Abstract-The present study was designed to examine roles of the phosphatidylinositol 3-kinase-Akt pathway and reduced nicotinamide-adenine dinucleotide phosphate oxidases in the reduced ATP-sensitive K ϩ channel function via superoxide produced by high glucose in the human artery. We evaluated the activity of the phosphatidylinositol 3-kinase-Akt pathway, as well as reduced nicotinamide-adenine dinucleotide phosphate oxidases, the intracellular levels of superoxide and ATP-sensitive K ϩ channel function in the human omental artery without endothelium. Levels of the p85-␣ subunit and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits, including p47phox, p22phox, and Rac-1, increased in the membrane fraction from arteries treated with D-glucose (20 mmol/L) accompanied by increased intracellular superoxide production. High glucose simultaneously augmented Akt phosphorylation at Ser 473, as well as Thr 308 in the human vascular smooth muscle cells. A phosphatidylinositol 3-kinase inhibitor LY294002, as well as tiron and apocynin, restored vasorelaxation and hyperpolarization in response to an ATP-sensitive K ϩ channel opener levcromakalim. Therefore, it can be concluded that the activation of the phosphatidylinositol 3-kinase-Akt pathway, in combination with the translocation of p47phox, p22phox, and Rac-1, contributes to the superoxide production induced by high glucose, resulting in the impairment of ATP-sensitive K ϩ channel function in the human visceral artery. (Hypertension. 2008;52:507-513.)

These results suggest that in parenchymal microvessels of the rat cerebral cortex, decreased pH corresponding with hypercapnia, but not hypercapnia itself, contributes to cerebral vasodilation produced by carbon dioxide and that ATP-sensitive K+ channels play a major role in vasodilator responses produced by mild hypercapnia.

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...

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.

Although inward rectifier K+ channels contribute to the regulation of cerebral circulation, dilation of cerebral microvasculature mediated by these channels has not been demonstrated in chronic hypertension. We designed the present study to examine the roles of inward rectifier K+ channels in the vasodilation produced by increased levels of extracellular K+ in cerebral parenchymal arterioles from hypertensive and normotensive rats. During constriction to prostaglandin F2alpha (5 x 10(-7) M), the arterioles within brain slices were evaluated using computer-assisted microscopy. Potassium chloride (KCl) induced vasodilation in cerebral arterioles from normotensive (5-10 mM) and hypertensive (5-15 mM) rats, whereas an inward rectifier K+ channel antagonist barium chloride (BaCl2; 10(-5) M) completely abolished the vasodilation in both strains. In arterioles of hypertensive rats, vasodilator responses to KCl were augmented compared with those in normotensive rats. In contrast, the vasodilator responses induced by sodium nitroprusside (3 x 10(-8) to 3 x 10(-6) M) in these two strains were similar. These results suggest that in cerebral cortex parenchymal microvessels, inward rectifier K+ channels play a crucial role in vasodilation produced by extracellular K+ and that the dilation of cerebral arterioles via these channels is augmented in chronic hypertension.

Either neuronal transmission-dependent or exogenous 20-HETE seems to induce cerebral parenchymal arteriolar constriction via superoxide production resulting from NADPH oxidase activation. Propofol is likely to prevent this constriction via inhibition of NADPH oxidase, but not by its scavenging effect on superoxide.

NMDA dilates cerebral parenchymal arterioles possibly via neuronal NOS activation, whereas it produces superoxide via NADPH oxidase. In these arterioles, propofol reduces both the dilatation and superoxide production in response to NMDA.

Serum S-100B protein was significantly increased 15 min after a pneumatic tourniquet deflation in patients undergoing knee arthroplasty with bone cement, but not in those undergoing reamed intramedullary nailing for tibial fracture without bone cement. These results suggest that bone cement may transiently induce astroglial injury.