• The Korean Journal of Physiology and Pharmacology
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• v.20 no.1
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• pp.75-82
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• 2016

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported to have an effect on several ion channels including human ether-a-go-go-related gene in a SSRI-independent manner. These results suggest that paroxetine may cause side effects on cardiac system. In this study, we investigated the effect of paroxetine on Kv1.5, which is one of cardiac ion channels. The action of paroxetine on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Paroxetine reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $4.11{\mu}M$ and 0.98, respectively. Paroxetine accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to 0 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance ${\delta}$ of 0.32. The binding ($k_{+1}$) and unbinding ($k_{-1}$) rate constants for paroxetine-induced block of Kv1.5 were $4.9{\mu}M^{-1}s^{-1}$ and $16.1s^{-1}$, respectively. The theoretical $K_D$ value derived by $k_{-1}/k_{+1}$ yielded $3.3{\mu}M$. Paroxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of paroxetine, were superimposed. Inhibition of Kv1.5 by paroxetine was use-dependent. The present results suggest that paroxetine acts on Kv1.5 currents as an open-channel blocker.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.5
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• pp.577-584
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• 2018

Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2-10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine $A_1$ receptor antagonist), udenafil (PDE5 inhibitor), prazosin (${\alpha}_1$-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in $PLC/IP_3$-mediated intracellular $Ca^{2+}$ release and PDE5 activity.

• Biomolecules & Therapeutics
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• v.10 no.3
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• pp.142-151
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• 2002

The present study was attempted to investigate the effect of apamin on catecholamine (CA) secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, cyclopiazonic acid and Bay-K-8644 from the isolated perfused rat adrenal gland and to establish the mechanism of its action. The perfusion of apamin (1 nM) into an adrenal vein for 20 min produced greatly potentiation in CA secretion evoked by ACh (5.32 $ imes$ $10^{-3}$ M), high $K^+$, (5.6 $ imes$ $10^{-2}$), DMPP ($10^{-4}$ M for 2 min), McN-A-343 ($10^{-4}$ M for 2 min), cyclopiazonic acid ($10^{-5}$ M for 4 min) and Bay-K-8644 ($10^{-5}$ M for 4 min). However, apamin itself did fail to affect basal catecholamine output. Furthermore, in adrenal glands preloaded with apamin (1 nM) under the presence of glibenclamide ($10^{-6}$ M), an antidiabetic sulfonylurea that has been shown to be a specific blocker of ATP-regulated potassium channels (for 20 min), CA secretion evoked by DMPP and McN-A-343 was not affected. However, the perfusion of high concentration of apamin (100 nM) into an adrenal vein for 20 min rather inhibited significantly CA secretory responses evoked by ACh, high $K^+$, DMPP, McN-A-343, cyclopiazonic acid and Bay-K-8644. Taken together, these results suggest that the low concentration of apamin causes greatly the enhancement of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization. These findings suggests that apamin-sensitive SK ($Ca^{2+}$) channels located in rat adrenal medullary chromaffin cells may play an inhibitory role in the release of catecholamines mediated by stimulation of cholinergic nicotinic and muscarinic receptors as well as membrane depolarization. However, it is thought that high concentration of apamin cause the inhibitory responses in catecholamine secretion evoked by stimulation of cholinergic receptors as well as by membrane depolarization from the rat adrenal gland without relevance with the SK channel blockade.

• Biomolecules & Therapeutics
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• v.4 no.4
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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.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.23 no.4
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• pp.319-328
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• 2020

Purpose: To examine the prevalence and clinical manifestations of eosinophilic esophagitis (EoE) in Korea children. Methods: The study was designed as a 1:2 matching case-control study. Using information from the endoscopic database of a tertiary center, we retrospectively reviewed the medical records of patients aged 18 years or younger who underwent upper gastrointestinal endoscopy between January 2014 and December 2017. A total of 21 patients were diagnosed with EoE based on current diagnostic criteria. In addition, 42 controls with normal esophageal biopsy findings matched to each EoE case by sex, age (±1 months), and season were randomly selected during the study period. Results: The mean age of EoE diagnosis was 12.1±4.0 years and the male-to-female ratio was 2:1. The proportion of allergic diseases in patients with EoE (28.6%) was higher than that in the controls (6.8%) (p=0.04). Most EoE patients tested for allergy were positive for at least one antigen, which was significantly different to the controls (88.2% vs. 47.4%, p=0.01). Characteristic endoscopic findings of EoE were noted in 19 patients (90.5%), but 2 patients (9.5%) showed normal esophageal mucosa. The clinical symptoms of EoE were improved by a proton-pump inhibitor in 10 patients (50.0%), and by an H₂ blocker in 9 patients (45.0%). Only one patient (5.0%) required inhaled steroids. Conclusion: While EoE is rare in the Korean pediatric population, the results of this study will improve our understanding of the clinical manifestations of the disease.

• Childhood Kidney Diseases
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• v.22 no.2
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• pp.91-96
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• 2018

Nephrotic syndrome in the first year of life, characterized by renal dysfunction and proteinuria, is associated with a heterogeneous group of disorders. These disorders are often related to genetic mutations, but the syndrome can also be caused by a variety of other diseases. We report an infant with nephrotic syndrome associated with a neuroblastoma. A 6-month-old girl was admitted with a 10% weight loss over 10 days and nephrotic-range proteinuria. She was ill-looking, and her blood pressure was higher than normal for her age. Her cystatin-C glomerular filtration rate was decreased, and levels of plasma renin, aldosterone, and catecholamines were elevated. Renal ultrasonography and abdominal computed tomography showed a retroperitoneal prevertebral mass encasing both renal arteries and the left renal vein. The mass was partially resected laparoscopically, and the pathologic diagnosis was neuroblastoma. Findings on a simultaneous renal biopsy were unremarkable. The patient was treated with chemotherapy and several anti-hypertensive drugs, including an alpha blocker. Two months later, the mass had decreased in size and the proteinuria and hypertension were gradually improving. In an infant with abnormal renin-angiotensin system activation, severe hypertension, and nephrotic-range proteinuria, neuroblastoma can be considered in the differential diagnosis.

• Korean Journal of Veterinary Research
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• v.36 no.3
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• pp.599-605
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• 1996

This study was designed to examine the mechanism of penile erection in adult bull by analyzing the responses of bovine proximal retractor penile muscle strips(BRP) to electtical field stimulation(EFS), exogenous nitric oxide(NO), NO synthesis precursor(L-arginine), NO synthase inhibitors(L-NAME, L-NMMA), guanylate cyclase inhibitor(methylene blue) and nonspecific potassium channel blocker(tetraethylammonium, TEA) treatments. Isometric tension of BRP was measured using physiograph. Results were summarized as follows: 1. EFS of nonadrenergic noncholinrgic(NANC) nerve in BRP produced frequency-dependent inhibitory responses to the contraction induced by co-treatment of epinephrine, guanethidine and atropine. The inhibitory responses to EFS were blocked by tetrodotoxin(TTX, $1{\mu}M$). 2. Treatment of L-NAME ($10,\;20{\mu}M$) inhibited the relaxation to EFS whereas L-NMMA ($100{\mu}M$) had no effect. 3. Treatment of NO($20,\;40{\mu}M$; as an acidified solution of $NaNO_2$) induced concentration-dependent relaxation whereas preincubation of TTX($1{\mu}M$) and L-NAME($20{\mu}M$) had no effect on the relaxation response. 4. L-arginine treatment(10mM) blocked the inhibitory effect of L-NAME($20{\mu}M$). 5. Pretreatment of methylene blue($40{\mu}M$) reduced the NANC-induced relaxation of BRP. 6. Tetraethylammonium(TEA, 80mM) reduced NANC relaxation. These results suggest that NO may act as a NANC neurotransmitter in BRP and the effects might be mediated by cGMP and potassium channel.

• Korean Journal of Clinical Laboratory Science
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• v.48 no.2
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• pp.153-157
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• 2016

Although the adenosine triphosphate (ATP) efflux pathway is thought to play a major regulatory role in RVD in some cells, including cholangiocarcinoma cells, the role of ATP in regulatory volume decrease (RVD) of normal cholangiocytes is not well defined. Thus, this study was conducted to investigate the role of extra cellular ATP and ATP pathways of BDCCs isolated from normal mice. Changes in cell volume of BDCCs were indirectly assessed by measurement of the cross-sectional area (CSA) by quantitative videomicroscopy. The relative CSA of BDCCs from normal mice increased with hypotonic maneuver to $1.20{\pm}0.02$ (n=20) within 10 min, but decreased to $1.06{\pm}0.03$ at 40 min. Administration of ATP, ATP hydrolase apyrase or the P2 receptor blocker suramin during RVD had no significant effects compared with untreated controls. In addition, treatment with the PKC inhibitors, Bisindolamide I and Ro 31-8220, during RVD had no significant effects when compared with untreated controls. These results indicate that unlike the results from cholangiocarcinoma cells, ATP plays no significant role in the RVD of normal mouse cholangiocytes.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.148-149
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• 1998

It has been known that potassium channel openers are a new class of molecules that have attracted general interest because of their potent antihypertensive activity in vivo and vasorelaxant activity in vitro (Hamilton and Weston, 1989). In the present study, it was attempted to examine the effect of the potassium channel opener on catecholamine (CA) secretion evoked by cholinergic stimulation, membrane depolarization and calcium mobilization from the isolated perfused rat adrenal gland. The perfusion of pinacidil (30-300 uM) into an adrenal vein for 20 min produced relatively dose-dependent inhibition in CA secretion evoked by ACh (5.32 mM), high $K^{+}$ (56 mM), DMPP (100 uM for 2 min), McN-A-343 (100 uM for 2 min), cyclopiazonic acid (10 uM for 4 min) and Bay-K-8644 (10 uM for 4 min). Also, under the presence of minoxidil (100 uM), which is also known to be a potassium channel activator, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were also significantly depressed. However, in adrenal glands preloaded with pinacidil (100 uM) under the presence of glibenclamide (1 uM), an antidiabetic sulfonylurea that has been shown to be a specific blocker of ATP-regulated potassium channels (for 20 min), CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were considerably recovered to a considerable extent of the normal release as compared to that of pinacidil only. These results, taken together, suggest that pinacidil cause the marked inhibition of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization, indicating strongly that this effect may be mediated by inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenomedullary chromaffin cells. Furthermore, these findings suggest strongly that these potassium channel openers-sensitive membrane potassium channels also play an important role in regulating CA secretion.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.146-146
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• 1998

The present study was designed to examine the effect of total ginseng saponin on contractile responses of vasoconstrictors in the rat aorta. Phenylephrine (an adrenergic ${\alpha}$$_1$-receptor agonist) and high potassium (a membrane depolarizing agent) caused greatly contractile responses in the rat aorta, respectively. However, in the presence of total ginseng saponin (600 $\mu\textrm{g}$/$m\ell$), the contractile responses of phenylephrine (10$\^$-5/ and 10$\^$-7/ M) and high potassium (3.5 ${\times}$ 10$\^$-2/ and 5.6 ${\times}$ 10$\^$-2/ M) were markedly potentiated whereas prostaglandin F$\sub$2${\alpha}$/ (5 ${\times}$ 10$\^$-6/ M)-induced contractile response was not affected. The contractile responses induced by phenylephrine (10$\^$-5/ M) and high potassium (3.5 ${\times}$ 10$\^$-2/ M) even in the presence of total ginseng saponin (600 $\mu\textrm{g}$/$m\ell$) were greatly inhibited by the pretreatment of nicardipine (10$\^$-6/ M), a calcium channel blocker. Taken together, these experimental results suggest that total ginseng saponin can enhance the contractile responses evoked by stimulation of adrenergic ${\alpha}$$_1$-receptor and the membrane depolarization in the rat aorta, which seems to be associated to calcium influx.