• The Korean Journal of Pain
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• 제25권4호
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• pp.221-227
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• 2012

Background: It has been reported that curcumin, the main active compound of Curcuma longa, also known as turmeric, exhibits antinociceptive properties. The aim of this study was to examine the participation of ATP-sensitive potassium channels ($K_{ATP}$ channels) and, in particular, that of the L-arginine-nitric oxide-cyclic GMP-$K_{ATP}$ channel pathway, in the antinociceptive effect of curcumin. Methods: Pain was induced by the intraplantar injection of 1% formalin in the right hind paw of Wistar rats. Formalin-induced flinching behavior was interpreted as an expression of nociception. The antinociceptive effect of oral curcumin was explored in the presence and absence of local pretreatment with L-NAME, an inhibitor of nitric oxide synthase, ODQ, an inhibitor of soluble guanylyl cyclase, and glibenclamide, a blocker of $K_{ATP}$ channels. Results: Oral curcumin produced a dose-dependent antinociceptive effect in the 1% formalin test. Curcumin-induced antinociception was not altered by local L-NAME or ODQ, but was significantly impaired by glibenclamide. Conclusions: Our results confirm that curcumin is an effective antinociceptive agent. Curcumin-induced antinociception appears to involve the participation of $K_{ATP}$ channels at the peripheral level, as local injection of glibenclamide prevented its effect. Activation of $K_{ATP}$ channels, however, does not occur by activation of the L-arginine-nitric oxide-cGMP-$K_{ATP}$ channel pathway.

• The Korean Journal of Physiology and Pharmacology
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• 제7권1호
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• pp.15-23
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• 2003

Cellular redox state is known to be perturbed during ischemia and that $Ca^{2+}$ and $K^2$ channels have been shown to have functional thiol groups. In this study, the properties of thiol redox modulation of the ATP-sensitive $K^2$ ($K_{ATP}$) channel were examined in rabbit ventricular myocytes. Rabbit ventricular myocytes were isolated using a Langendorff column for coronary perfusion and collagenase. Single-channel currents were measured in excised membrane patch configuration of patch-clamp technique. The thiol oxidizing agent 5,5'-dithio-bis-(2-nitro-benzoic acid) (DTNB) inhibited the channel activity, and the inhibitory effect of DTNB was reversed by dithiothreitol (disulfide reducing agent; DTT). DTT itself did not have any effect on the channel activity. However, in the patches excised from the metabolically compromised cells, DTT increased the channel activity. DTT had no effect on the inhibitory action by ATP, showing that thiol oxidation was not involved in the blocking mechanism of ATP. There were no statistical difference in the single channel conductance for the oxidized and reduced states of the channel. Analysis of the open and closed time distributions showed that DTNB had no effect on open and closed time distributions shorter than 4 ms. On the other hand, DTNB decreased the life time of bursts and increased the interburst interval. N-ethylmaleimide (NEM), a substance that reacts with thiol groups of cystein residues in proteins, induced irreversible closure of the channel. The thiol oxidizing agents (DTNB, NEM) inhibited of the $K_{ATP}$ channel only, when added to the cytoplasmic side. The results suggested that metabolism-induced changes in the thiol redox can also modulate $K_{ATP}$ channel activity and that a modulatory site of thiol redox may be located on the cytoplasmic side of the $K_{ATP}$ channel in rabbit ventricular myocytes.

• The Korean Journal of Physiology and Pharmacology
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• 제6권4호
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• pp.183-186
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• 2002

Ischemic damage is one of the most serious problems. The openers of KATP channel have been suggested to have an effect to limit the ischemic damage. However, it is not yet clear how KATP channels of a cell correspond to hypoxic damage. To address the question, N2a cells were exposed to two different hypoxic conditions as follows: 6 hours hypoxia followed by 3 hours reperfusion and 12 hours hypoxia followed by 3 hours reperfusion. As the results, 6 hours hypoxic treatment increased glibenclamide- sensitive basal $K_{ATP}$ current activity (approximately 6.5-fold at 0 mV test potential) when compared with nomoxic condition. In contrast, 12 hours hypoxic treatment induced a relatively smaller change in the $K_{ATP}$ current density (2.5-fold at 0 mV test potential). Additionally, in experiments where $K_{ATP}$ channels were opened using diazoxide, the hypoxia for 6 hours significantly increased the current density in comparison to control condition (p＜0.001). Interestingly, the augmentation in the $K_{ATP}$ current density reduced after exposure to the 12 hours hypoxic condition (p＜0.001). Taken together, these results suggest that $K_{ATP}$ channels appear to be recruited more in cells exposed to the 6 hours hypoxic condition and they may play a protective role against hypoxia-reperfusion damage within the time range.

• 대한약학회:학술대회논문집
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• 대한약학회 2001년도 Proceedings of the Pharmaceutical Society of Korea
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• pp.123.1-123.1
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• 2001

• The Korean Journal of Physiology and Pharmacology
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• 제9권4호
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• pp.187-193
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• 2005

Several signal transduction pathways have been implicated in ischemic preconditioning induced by the activation of ATP-sensitive $K^+$ $(K_{ATP})$ channels. We examined whether protein kinase C (PKC) modulated the activity of $K_{ATP}$ channels by recording $K_{ATP}$ channel currents in rabbit ventricular myocytes using patch-clamp technique and found that phorbol 12,13-didecanoate (PDD) enhanced pinacidil-induced $K_{ATP}$ channel activity in the cell-attached configuration; and this effect was prevented by bisindolylmaleimide (BIM). $K_{ATP}$ channel activity was not increased by $4{\alpha}-PDD$. In excised insideout patches, PKC stimulated $K_{ATP}$ channels in the presence of 1 mM ATP, and this effect was abolished in the presence of BIM. Heat-inactivated PKC had no effect on channel activity. PKC-induced activation of $K_{ATP}$ channels was reversed by PP2A, and this effect was not detected in the presence of okadaic acid. These results suggest that PKC activates $K_{ATP}$ channels in rabbit ventricular myocytes.

• Biomolecules & Therapeutics
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• 제4권4호
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• pp.373-377
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• 1996

The effect of potassium channel openers, KR-30450, KR-30818 and lemakalim have been compared against several spasmogens in guinea pig bronchi. In guinea pig bronchi, KR-30450 had a greater relaxant effect than lemakalim and KR-30818 against tone induced by histamine $10^{-5}M$ ($EC_{50}$ $\mu$M: KR-30450, 0.108$\pm$0.077; KR-30818, 0.403$\pm$0.023; lemakalim, 0.968$\pm$0.036) and prostaglandin $F_{2\alpha} 3\times10^{-6} M$ ($EC_{50}$ $\mu$M: KR-30450, 0.018$\pm$0.001; KR-30818, 0.028$\pm$0.003; lemakalim, 0.138$\pm$0.019). Relaxant effect of KR-30450 and KR-30818 were significantly reduced by 20 min pretreatment of tissues with $10^[-6}$ M glibenclamide, a selective blocker of ATP-sensitive potassium channel. Against acetylcholine-induced tone in guinea pig bronchi, however, these compounds had little effect. In summary, KR-30450 and KR-30818 showed greater relaxant effect than lemakalim in guinea pig bronchi (KR-30450>KR-30818>lemakalim). These relaxant actions are suggested to be mediated at least in part by a mechanism which involves the opening of ATP-sensitive potassium channel.

• The Korean Journal of Physiology and Pharmacology
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• 제5권2호
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• pp.165-175
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• 2001

Background: Recent in vivo experimental evidence suggests that isoflurane-induced cardioprotection may involve $K_{ATP}$ channel activation. However, it was demonstrated that isoflurane inhibited $K_{ATP}$ channel activities in the inside-out patch mode. To explain this discrepancy, the present investigation tested the hypothesis that a metabolite of isoflurane, trifluoroacetic acid (TFA), contributes to isoflurnae-induced cardioprotection via $K_{ATP}$ channel activation during myocardial ischemia and reperfusion. Methods: Single ventricular myocytes were isolated from rabbit hearts by an enzymatic dissociation procedure. Patch-clamp techniques were used to record single-channel currents. $K_{ATP}$ channel activities were assessed before and after the application of TFA with the inside-out patch mode. Results: TFA enhanced channel activity in a concentration-dependent fashion. The concentration of TFA for half-maximal activation and the Hill coefficient were 0.03 mM and 1.2, respectively. TFA did not affect the single channel conductance of $K_{ATP}$ channels. Analysis of open and closed time distributions showed that TFA increased burst duration and decreased the interburst interval without changes in open and closed time distributions shorter than 5 ms. TFA diminished ATP sensitivity of $K_{ATP}$ channels in a concentration-response relationship for ATP. Conclusions: TFA, a metabolite of isoflurane, enhanced $K_{ATP}$ channel activity in a concentration-dependent fashion. These results imply that TFA could mediate isoflurane-induced cardioprotection via $K_{ATP}$ channel activation during myocardial ischemia and reperfusion.

• Clinical and Experimental Pediatrics
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• 제58권8호
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• pp.309-312
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• 2015

Permanent neonatal diabetes mellitus refers to diabetes that occurs before the age of 6 months and persists through life. It is a rare disorder affecting one in 0.2-0.5 million live births. Mutations in the gene KCNJ11, encoding the subunit Kir6.2, and ABCC8, encoding SUR1 of the ATP-sensitive potassium ($K_{ATP}$) channel, are the most common causes of permanent neonatal diabetes mellitus. Sulfonylureas close the $K_{ATP}$ channel and increase insulin secretion. KCNJ11 and ABCC8 mutations have important therapeutic implications because sulfonylurea therapy can be effective in treating patients with mutations in the potassium channel subunits. The mutation type, the presence of neurological features, and the duration of diabetes are known to be the major factors affecting the treatment outcome after switching to sulfonylurea therapy. More than 30 mutations in the KCNJ11 gene have been identified. Here, we present our experience with a patient carrying a novel p.H186D heterozygous mutation in the KCNJ11 gene who was successfully treated with oral sulfonylurea.

• 대한수의학회지
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• 제35권2호
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• pp.245-254
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• 1995

The density of ATP-sensitive potassium($K_{APT}$) channels, that open as intracellular ATP concentration falls below a critical level, is very high in skeletal muscle surface membrane and those high density may imply that $K_{ATP}$ channels have very important physiological roles. To elucidate a role of $K_{ATP}$ in relation to fatigue, the modulating effects of potassium channel openers and blockers on the fatigue velocity(FV) of mouse extensor hallucis longus muscle(EHL) were investigated in vitro. Twitch contraction was induced by an electrical field stimulation (EFS: 24-48V, 20ms, 0.2-4Hz) and resulting contraction force was isometrically recorded. The twitch forces were gradually decreased to 25% of initial contraction force(ICF) in $37.52{\pm}1.55sec$($mean{\pm}s.e.m.$, n=135), indicating the fatigue phenomena. The mean velocity for development of the fatigue was measured during the period that twitch force decreased to half($FV_{0/0.5}$) and during the period from half to 25%($FV_{0.5/0.25}$) of ICF. The fatigue was induced once every one hour and the tissue response was stable for up to 4 hours. In control condition, ICF was $5.8{\pm}0.12g$ (n=144) and decreased to 50% of ICF with the mean fatigue velocity of $0.182{\pm}0.006g/sec$($FV_{0/0.5}$, n=135) and from 50% to 25% of ICF with $0.084{\pm}0.004g/sec$($FV_{0.5/0.25}$, n=135). Cromakalim($50{\mu}M$) significantly increased $FV_{0.5/0.25}$(n=4). Glibenclamide($IC_{50}>50{\mu}M$), $Ba^{2+}$($IC_{50}=10{\mu}M$), 4-aminopyridine($FV_{0/0.5}$, $IC_{50}=0.5mM$; $FV_{0.5/0.25}$, $IC_{50}=2mM$) decreased both $FV_{0/0.5}$ and $FV_{0.5/0.25}$ concentration-dependently up to 75%. $TEA^+$(30mM), E-4031($10{\mu}M$), tolbutamide(1mM) decreased $FV_{0.5/0.25}$, but apamin(300nM) and $TEA^+$(10mM) showed no significant effects. Our results suggest that activation of the $K_{ATP}$ channels may be major cause of $K^+$ outflux during development of the fatigue and the isolated EHL muscle could be an useful experimental preparation in studying the fatigue phenomena in skeletal muscle. In addition, the possibility of activation of delayed rectifier during the fatigue development remains to be studied further.

• Journal of Korean Neurosurgical Society
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• 제29권6호
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• pp.719-724
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• 2000

Objectives : It has been reported that the presence of a pharmacologically inactive foreign substance, polystyrene latex bead, in subarachnoid space activates a non-specific immunological response and elicits arterial narrowing. Recently the activation of potassium($K^+$) channels may be of benefit in relieving cerebral vasospasm. The present study examined the effects of systemic administration of a ATP-sensitive $K^+$ channel activator, cromakalim, on the polystyrene latex bead-induced cerebral vasospasm. Methods : The spasm models similar to that caused by subarachnoid blood injection were created by injection of bead into rabbit cisterna magna. Intravenous injections of cromakalim were administered twice daily(bid) 30 minutes after induction of vasospasm. Animals were killed by perfusion-fixation 2 days after vasospasm. Basilar arteries were removed and sectioned, and the luminal cross-sectional areas were measured. Results : Injection of bead elicited an arterial constriction, reducing arterial diameter to 33.3% of resting tone. Cromakalim inhibited bead-induced constriction at a dose of 0.3mg/kg(Mann-Whitney test, p<0.01). Conclusion : These results support the concept that the cellular events triggered by inactivation of ATP-sensitive $K^+$ channels are responsible for the pathogenesis of vasospasm. The findings also indicate that cromakalim represents a potential therapeutic agents for the treatment of cerebral vasospasm.