TY - JOUR. T1 - K(ATP) channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. T2 - Implications for liver growth control and potential therapeutic targeting. AU - Malhi, Harmeet. AU - Irani, Adil N.. AU - Rajvanshi, Pankaj. AU - Suadicani, Sylvia O.. AU - Spray, David C.. AU - McDonald, Thomas V.. AU - Gupta, Sanjeev. N1 - Copyright: Copyright 2007 Elsevier B.V., All rights reserved.. PY - 2000/8/25. Y1 - 2000/8/25. N2 - To determine whether K(ATP) channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K(ATP) channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K(ATP) channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K+ channels, whole-cell patch-clamp ...

TY - JOUR. T1 - Intrahippocampal infusions of K-ATP channel modulators influence spontaneous alternation performance. T2 - Relationships to acetylcholine release in the hippocampus. AU - Stefani, Mark R.. AU - Gold, Paul E.. PY - 2001/1/15. Y1 - 2001/1/15. N2 - One mechanism by which administration of glucose enhances cognitive functions may be by modulating central ATP-sensitive potassium (K-ATP) channels. K-ATP channels appear to couple glucose metabolism and neuronal excitability, with channel blockade increasing the likelihood of neurosecretion. The present experiment examined the effects of glucose and the direct K-ATP channel modulators glibenclamide and lemakalim on spontaneous alternation performance and hippocampal ACh release. Rats received either artificial CSF vehicle or vehicle plus drug for two consecutive 12 min periods via microdialysis probes (3 mm; flow rate of 2.1 μl/min) implanted in the left hippocampus. During the second 12 min period, rats were tested for spontaneous ...

Iptakalim was unable to open pancreatic β-cell KATP channels, perhaps due to the presence of the SUR1, instead of the SUR2, subunit in these cells. Moreover, an intriguing finding was that iptakalim closed pancreatic β-cell-type KATP channels. It has been reported that PNU-99963, a nonsulfonylurea-based KATP channel inhibitor that has a structure similar to the KATP channel opener pinacidil, inhibits β-cell KATP channels (Cui et al., 2003). Structurally, iptakalim is also similar to the core portion of pinacidil; therefore, it is possible that KATP channel opener analogs with such a structure can inhibit KATP channels. Iptakalim may directly block β-cell KATP channels by acting on the Kir6.2 subunit (or some closely associated regulatory proteins). It is well documented that some KATP channel modulators, such as nicorandil, pinacidil, and glibenclamide, regulate KATP channel activity by targeting the regulating subunit SUR (Gribble and Ashcroft, 2000a; Hansen, 2006), whereas others (e.g., ...

TY - JOUR. T1 - The KATP channel activator diazoxide ameliorates amyloid-β and Tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimers disease. AU - Liu, Dong. AU - Pitta, Michael. AU - Lee, Jong Hwan. AU - Ray, Balmiki. AU - Lahiri, Debomoy. AU - Furukawa, Katsutoshi. AU - Mughal, Mohamed. AU - Jiang, Haiyang. AU - Villarreal, Julissa. AU - Cutler, Roy G.. AU - Greig, Nigel H.. AU - Mattson, Mark P.. PY - 2010. Y1 - 2010. N2 - Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimers disease (AD). ATP-sensitive potassium (KATP) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then ...

ATP-sensitive potassium channels (KATP) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that KATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that KATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle KATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit. Using a combination of molecular, electrophysiological, in vitro, and in vivo techniques, we confirmed the absence of Kir6.1 and KATP currents and responses specifically in smooth muscle. Mice with conditional deletion of Kir6.1 showed no obvious arrhythmic phenotype even after provocation with ergonovine. However, these mice were hypertensive and vascular ...

TY - JOUR. T1 - Advances in cardiac ATP-Sensitive K + channelopathies from molecules to populations. AU - Terzic, Andre. AU - Alekseev, Alexey E.. AU - Yamada, Satsuki. AU - Reyes, Santiago. AU - Olson, Timothy Mark. PY - 2011/8. Y1 - 2011/8. N2 - Deficient cellular energetics set by aberrant K ATP channel function increasingly is implicated in a spectrum of conditions underlying metabolic imbalance and electric instability. 5 Indeed, cardiac K ATP channelopathies are emerging as a recognized disease entity underlying heart failure and arrhythmia. 19 Understanding the molecular structure and function of K ATP channel subunits, 8 and their relationship to cellular metabolic signaling, 99 has been instrumental in interpreting the pathophysiology of channel malfunction associated with heart disease predisposition (Figure 3). 12 From individual patients to populations, variants in K ATP channel genes now have been documented in human dilated cardiomyopathy 21 and atrial fibrillation 20 and as risk ...

BACKGROUND: Alterations in coronary vasomotor tone may participate in the pathogenesis of acute myocardial infarction (AMI). Vascular ATP-sensitive K(+) (KATP) channels, formed by Kir6.x/SUR2B, are key regulators of coronary tone and mutations in cardiac (Kir6.2/SUR2A) KATP channels result in heart disease. Here we explore the pathophysiological mechanism of a rare mutation (V734I) found in exon 17 of the ABCC9 gene, estimated to cause a 6.4-fold higher risk of AMI before the age of 60. METHODS AND RESULTS: Eleven patients carrying the mutation were identified; they presented AMI of vasospastic origin associated with increased plasma levels of endothelin-1 and increased leukocyte ROCK activity. The effects of the mutation on the functional properties of the two splice variants of ABCC9 (SUR2A and SUR2B) were studied using patch-clamp electrophysiology. The mutation reduced the sensitivity to MgATP inhibition of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A and Kir6.1/SUR2B channels. Furthermore, the

KATP channels are unique amongst known potassium channels in requiring an unrelated ABC protein subunit (SUR1) in addition to an inward rectifier K channel (Kir6.2) subunit (Inagaki et al., 1995a). In other cloned inward rectifiers, strong inward rectification is controlled by a pore-lining residue in the M2 transmembrane segment (Fakler et al., 1994; Ficker et al., 1994; Lopatin et al., 1994; Lu and MacKinnon, 1994; Stanfield et al., 1994). Mutation of the corresponding residue in Kir6.2 from asparagine to aspartate results in generation of KATP channels that rectify strongly in the presence of cytoplasmic spermine (Fig. 1 b; Clement et al., 1997; Shyng et al., 1997), single channel conductance being unaltered and channels remaining sensitive to inhibition by ATP (Shyng et al., 1997). The requirement for SUR1 to form active channels still raises the possibility that the receptor might also contribute to the pore, and perhaps reduce or otherwise alter the number of Kir6.2 subunits involved. The ...

Extracellular Zn(2+) has been identified as an activator of pancreatic K(ATP) channels. We further examined the action of Zn(2+) on recombinant K(ATP) channels formed with the inward rectifier K(+) channel subunit Kir6.2 associated with either the pancreatic/neuronal sulphonylurea receptor 1 (SUR1) …

Most information currently available regarding vascular K+ channel function in diabetes concerns KATP channels. As for chronic hypertension, there are now several reports of impaired vascular relaxant responses to synthetic openers of KATP channels in long-term diabetes. These studies have mostly utilized the streptozotocin-injected rat model of diabetes and have examined vessels at 2.5 to 4 months after streptozotocin treatment. In this model in which plasma glucose levels are increased 3- to 4-fold, impaired relaxation of the isolated aorta122 123 124 and mesenteric vascular bed125 and reduced dilatation of large126 and small127 cerebral arteries in vivo typically develop. These changes are thought to be the result of a decreased number of vascular KATP channels and/or reduced sensitivity of these channels to synthetic openers. Nonspecific cytotoxic effects of streptozotocin seem an unlikely cause of these changes because, like other manifestations of vascular dysfunction, abnormal vasodilator ...

Most information currently available regarding vascular K+ channel function in diabetes concerns KATP channels. As for chronic hypertension, there are now several reports of impaired vascular relaxant responses to synthetic openers of KATP channels in long-term diabetes. These studies have mostly utilized the streptozotocin-injected rat model of diabetes and have examined vessels at 2.5 to 4 months after streptozotocin treatment. In this model in which plasma glucose levels are increased 3- to 4-fold, impaired relaxation of the isolated aorta122 123 124 and mesenteric vascular bed125 and reduced dilatation of large126 and small127 cerebral arteries in vivo typically develop. These changes are thought to be the result of a decreased number of vascular KATP channels and/or reduced sensitivity of these channels to synthetic openers. Nonspecific cytotoxic effects of streptozotocin seem an unlikely cause of these changes because, like other manifestations of vascular dysfunction, abnormal vasodilator ...

In the present study, the novel KATP channel antagonist HMR 1402 did not alter the cardiac action potential under control conditions but significantly attenuated the shortening of the APD90 induced either by the KATP channel agonist rilmakalim or by hypoxia. In a similar manner, the same concentration of this drug that attenuated these reductions in APD90 did not inhibit the activation of pancreatic or coronary vascular KATP channels in vitro. In conscious dogs, HMR 1402 prevented ischemically induced ventricular fibrillation without altering the increases in mean coronary blood flow induced either by submaximal exercise or by the reactive hyperemic response to brief (15-s) coronary artery occlusions. These findings were in marked contrast to glibenclamide that provoked large reductions in coronary blood flow (Billman et al., 1993, 1998). Finally, HMR 1402, in contrast to glibenclamide (Billman et al., 1998), did not alter plasma insulin concentrations. When considered together, these data ...

This study tests the hypothesis that glycolytic regulation of KATP channel activity is altered in myocardial hypertrophy. Left ventricular (LV) subendocardial myocytes were isolated from cats with normal or left ventricular hypertrophied hearts (LVH)

In addition to the pancreatic β-cell the KATP channel resides on smooth and cardiac muscles and other nonneural tissues. The KATP channel is present on brain GR neurons but not glia (20). The Kir6.2 pore-forming unit (20, 32, 35,63) and both a high (SUR1)- and low (SUR2)-affinity form of the SUR have been cloned and identified in brain (21, 33, 49, 51, 63, 114). A presumptive endogenous ligand for the SUR, α-endosulfine, was also identified in the brain (84) but little is known about its regulation or regional distribution. Similar to the pancreatic β-cell, the KATP channel on GR neurons is inactivated by an increased intracellular ATP-to-ADP ratio or the presence of sulfonylureas. This leads to accumulation of intracellular K+ with subsequent membrane depolarization and cell firing (6, 21, 87, 89). Although it is clear that GR neurons use glucose as a signaling molecule acting via the KATP channel, several unresolved issues remain. First, the neuronal glucose transporter (GLUT-3) (26) and ...

Recombinant KATP channels consisting of CFP-Kir6.2 or CFP-Kir6.2-YFP (Fig. 1A) with or without SUR1 or SUR2A were expressed in HEK cells and illuminated at 440 nm, the excitation wavelength of the donor fluorophore CFP. Fluorescence was recorded at both 535 nm, the peak emission wavelength of the acceptor fluorophore YFP, and at 480 nm, the peak emission wavelength of CFP. The extent of FRET was quantified as the fluorescence ratio F535/F480.. Figure 1B shows the F535/F480 ratio recorded for each combination of subunits studied. This value was negligible for CFP-Kir6.2 (which lacks the YFP fluorophore), demonstrating that our method of correction for CFP bleedthrough was effective. In contrast, cells expressing CFP-Kir6.2-YFP showed significant FRET (Fig. 2B). This result indicates that CFP and YFP lie within a few nanometers of each other. Because CFP is attached to the NH2-terminus of Kir6.2 and YFP to the COOH-terminus, the distal parts of the intracellular domains of Kir6.2 must also lie ...

The intersection of cell metabolism with electrical signaling links the environment and cell function over time scales ranging from milliseconds to lifetimes. In responding to cellular metabolites, adenosine triphosphate (ATP)-sensitive potassium (KATP) channels are an important component of this intersection. Recent studies have begun to delineate the roles of KATP channels in multiple tissues and the far-reaching consequences of aberrant KATP channel activity and disturbed sensing of cell metabolism.. ...

The results reported here demonstrate that NNC 55-9216 activates Kir6.2/SUR1, but not Kir6.2/SUR2A or Kir6.2/SUR2B currents, by interaction with the SUR1 subunit of the KATP channel. They also imply that the drug will stimulate native KATP channels in pancreatic β-cells but not in cardiac or smooth muscles. This selectivity is particularly interesting in view of the fact that the drug shares some structural similarity with diazoxide, which interacts with KATP channels containing SUR2A and SUR2B as well as SUR1 (28,59).. Activation of Kir6.2/SUR1 currents by NNC 55-9216 is dependent on the presence of intracellular MgATP. The adenine dinucleotide MgADP is unable to substitute for MgATP, and in this respect, the nucleotide requirements of NNC 55-9216 differ from those of diazoxide (Fig. 1), which is supported by MgADP (28). The lack of effect of MgADP, and of ATP in the absence of Mg2+, suggests that MgATP hydrolysis might be needed for NNC 55-9216 activation. The ability of MgATPγS to support ...

This is the Authors Original Manuscript of an article published by Taylor & Francis in Channels on 02 Jan 2018 available online: https://doi.org/10.1080/19336950.2017.1412151 ...

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TY - JOUR. T1 - Short-term effects of glipizide (an adenosine triphosphate-sensitive potassium channel inhibitor) on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. AU - Lange, Matthias. AU - Szabo, Csaba. AU - Van Aken, Hugo. AU - Williams, William. AU - Traber, Daniel L.. AU - Daudel, Fritz. AU - Bröking, Katrin. AU - Salzman, Andrew L.. AU - Bone, Hans Georg. AU - Westphal, Martin. PY - 2006/11. Y1 - 2006/11. N2 - In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific KATP channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to ...

ATP-sensitive K+ (K(ATP)) channels are hetero-octamers of inwardly rectifying K+ channel (Kir6.2) and sulphonylurea receptor subunits (SUR1 in pancreatic beta-cells, SUR2A in heart). Heterozygous gain-of-function mutations in Kir6.2 cause neonatal diabetes, which may be accompanied by epilepsy and developmental delay. However, despite the importance of K(ATP) channels in the heart, patients have no obvious cardiac problems. We examined the effects of adenine nucleotides on K(ATP) channels containing wild-type or mutant (Q52R, R201H) Kir6.2 plus either SUR1 or SUR2A. In the absence of Mg2+, both mutations reduced ATP inhibition of SUR1- and SUR2A-containing channels to similar extents, but when Mg2+ was present ATP blocked mutant channels containing SUR1 much less than SUR2A channels. Mg-nucleotide activation of SUR1, but not SUR2A, channels was markedly increased by the R201H mutation. Both mutations also increased resting whole-cell K(ATP) currents through heterozygous SUR1-containing channels to a

TY - JOUR. T1 - Spontaneous contractions of the pig urinary bladder. T2 - The effect of ATP-sensitive potassium channels and the role of the mucosa. AU - Akino, Hironobu. AU - Chapple, Christopher R.. AU - McKay, Neil G.. AU - Cross, Rebecca L.. AU - Murakami, Shigetaka. AU - Yokoyama, Osamu. AU - Chess-Williams, Russell. AU - Sellers, Donna J.. PY - 2008/11. Y1 - 2008/11. N2 - OBJECTIVE: To investigate the influence of the mucosa on the inhibitory effects of the ATP-sensitive potassium channel (KATP channel) opener, cromakalim, on the spontaneous contractions of pig bladder strips from the bladder dome and trigone. Little is known about the influence of the mucosa on spontaneous contractions and whether the nature of these contractions differs between the bladder dome and trigone. MATERIALS AND METHODS: Paired longitudinal strips of female pig bladders were isolated from the dome and trigone. The mucosa was removed from one strip per pair and tissues were set up in organ baths. Spontaneous ...

In response to intracellular energy supply, ATP-sensitive potassium (KATP) channels alter membrane potential and mediate cell stress response. The Abcc9 gene encodes the major regulatory subunit in the heart, sulfonylurea receptor 2 (SUR2), as well as smaller mitochondria-enriched proteins that contribute to sulfonylurea-insensitive KATP channels. Pharmacological studies suggest mitochondrial KATP channels are critical regulators of cell stress, however the molecular composition of this channel has been unclear. We now studied the role of KATP channels by deleting exon 5 of Abcc9. This strategy ablated expression of both full length SUR2 protein as well as the smaller mitochondrial 55 KDa protein. Homozygous exon 5 (Ex5) mice died within 14 days of birth with progressive cardiac contractile dysfunction. Diazoxide was found to depolarize mitochondria from wildtype cardiomyocytes but not Ex5 mitochondria, consistent with disrupted mitochondrial KATP channels. Ex5 mitochondria had a reduced cross ...

Opening of K(ATP)-channels reduces beta-cell vulnerability to apoptosis induced by h-IAPP oligomers. This effect is not due to a direct interaction of K(ATP)CO with h-IAPP, but might be mediated through hyperpolarization of the beta-cell membrane induced by opening of K(ATP)-channels. Induction of b …

The regulation of a K(+) current activating during oscillatory electrical activity (I(K,slow)) in an insulin-releasing beta-cell was studied by applying the perforated patch whole-cell technique to intact mouse pancreatic islets. The resting whole-cell conductance in the presence of 10 mM glucose amounted to 1.3 nS, which rose by 50 % during a series of 26 simulated action potentials. Application of the K(ATP)-channel blocker tolbutamide produced uninterrupted action potential firing and reduced I(K,slow) by approximately 50 %. Increasing glucose from 15 to 30 mM, which likewise converted oscillatory electrical activity into continuous action potential firing, reduced I(K,slow) by approximately 30 % whilst not affecting the resting conductance. Action potential firing may culminate in opening of K(ATP) channels by activation of ATP-dependent Ca(2+) pumping as suggested by the observation that the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin (4 microM) inhibited I(K,slow) by

Background: ATP-sensitive potassium channels (KATP), existing in both sarcolemmal and mitochondrial inner membranes, are thought to serve as metabolic sensors of the cell. In pathological hypertrophy, the heart requires increased workload to pump blood to meet the bodys needs. However, roles of KATP in hypertrophy stress signaling are not fully understood.. Methods & Results: We aimed at investigating regulation of SUR2, the regulatory subunit of KATP, via a systems biology approach. We hypothesized that mitochondrial KATP mediates the protective response in hypertrophied hearts. A pressure-overload model by transverse aortic constriction (TAC) was employed to induce hypertrophy in SUR2 knockout (SUR2KO) males. These mice had enlarged left ventricles at baseline and developed further hypertrophy post TAC. Hypertrophied KO hearts exhibited significantly higher mortality, cardiac dysfunction, reduced mitochondrial DNA content and elevated ROS formation, which were associated with the altered SUR2 ...

TY - JOUR. T1 - Hydrochlorothiazide: An hyperglycaemia-inducing agent and K-ATP channel agonist in human beta-cells and clonal insulin-secreting cells.. AU - Barnes, PD. AU - OBrien, RE. AU - Abdel-Wahab, Yasser. AU - Cosgrove, KE. AU - Flatt, Peter. AU - Dunne, MJ. PY - 1999/8. Y1 - 1999/8. M3 - Article. VL - 42. SP - 482. JO - Diabetologia. JF - Diabetologia. SN - 0012-186X. IS - Suppl.. ER - ...

TY - JOUR. T1 - Autocrine insulin increases plasma membrane KATP channel via PI3K-VAMP2 pathway in MIN6 cells. AU - Xu, Shanhua. AU - Kim, Ji Hee. AU - Hwang, Kyu Hee. AU - Das, Ranjan. AU - Quan, Xianglan. AU - Nguyen, Tuyet Thi. AU - Kim, Soo Jin. AU - Cha, Seung Kuy. AU - Park, Kyu Sang. PY - 2015/12/25. Y1 - 2015/12/25. N2 - Regulation of ATP-sensitive inwardly rectifying potassium (KATP) channel plays a critical role in metabolism-secretion coupling of pancreatic β-cells. Released insulin from β-cells inhibits insulin and glucagon secretion with autocrine and paracrine modes. However, molecular mechanism by which insulin inhibits hormone secretion remains elusive. Here, we investigated the effect of autocrine insulin on surface abundance of KATP channel in mouse clonal β-cell line, MIN6. High glucose increased plasmalemmal sulfonylurea receptor 1 (SUR1), a component of KATP channel as well as exogenous insulin treatment. SUR1 trafficking by high glucose or insulin was blocked by ...

Context: ATP-sensitive potassium (KATP) stations regulate insulin secretion by coupling glucose rate of metabolism to β-cell membrane potential. gating properties of the producing channels were assessed biochemically and electrophysiologically. Results: Both E208K and V324M augment channel response to MgADP activation without altering level of sensitivity to ATP4? or sulfonylureas. Remarkably whereas E208K causes only a small increase in MgADP response consistent with the slight transient diabetes phenotype V324M causes a severe activating gating defect. Unlike E208K V324M also impairs channel expression in the cell surface which is definitely expected ON-01910 to dampen its practical impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding website of SUR1 previously shown to abolish Mg-nucleotide response the activating effect of E208K and V324M was also abolished. Moreover combination of E208K and V324M results in channels with Mg-nucleotide level ...

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Among the several ion channels expressed in skeletal muscle, this laboratory has largely focused on the ATP-sensitive K + channel or KATP channel. This channel is interesting because its activity is regulated by the energy state of the muscle fibers, where a decrease in energy reserve increases the activity of the channel. It therefore behaves as an energy sensor. Being an ion channel, it is also an effector, which links the energy state of the fiber to the electrical activity of the cell membrane.. Our studies have now clearly demonstrated that the KATP channel is crucial in preventing fiber damage during treadmill running and fatigue elicited in vitro (References #4-5). We are in the process of elucidating two major mechanisms of action for the channel. The first mechanism involves a reduction in action potential amplitude (Reference #6). As a consequence of lower action potential amplitude, less Ca 2+ is released by the sarcoplasmic reticulum and less force is developed by the contractile ...

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In experiments on the anaesthetized dogs the influence of a new fluorine-containing opener of ATP-sensitive potassium (K(ATP)) channels flocalin on the cardiohemodynamic of great animals in vivo was studied. Flocalin introduced intravenously in doses 0.01 - 1.5 mgs/kg. It is shown that it reduces in dose-dependent manner a system arterial pressure, perfusion pressure in coronary artery and general peripheral resistance of vessels with maximal effects on 56.8 +/- 2.7, 22.4 +/- 4.7 and 47.2% +/- 6.5% accordingly at most dose 1.5 mgs/kg. Flocalin causes development of cardiodepressive reactions in heart, that is exhibited in dose-dependent the decrease of pressure in the left ventricle, speed of growth (dP/dt(max)) and reduction (dP/dt(min)) in its of pressure with maximal effects on 37.1 +/- 5.1, 51.2 +/- 9.4 and 55.6% +/- 6.9% accordingly at introduction of most dose of flocalin. Diminish of the cardiac out put and heart rate with a maximal effects on 23.1% +/-12.7% and 19.2% +/- 1.7% ...

心不全によるK_,ATP,チャネルの変調 : レシピエントから得た心筋による検討 Alterations in ATP-sensitive potassium channel sensitivity to ATP in failing human hearts ...

Propofol reportedly possesses potential antioxidant properties caused by its chemical structure similar to that of phenol-based free-radical scavengers such as vitamin E.10 Previous in vivo or in vitro studies documented that this intravenous anesthetic reduces oxidative stress toward blood vessels.11,12 These results suggest that this anesthetic may be protective against the vascular dysfunction caused by increased oxidative stress. Indeed, propofol (3 × 10−7to 10−6m) recovered vascular ATP-sensitive K+channel function via reduction of superoxide levels within arterial walls. In addition, 10−6m of this agent completely inhibited protein expression of a Nox2-related NADPH oxidase subunit p47phox. The plasma concentration of propofol during induction of anesthesia in humans has been reported as up to 3 × 10−5m, and burst suppression doses of propofol for cerebral protection are up to 6 × 10−5m.20-22 Effective concentrations of propofol (3 × 10−7to 10−6m) to inhibit NADPH oxidase ...

ATP-sensitive potassium (K(ATP)) channels comprise Kir and SUR subunits. Using recombinant K(ATP) channels expressed in Xenopus oocytes, we observed that MgATP (100 microm) block of Kir6.2/SUR2A currents gradually declined with time, whereas inhibition of Kir6.2/SUR1 or Kir6.2DeltaC36 currents did not change. The decline in Kir6.2/SUR2A ATP sensitivity was not observed in Mg(2+) free solution and was blocked by the phosphatidylinositol (PI) 3-kinase inhibitors LY 294002 (10 microm) and wortmannin (100 microm), and by neomycin (100 microm). These results suggest that a MgATP-dependent synthesis of membrane phospholipids produces a secondary decrease in the ATP sensitivity of Kir6.2/SUR2A. Direct application of the phospholipids PI 4,5-bisphosphate and PI 3,4,5-trisphosphate in the presence of 100 microm MgATP activated all three types of channel, but the response was faster for Kir6.2/SUR2A. Chimeric studies indicate that the different responses of Kir6.2/SUR2A and Kir6.2/SUR1 are mediated by the first

Endotoxemia causes hypotension characterized by vasodilation and resistance to vasopressor agents. The molecular mechanisms responsible for these changes are unclear. The ATP-regulated K+ (K+ATP) channel has recently been found to be an important modulator of vascular smooth muscle tone which may transduce local metabolic changes into alterations of vascular flow. We report here that in endotoxic hypotension, the sulfonylurea glyburide, a specific inhibitor for the K+ATP channel, caused vasoconstriction and restoration of blood pressure. Glyburide also induced vasoconstriction and restoration of blood pressure in the vasodilatory hypotension caused by hypoxic lactic acidosis, while it was ineffective in the hypotension induced by sodium nitroprusside. Thus, vasodilation and hypotension in septic shock are, at least in part, due to activation of the K+ATP channel in vascular smooth muscle, and anaerobic metabolism with acidosis is a sufficient stimulus for channel activation. Because anaerobic ...

Consistent with the report by Han et al. ,22 the single-channel conductance was not altered by isoflurane in our study. However, in contrast to findings in other species,22,24 application of isoflurane to the inside-out membrane patches from rat non-APC myocytes increased the probability of channel opening. Characteristically, Po was increased during exposure to isoflurane but declined upon anesthetic washout. Because single-channel recordings were made at intracellular pH 7.2, which is in the range of normal physiologic intracellular pH in rat cardiomyocytes,25 the effect of isoflurane on channel activity in rats seems different from those in guinea pigs, where isoflurane increased Po only at more acidic, ischemic-like pH of 6.8,23 and in rabbits where isoflurane clearly had an inhibitory effect on Po at intracellular pH of 7.4.22 The in vivo APC in rats produced no lasting change in channel activity, and Po values of channels in APC and non-APC myocytes were similar. The observation that Po of ...

We found in the present study that ICV injections of glibenclamide produced a dose-dependent pressor effect in rats with bilateral ligation of the carotid arteries but not in sham-operated rats. Because glibenclamide is a specific and potent blocker of KATP18 and because intravenous administration of glibenclamide did not elicit any cardiovascular response in rats with bilateral ligation of the carotid arteries, this pressor effect must be closely related to inhibition of KATP in the ischemic brain. Intravenous glibenclamide can reach the brain after bilateral ligation of the carotid artery because the residual blood flow still exists, although the amount of glibenclamide must be lower than the ICV injection because of the dilution with blood. A lack of vasopressor effects with intravenous injections of glibenclamide suggests that a large amount of glibenclamide is needed to inhibit KATP in rat brain. Otherwise, glibenclamide may not penetrate the blood-brain barrier.. Although KATP in the ...

AMP-activated protein kinase connects cellular energy metabolism to KATP channel function. J Mol Cell Cardiol. 2012 Feb; 52(2):410-8 ...

Shaker-type, voltage-gated K+ (KV1) channels are an important determinant of the resting membrane potential and diameter of small cerebral arteries. During hype...

Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits.: Kir6.1\SUR2B has intrinsic sensitivity

Hari ni Ida nk tayang sayur petola ular goreng... pernah makan ke sayur petola ular ni? mana la tau kot2 dengar nama pun dh geli.. hehehe.. Ida jarang2 je makan.. tu pun kalau my mom beli.. tapi sekali sekala makan sedap jugak.. tak cukup dibuatnya heheheh ...

TY - JOUR. T1 - Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism. AU - Lin, Yu Wen. AU - Bushman, Jeremy D.. AU - Yan, Fei Fei. AU - Haidar, Sara. AU - MacMullen, Courtney. AU - Ganguly, Arupa. AU - Stanley, Charles A.. AU - Shyng, Show-Ling. PY - 2008/4/4. Y1 - 2008/4/4. N2 - The inwardly rectifying potassium channel Kir6.2 is the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, which controls insulin secretion by coupling glucose metabolism to membrane potential in β-cells. Loss of channel function because of mutations in Kir6.2 or its associated regulatory subunit, sulfonylurea receptor 1, causes congenital hyperinsulinism (CHI), a neonatal disease characterized by persistent insulin secretion despite severe hypoglycemia. Here, we report a novel KATP channel gating defect caused by CHI-associated Kir6.2 mutations at arginine 301 (to cysteine, glycine, histidine, or proline). These mutations in ...

TY - JOUR. T1 - Blockade of ATP-sensitive potassium channels prevents the attenuation of the exercise pressor reflex by tempol in rats with ligated femoral arteries. AU - Yamauchi, Katsuya. AU - Stone, Audrey J.. AU - Stocker, Sean D.. AU - Kaufman, Marc P.. PY - 2012/8/1. Y1 - 2012/8/1. N2 - We reported previously that tempol attenuated the exercise pressor and muscle mechanoreceptor reflexes in rats whose femoral arteries were ligated, whereas tempol did not attenuate these reflexes in rats whose femoral arteries were freely perfused. Although the mechanism whereby tempol attenuated these reflexes in rats whose femoral artery was ligated was independent of its ability to scavenge reactive oxygen species, its nature remains unclear. An alternative explanation for the tempol-induced attenuation of these reflexes involves ATP-sensitive potassium channels (K Atp) and calcium-activated potassium channels (BK Ca), both of which are opened by tempol. We tested the likelihood of this explanation by ...

JTV-506, a new K(ATP) channel opener, relaxes pulmonary artery isolated from monocrotaline-treated pulmonary hypertensive rats. - Yohsuke Tsutsumi, Tetsuji Makita, Koji Yamaguchi, Osamu Shibata, Koji Sumikawa

Patients on hemodialysis for end-stage renal disease are at high risk for death from ischemic heart disease. It was reported that nicorandil, a hybrid compound on adenosine triphosphate-sensitive potassium channel opener and nitric oxide door, was potentially effective to prevent cardiovascular events in patients with CAD receiving hemodialysis. Therefore, investigators prospectively examine whether nicorandil is effective in reducing the incidence of cardiovascular events in patients with CAD on hemodialysis.. The primary endpoint is a composite of cardiovascular death, sudden cardiac death, nonfatal myocardial infarction, hospitalization for recurrent symptomatic myocardial ischemia and stroke. The secondary endpoints are total mortality, revascularization therapy, hospitalization for heart failure, hospitalization for peripheral artery disease and newly onset of atrial fibrillation.. Patient population that needs to prove the hypothesis is estimate to be 300 cases in total (150 cases in each ...

TY - JOUR. T1 - Myocardial protection in the acutely injured heart. T2 - Hyperpolarizing versus depolarizing hypothermic cardioplegia. AU - Lawton, J. S.. AU - Hsia, P. W.. AU - Allen, C. T.. AU - Damiano, Jr. N1 - Funding Information: Supported by a National Institutes of Health National Research Service Award, grant HL09125-02 (J. S. L., R. J. D.) and National Institutes of Health grant RO1 HL51032 (R. J. D.). PY - 1997. Y1 - 1997. N2 - Objectives: The superiority of hyperpolarized arrest with adenosine triphosphate-sensitive potassium channel openers over standard hyperkalemic depolarizing cardioplegia during normothermic ischemia has been documented. This study examined the hypothesis that pinacidil would provide superior protection in a more clinically relevant model of an acutely injured heart and hypothermic cardioplegic arrest. Methods: In a blood-perfused, parabiotic, rabbit heart Langendorff model, hearts underwent 15 minutes of unprotected global normothermic ischemia before the ...

The mitochondrial ATP sensitive K+ channel (mitoKATP) plays a significant role in mitochondrial physiology and protects against ischemic reperfusion injury in mammals. Although fish frequently face oxygen fluctuations in their environment the role of mitoKATP channel in regulating the responses to oxygen stress is rarely investigated in this class of animals. To elucidate if and how mitoKATP channel protects against hypoxia-reoxygenation (H-R)-induced mitochondrial dysfunction in fish, we first determined the mitochondrial bioenergetic effects of two key modulators of the channel, diazoxide and 5-hydroxydecanoate (5-HD), using a wide range of doses. Subsequently, the effects of low and high doses of the modulators on mitochondrial bioenergetics and volume under normoxia and after H-R using buffers with and without magnesium and ATP (Mg-ATP) were tested. In the absence of Mg-ATP (mitoKATP channel open) both low and high doses of diazoxide improved mitochondrial coupling but only the high dose of ...

Read Kinetic Analysis of the Inhibitory Effect of Glibenclamide on KATP Channels of Mammalian Skeletal Muscle, The Journal of Membrane Biology on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.

1. ATP-sensitive potassium (KATP) channels are composed of pore-forming Kir6.2 and regulatory SUR subunits. A truncated isoform of Kir6.2, Kir6.2DeltaC26, forms ATP-sensitive channels in the absence of SUR1, suggesting the ATP-inhibitory site lies on Kir6.2. 2. Previous studies have shown that mutation of the lysine residue at position 185 (K185) in the C-terminus of Kir6.2 to glutamine, decreased the channel sensitivity to ATP without affecting the single-channel conductance or the intrinsic channel kinetics. This mutation also impaired 8-azido[32P]-ATP binding to Kir6.2. 3. To determine if K185 interacts directly with ATP, we made a range of mutations at this position, and examined the effect on the channel ATP sensitivity by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing wild-type or mutant Kir6.2DeltaC26. 4. Substitution of K185 by a positively charged amino acid (arginine) had no substantial effect on the sensitivity of the channel to ATP. Mutation to a

Radikal Therapeutics (RTX) is developing a novel cytoprotective agent (R-801) for the prevention of ischemia-reperfusion injury (IRI) following lung transplanta...

Fingerprint Dive into the research topics of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3, 2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): A novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. I. In vitro characterization. Together they form a unique fingerprint. ...

Activating mutations in the K(ATP)-channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K(ATP) mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6-yr-old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75-fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K(ATP)-induced NDM, unless glycemia is well ...

TY - JOUR. T1 - Az ATP-fuggo K+-csatorna-(K+(ATP))-aktivalo pinacidil pre- es poszt- szinaptikus hatasa nyul pulmonaris arterian. AU - Rácz, Dániel. AU - Zillkens, Stefán. AU - Forstreuter, Péter. AU - Nagykáldi, Zsolt. AU - Magyar, K.. AU - Torök, Tamás. PY - 1999/6. Y1 - 1999/6. N2 - Low frequency (2 Hz) of electrical depolarisation induced [3H]noradrenaline ([3H]NA) release has been measured from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3x10-5M and corticosterone, 5x10-5M), with parallel measurements of post- junctional contractile responses. The K+(ATP)-channel opener pinacidil (10- 6-10-4M), slightly potentiated the nerve-evoked release of [3H]NA which failed to show close concentration-dependency. Large concentration of pinacidil (10-4M) increased the ratio of [3H]NA release from 0.99±0.02 to 1.28±0.05 (P-4M caused nearly 70% inhibition of contractile response. The pre- and post-junctional effects of pinacidil were studied under ...

Levosimendan, a new type of inodilator drugs, is known to activate membrane adenosine 3′,5′-triphosphate-sensitive potassium (KATP) channels in some vascular smooth muscles and causes vasorelaxation.

Effects of PPIs on ATP sensitivity at the single-channel level. Single-channel KATP current recorded in an inside-out patch at 0 mV from a rat ventricular cell

Page 2 of 3 - Polydatin - Better than Resveratrol? - posted in Resveratrol: There are some papers mentioned by hedgehog in this POST. Polydatin does metabolize to resveratrol in significant amounts. Right, I am not sure of the benefits of taking polydatin. Yes, it does absorb much better (and dissolves easier, of course) but as niner mentioned, its pretty quickly metabolized to resveratrol in the liver and then glucuronidated just like resveratrol.The main thing would be if the AUCs and...

BMS-191095 is an activators of mitochondrial ATP-sensitive potassium (mitoKATP) channels. ...Quality confirmed by NMR,HPLC & MS.

AMERICAN FAMILY RADIO Christian Inspirational KTXG/DALLAS brings on TIM MARX as Production Director/afternoons. Previously MARX was PD/mornings at CLEAR CHANNEL Country KATP (101.9 THE KAT)/AMARILLO, TX.

Ce document de travail donne un aperçu des nouvelles possibilités offertes par la 4e révolution industrielle et aborde certaines questions spécifiques qui concernent ses effets sur le marché du travail, notamment sur le statut des salariés, sur les conditions de travail et sur la formation. Il... lire plus. ...

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