Diabetes Mellitus Impairs Vasodilation to Hypoxia in Human Coronary Arterioles

Miura, Hiroto; Wachtel, Ruth E.; Loberiza, Fausto R.; Saito, Takashi; Miura, Mamoru; Nicolosi, Alfred C.; Gutterman, David D.

doi:10.1161/01.res.0000052671.53256.49

Cited by 166 publications

(177 citation statements)

References 55 publications

(68 reference statements)

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…K ATP channels also subserve important functions in the cardiovascular system [2]. In the coronary artery bed of many species, including man, Kir6.1/SUR2B channels play a major role in regulating vascular tone at rest [4][5][6] and in recruiting coronary reserve in cardiac ischaemia [7,8]. In cardiac myocytes, Kir6.2/SUR2A channels are required for the adaptation of the heart to adrenergic stress [9], are essential mediators of cardiac preconditioning [2,10] and, in the electrocardiogram, cause the ST segment elevation indicative of transmural myocardial infarction [11].…”

Section: Introductionmentioning

confidence: 99%

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis Sulfonylureas and glinides close beta cell ATP-sensitive K + (K ATP ) channels to increase insulin release; the concomitant closure of cardiovascular K ATP channels, however, leads to complications in patients with cardiac ischaemia. The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K ATP channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K ATP channels may be overstated. We therefore re-examined repaglinide's potency at and affinity for the recombinant pancreatic, myocardial and vascular K ATP channels in comparison with glibenclamide. Results Repaglinide and glibenclamide, respectively, were ≥30 and ≥1,000 times more potent in closing the pancreatic than the cardiovascular channels and they did not lead to complete inhibition of the myocardial channel. Binding assays showed that the selectivity of glibenclamide was essentially based on high affinity for the pancreatic SUR, whereas binding of repaglinide to the SUR subtypes was rather non-selective. After coexpression with Kir6.x to form the assembled channels, however, the affinity of the pancreatic channel for repaglinide was increased 130-fold, an effect much larger than with the cardiovascular channels. This selective effect of coexpression depended on the piperidino substituent in repaglinide. Conclusions/interpretation Repaglinide and glibenclamide show higher potency and efficacy in inhibiting the pancreatic than the cardiovascular K ATP channels, thus supporting their clinical use.

show abstract

Section: Introductionmentioning

confidence: 99%

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

et al. 2006

View full text Add to dashboard Cite

show abstract

“…In this issue of Circulation Research, Miura and colleagues 7 provide evidence that hypoxic dilation of human coronary microvessels is mediated primarily by activation of K ATP channels in vascular smooth muscle cells (SMCs), independent of the endothelium. Moreover, they report that both hypoxic dilation and vasodilation induced by the K ATP opener aprikalim are attenuated in microvessels from patients with diabetes mellitus, suggesting impaired K ATP function.…”

mentioning

confidence: 99%

“…The findings are consistent with recent reports showing impaired relaxation responses to KCO in human saphenous veins and corporeal tissue strips from diabetic patients. 24,25 In the study by Miura et al, 7 K ATP dysfunction in human coronary microvessels cannot be ascribed to sulfonylurea drugs, because impaired dilation to aprikalim was observed in microvessels from type I as well as type II diabetics (patients with type I diabetes are not treated with sulfonylurea drugs). Also, because the inhibitory effects of glibenclamide were reversible, rinsing the microvessels should have removed the drug even if it were taken before surgery.…”

mentioning

confidence: 99%

Impaired Hypoxic Coronary Vasodilation and ATP-Sensitive Potassium Channel Function

Weintraub

2003

Circulation Research

View full text Add to dashboard Cite

H ypoxic coronary vasodilation contributes to the maintenance of oxygen supply to the working heart during increased metabolic demand. Mechanisms of hypoxic coronary dilation have been studied extensively and differ considerably depending upon the species and experimental model. In isolated coronary vessels, several mechanisms have been implicated either alone or in combination, including release of vasodilatory factors (ie, nitric oxide, prostaglandins, and adenosine), activation of ATP-sensitive potassium (K ATP ) channels and Ca 2ϩ -activated K ϩ channels, and inhibition of voltage-gated Ca 2ϩ channels. [1][2][3][4][5] To date, however, relatively few studies have been conducted in human blood vessels. Furthermore, whereas most prior studies have examined hypoxic dilation in conduit coronary arteries, coronary microvessels (Ͻ150 m in diameter) are considered to be the principal regulators of coronary blood flow in response to metabolic stress. 6 Thus, despite extensive studies conducted over the past several decades, surprisingly little is known about mechanisms of hypoxic coronary microvascular dilation in humans, and how it might be altered in disease states.In this issue of Circulation Research, Miura and colleagues 7 provide evidence that hypoxic dilation of human coronary microvessels is mediated primarily by activation of K ATP channels in vascular smooth muscle cells (SMCs), independent of the endothelium. Moreover, they report that both hypoxic dilation and vasodilation induced by the K ATP opener aprikalim are attenuated in microvessels from patients with diabetes mellitus, suggesting impaired K ATP function. These findings provide new insight into mechanisms of coronary vasoregulation in humans, and they suggest that impaired microvascular K ATP channel function might contribute to increased cardiovascular morbidity and mortality in patients with diabetes.K ATP channels are distributed in a variety of tissues, including cardiomyocytes, SMCs, skeletal muscle, and pancreatic ␤-cells. 8 These octameric channels are composed of four inwardly rectifying potassium channel subunits (Kir) and four regulatory sulfonylurea receptor subunits (SUR). Channel complexes composed of less than 8 subunits are retained in the endoplasmic reticulum and thus cannot be targeted to the cell membrane. 9 Two different KIR (KIR6.1 and KIR6.2) and SUR (SUR1 and SUR2) gene products have been identified to make up K ATP channels. Splice variants of SUR2 (SUR2A and SUR2B) further add to the structural diversity of K ATP channels. The molecular structure of K ATP channels varies depending upon the species and tissue and is an important determinant of channel function, including sensitivity to ATP, nucleotide diphosphates, and potassium channel openers (KCO). Channel activity may also be regulated by posttranslational modification (ie, glycosylation, phosphorylation, and inositol phosphate metabolism). A characteristic feature of K ATP channels is inhibition by sulfonylurea compounds such as glibenclamide. 8 Recently, Farouque et ...

show abstract

“…Our results with high glucose appear to be consistent with a recent study on diabetic patients, demonstrating the reduction of vasorelaxation induced by hypoxia via ATP-sensitive K ϩ channels in the human coronary arteriole. 4 Similarly, high glucose impaired the preconditioning effects toward the ischemic in the canine heart, indicating the inhibitory effect of high glucose on the activity of mitochondrial ATP-sensitive K ϩ channels in animals. 16 These results also suggest that acute exposure of high glucose may simultaneously modulate the activity of different subtypes of ATP-sensitive K ϩ channels expressed on blood vessels as well as mitochondria.…”

Section: Discussionmentioning

confidence: 96%

“…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.…”

mentioning

confidence: 99%

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

Kinoshita

Azma²,

Nakahata³

et al. 2004

ATVB

View full text Add to dashboard Cite

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...

show abstract

Diabetes Mellitus Impairs Vasodilation to Hypoxia in Human Coronary Arterioles

Cited by 166 publications

References 55 publications

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Impaired Hypoxic Coronary Vasodilation and ATP-Sensitive Potassium Channel Function

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

Contact Info

Product

Resources

About

Diabetes Mellitus Impairs Vasodilation to Hypoxia in Human Coronary Arterioles

Cited by 166 publications

References 55 publications

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Impaired Hypoxic Coronary Vasodilation and ATP-Sensitive Potassium Channel Function

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

Contact Info

Product

Resources

About

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