2003). Our recent study has demonstrated that in the human artery, high concentrations of glucose reduce the activity of ATP-sensitive K ϩ channels (Kinoshita et al, 2004). These studies indicate that hyperglycemia as well as diabetes mellitus affects vasodilation mediated by ATP-sensitive K ϩ channels in human blood vessels.…”

“…These studies indicate that hyperglycemia as well as diabetes mellitus affects vasodilation mediated by ATP-sensitive K ϩ channels in human blood vessels. In addition, these pathophysiological conditions appear to produce increased levels of superoxide in the vasculature, leading to inhibition of ATP-sensitive K ϩ channel activity (Liu and Gutterman, 2002;Kinoshita et al, 2004). Therefore, it is crucial to explore tools by which one can reduce oxidative stress in blood vessels to ameliorate the impaired vascular function produced by glucose intolerance.…”

Endothelium-Dependent Contractions in Hypertension

“…85,86 In addition, ROS directly depolarize vascular smooth muscle cells by inhibiting various potassium channels. [87][88][89] The Intercellular Links: Gap Junctions Endothelium-dependent contractions to acetylcholine are smaller in layered bioassay ("sandwich") preparations than in intact rings, 77 illustrating that the contact between endothelial and vascular smooth muscle cells is important in the genesis of EDCF-mediated responses. In bioassay preparations, the endothelium-derived prostanoids diffuse freely across the intercellular gap between the donor (containing endothelial cells) and the effector (without endothelium, responsible for the contraction), and cell-impermeable antioxidants reduce the response to acetylcholine, whereas they do not in intact rings in which intracellular antioxidants inhibit EDCFmediated responses.…”

“…85,86 In addition, ROS directly depolarize vascular smooth muscle cells by inhibiting various potassium channels. [87][88][89] …”

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.…”