Effect of ATP-Sensitive Potassium Channel Inhibition on Resting Coronary Vascular Responses in Humans

Farouque, H.M. Omar; Worthley, Stephen G.; Meredith, Ian T.; Skyrme-Jones, R. Andrew P.; Zhang, Michael J.

doi:10.1161/hh0202.103713

Cited by 57 publications

(52 citation statements)

References 46 publications

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“…This phenotype resembles Prinzmetal (vasospastic) angina in humans (25,30), and it suggests that, in humans, loss-of-function mutations in the Kir6.1 or SUR2B genes may genetically predispose for Prinzmetal angina. In patients with coronary artery disease, infusion of glibenclamide (40 g/min) in a coronary conduit artery decreased vessel diameter by 7.2%, increased coronary resistance by 28%, and reduced flow by 18%; higher doses were not given in order to avoid confounding effects on insulin levels and blood glucose (31). However, another study showed that at therapeutic doses of glibenclamide (50 g/kg i.v.…”

Section: Function Of K Atp Channels In the Coronary Vascular Bed In Nmentioning

confidence: 99%

“…They are generally treated with insulin secretagogues, and, as outlined above, these drugs differ greatly in their selectivity for the pancreatic over the cardiovascular K ATP channels. Hence, some of these drugs may inadvertently reduce coronary blood flow at rest (31) and in hypoxia (33). In addition, they may interfere with the ability of the heart to adapt to stress (34), with ischemic preconditioning (44 -48), and with the diagnostically important electrocardiographic ST elevation in acute myocardial infarction (39).…”

Section: Clinical Perspectivesmentioning

confidence: 99%

“…Second, the interference of insulin secretagogues with coronary blood flow is considered more rarely (notable exceptions are refs. [31][32][33]50,55). The dramatic phenotype of the mice lacking the vascular K ATP channel (25,30) may stimulate more work on the channel in the human coronary circulation.…”

Section: Clinical Perspectivesmentioning

confidence: 99%

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The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

et al. 2004

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Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K ؉ channel (K ATP channel) in the pancreatic ␤-cell membrane. K ATP channels subserve important functions also in the heart. First, K ATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, K ATP channels in the sarcolemma of cardiomyocytes (sarcK ATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcK ATP channels and of K ATP channels in the inner membrane of mitochondria (mitoK ATP channels) plays a central role in ischemic preconditioning. Opening of sarcK ATP channels also underlies the STsegment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular K ATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular K ATP channels, being either highly selective (ϳ1,000؋; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10 -20؋; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2؋; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested. Diabetes 53 (Suppl. 3):S156 -S164, 2004 I nsulin secretagogues are widely prescribed in the treatment of type 2 diabetes. They close the ATPsensitive K ϩ channel (K ATP channel) in the membrane of the pancreatic ␤-cell, thereby depolarizing the cell and triggering insulin secretion. K ATP channels are gated by intracellular nucleotides with ATP inducing channel closure and MgADP channel opening. The ␤-cell is special in that physiological changes in plasma glucose change the intracellular ATP and ADP concentrations such that the channel opens and closes; hence, the channel functions as the glucose sensor in this cell (1-3). K ATP channel subtypes are found in many cell types. The generation of mice in which the genes for the K ATP channel subunits were deleted have shed new light on the diverse functions of the K ATP channels in various tissues in physiological and pathophysiological conditions (1). In brain, K ATP channels are involved in actions as diverse as the control of glucose homeostasis and the regulation of neuronal excitability in hypoxia (1); however, the insulin secretagogues do not cross the blood-brain barrier easily enough to affect these channels at therapeutic plasma levels (4). In several vascular beds, the K ATP channel in the vascular myocytes is involved in the regulation of vessel tone; opening is triggered in particular by stimuli inc...

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Section: Function Of K Atp Channels In the Coronary Vascular Bed In Nmentioning

confidence: 99%

Section: Clinical Perspectivesmentioning

confidence: 99%

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The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

et al. 2004

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“…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

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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.

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“…In contrast to this finding, a recent human study has documented that direct administration of glibenclamide to the large coronary artery provokes reduction of resting vessel diameter, suggesting that these channels may modulate resting tone of the large coronary artery in humans. 15 We cannot rule out the possible involvement of the regional difference in the modulator role of ATP-sensitive K ϩ channels in the human vascular tone.…”

Section: Discussionmentioning

confidence: 98%

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

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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...

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Effect of ATP-Sensitive Potassium Channel Inhibition on Resting Coronary Vascular Responses in Humans

Cited by 57 publications

References 46 publications

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

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

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

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Effect of ATP-Sensitive Potassium Channel Inhibition on Resting Coronary Vascular Responses in Humans

Cited by 57 publications

References 46 publications

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

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

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

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