• 한국임상약학회지
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• 제7권1호
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• pp.33-39
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• 1997

Cardiac and antihypertensive effects of BMS-180448, a cardiac-selective ATP-sensitive potassium channel opener, and its newly synthesized derivatives KR-31281, KR-31282 and KR-31299 were evaluated in isolated perfused rat hearts (25 min global ischemia/30 min reperfusion) and conscious rats. Three new compounds $(10\;{\mu}M)$ induced positive inotropism as evidenced by increased LVDP (left ventricular developed pressure) and RPP (Rate-Pressure Product) in nonischemic rat heart. HR-31299 increased CF (coronary flow) and HR (heart rate) but the other two had no effects. KR-31282, KR-31281 and HR-31299 had a tendency to increase reperfusion LVDP and RPP compared with vehicle, while the latter two significantly reduced reperfusion EDP with a tendency to inclose TTC (time to contracture). All three KR-compounds had very weak effects on MBP and HR in conscious rats. These results indicate that KR-31281 and HR-31299 may have some cardioprotective effects, although weaker than BMS-180448, and their mode of action different from that of BMS-180448, despite the similarity in major structural moeity.

• Clinical and Experimental Pediatrics
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• 제59권sup1호
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• pp.116-120
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• 2016

Congenital hyperinsulinism (CHI) is a rare condition that can cause irreversible brain damage during the neonatal period owing to the associated hypoglycemia. Hypoglycemia in CHI occurs secondary to the dysregulation of insulin secretion. CHI has been established as a genetic disorder of islet-cell hyperplasia, associated with a mutation of the ABCC8 or KCNJ11 genes, which encode the sulfonylurea receptor 1 and the inward rectifying potassium channel (Kir6.2) subunit of the ATP-sensitive potassium channel, respectively. We report the case of a female newborn infant who presented with repetitive seizures and episodes of apnea after birth, because of hypoglycemia. Investigations revealed hypoglycemia with hyperinsulinemia, but no ketone bodies, and a low level of free fatty acids. High dose glucose infusion, enteral feeding, and medications could not maintain the patient's serum glucose level. Genetic testing revealed a new variation of ABCC8 mutation. Therefore, we report this case of CHI caused by a novel mutation of ABCC8 in a half-Korean newborn infant with diazoxide-unresponsive hyperinsulinemic hypoglycemia.

• Journal of Ginseng Research
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• 제39권4호
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• pp.314-321
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• 2015

Background: Ginseng belongs to the genus Panax. Its main active ingredients are the ginsenosides. Interstitial cells of Cajal (ICCs) are the pacemaker cells of the gastrointestinal (GI) tract. To understand the effects of ginsenoside Re (GRe) on GI motility, the authors investigated its effects on the pacemaker activity of ICCs of the murine small intestine. Methods: Interstitial cells of Cajal were dissociated from mouse small intestines by enzymatic digestion. The whole-cell patch clamp configuration was used to record pacemaker potentials in cultured ICCs. Changes in cyclic guanosine monophosphate (cGMP) content induced by GRe were investigated. Results: Ginsenoside Re ($20-40{\mu}M$) decreased the amplitude and frequency of ICC pacemaker activity in a concentration-dependent manner. This action was blocked by guanosine 50-[${\beta}-thio$]diphosphate [a guanosine-5'-triphosphate (GTP)-binding protein inhibitor] and by glibenclamide [an adenosine triphosphate (ATP)-sensitive $K^{+}$ channel blocker]. To study the GRe-induced signaling pathway in ICCs, the effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) and RP-8-CPT-cGMPS (a protein kinase G inhibitor) were examined. Both inhibitors blocked the inhibitory effect of GRe on ICC pacemaker activity. L-NG-nitroarginine methyl ester ($100{\mu}M$), which is a nonselective nitric oxide synthase (NOS) inhibitor, blocked the effects of GRe on ICC pacemaker activity and GRe-stimulated cGMP production in ICCs. Conclusion: In cultured murine ICCs, GRe inhibits the pacemaker activity of ICCs via the ATP-sensitive potassium ($K^{+}$) channel and the cGMP/NO-dependent pathway. Ginsenoside Re may be a basis for developing novel spasmolytic agents to prevent or alleviate GI motility dysfunction.

• 생명과학회지
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• 제27권11호
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• pp.1349-1356
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• 2017

$K^+$ 통로 개방제들은 심근, 뇌, 골격근 등에서 세포막 혹은 미토콘드리아 내막에 존재하는 큰 전도성의 $Ca^{2+}$-의 존성 $K^+$ (BK) 통로 및 ATP-조절성 $K^+$ 통로(ATP-sensitive $K^+$ channels, $K_{ATP}$)에 작용하여 허혈성 혹은 산화성 세포 손상을 완화하는 효과가 있는 것으로 보고되어 있다. 본 연구에서는 망막 색소 상피세포주인 ARPE-19 세포를 실험 모델로 하여 큰 전도성의 BK 통로 개방제인 NS 1619가 유사한 보호 효과를 나타낼 수 있는지, 또한 그 작용기전이 무엇인지를 확인하고자 하였다. AREE-19 세포를 여러 형태의 산화 스트레스에 노출시켜 세포 손상을 유발하고 그 손상의 정도 및 이에 미치는 NS 1619의 효과를 trypan blue 배출능, Tunel 염색 분석을 통하여 측정하였다. NS 1619는 여러 형태의 산화 스트레스에 의한 괴사성 및 apoptosis에 의한 세포 손상을 효과적으로 방지하였으며 그 보호 효과는 BK 통로 봉쇄제인 paxilline 의해 차단되었다. NS 1619는 $H_2O_2$에 의한 세포내 ATP 고갈을 현저히 완화시켰으며, 또한 MTT 환원능으로 측정한 미토콘드리아의 기능을 보호하는 효과를 보였다. 유세포형광 분석법을 이용한 실험에서 NS 1619는 $H_2O_2$에 의한 미토콘드리아 막전압의 소실을 유의하게 방지하였다. 이상의 결과들을 종합하면 NS 1619는 망막 색소 상피세포에서 산화성 세포 손상을 방지하는 효과를 나타내며 그 기전에 미토콘드리아 기능에 대한 보호 작용이 연관되어 있는 것으로 사료된다.

• Archives of Pharmacal Research
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• 제28권1호
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• pp.61-67
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• 2005

We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers $(K_{ATP}\;openers)$ on washed human platelets, and the study's emphasis was on the role of mitochondrial $K_{ATP}$ in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective $K_{ATP}$ openers, and also by cardioselective BMS-180448 and BMS-191095 $(IC_{50}\;:\;1,130,\;>\;1,500,\;305.3\;and\;63.9\;{\mu}M,\;respectively)$, but a significantly greater potency was noted for the cardioselective $K_{ATP}$ openers. The latter two $K_{ATP}$ openers also inhibited platelet aggregation induced by thrombin, another important blood-borne platelet activator, with similar rank order of potency $(IC_{50}\;:\;498.0\;and\;104.8{\mu}M\; for\;BMS-180448\;and\;BMS-191095,\;respectively)$. The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with glyburide $(1{\mu}M)$ or sodium 5-hydroxyde­canoate$(5-HD,\;100{\mu}M)$, a nonselective and selective mitochondrial $K_{ATP}$ antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial $K_{ATP}$ in the antiplatelet activity of BMS-191095. However, glyburide and 5-HD had no effect when they were added to the platelet cuvette immediately prior to the addition of BMS-191095. These findings indicate that cardioselective mitochondrial $K_{ATP}$ openers like BMS-191095 are able to exert cardioprotective effects in cardiac ischemia/reperfusion injury via dual mechanisms directed at the inhibition of platelet aggregation and the protection of cardiomyocytes, and both these mechanisms are mediated by mitochondrial$K_{ATP}$.

• 대한약리학회지
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• 제30권2호
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• pp.191-203
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• 1994

$K^+$ channel openers (KCOs) are known to have a wide range of effects by opening the $K^+$ channel in plasma membranes of various smooth muscles, cardiac muscle and pancreatic ${\beta}-cell$. In the present study, we investigated the effects of 5 types of KCOs, cromakalim, RP49356, pinacidil, nicorandil and diazoxide on the contractility of isolated rat uterus. All KCOs tested inhibited the uterine contraction induced by 0.2 nM oxytocin in a dose-dependent manner. Individual KCO and its $pD_2$ values were cromakalim 6.5, RP49356 6.3, pinacidil 5.92, nicorandil 4.43 and diazoxide 4.18. The relaxant effects of KCO were inhibited by glibenclamide (0.3, 1 and $10\;{\mu}M$) with $pA_2$ values of cromakalim 6.91, RP49356 6.59, pinacidil 6.55, nicorandil 5.97 and diazoxide 6.37. In addition, the relaxant effect of cromakalim or pinacidil was antagonised by TEA, a non-selective $K^+$ channel blocker, but not by apamin. Contractions induced by low concentration of KCI (< 40 mM) were inhibited by cromakalim $(100{\mu}M)$ and nicorandil $(300{\mu}M)$, but those evoked by higher concentration (> 40 mM) of KCI were little affected. In ovariectomized rat uterus, cromakalim dose-dependently inhibited oxytocin-induced contraction and glibenclamide $(10{\mu}M)$ inhibited the relaxant effect of cromakalim with $pD_2$ and $K_B$ values of 7.48 and $1.26{\times}10^{-7}M$, respectively. In estrogen-primed rat uterus, these values were 6.51 and $1.57{\times}10^{-7}M$, respectively, indicating that the cromakalim is less effective on the estrogen-treated uterine smooth muscle. Our results suggest that the KCO-sensitive $K^+$ channels participate in the motility of uterine smooth muscle and such channels are, at least in part, under the control of estrogen. In addition, our data Indicate that the type of $K^+$ channels activated by KCO is ATP-sensitive $K^+$ channels which is blocked by glibenclamide.

• Journal of Plant Biotechnology
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• 제34권4호
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• pp.313-322
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• 2007

Extract of Japanese red pine needles has been used in Asia pacific regions since long periods believing its valuable properties as tonic and ability of curing diseases of unidentified symptoms. Some selective compounds present in the extract and their effects were analyzed. Carbohydrates and vitamin c were identified using HPLC; terpenoid compounds by GC-MS; anti-bacterial analysis by paper discs, plates count and gastrointestinal motility by whole cell patch clamp. The extract is a mixture of compounds therefore its diverse effect was expected. Self-fermentation in extract proceeds after spontaneous appearance of yeast strains without inoculation. Effects and composition of the extract vary with varying period of self-fermentation. Extract inhibits the growth of bacteria dose dependently exhibiting its antibacterial properties however effectiveness increases with increase in fermentation period. The extract also can modulate gastrointestinal motility in murine small intestine by modulating pace maker currents in ICC mediated through ATP sensitive potassium channel.

• The Korean Journal of Physiology and Pharmacology
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• 제10권4호
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• pp.199-205
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• 2006

The functional expression of potassium $(K^+)$ channels has electrophysiologically been studied in bone cells from several species, however, their identity and regulation of gene expressions in bone cells are not well known. In the present study, to investigate how $K^+$ channel expressions are regulated by estrogen, we measured changes of transcript levels of various $Ca^{2+}$-activated ($K_{Ca}$) and ATP-sensitive $K^+$ channels in rat osteoblastic ROS 17/2.8 cells after treatment with estrogen. Application of 17${\beta}$-estradiol $(E_2)$ for 24 h and 48 h increased mRNA and protein expressions of inwardly rectifying $K^+$ channel (Kir) 6.2 and type 2 small conductance $K_{Ca}$ channel (SK2), respectively. Combined treatment of cells with 17${\beta}-E_2$ and ICI 182,780, a pure antiestrogen, suppressed 17${\beta}-E_2$-induced alterations of SK2 and Kir6.2 mRNA levels. In addition, treatment of cells with U0126, a specific inhibitor of extracellular receptor kinases (ERK)1/2, and SP600125, a specific inhibitor of c-jun N-terminal kinase (JNK) blocked the enhancing effects of 17${\beta}-E_2$ on SK2 and Kir6.2 protein expressions. On the other hand, blocking of p38 mitogen-activated protein kinase had no effect. Taken together, these results indicate that 17${\beta}-E_2$ modulates SK2 and Kir6.2 expressions through the estrogen receptor, involving ERK1/2 and JNK activations.

• 대한핵의학회지
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• 제34권4호
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• pp.303-311
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• 2000

목적: 생체 내에서 potassium과 유사한 역학을 보이는 thallium은 종양의 영상에 널리 사용된다. $K^+$ 통로개방제는 세포 내의 potassium을 외부로 배출되게 하는 기능이 있어 Tl-201을 이용한 종양영상에도 영향을 미칠 수 있을 것이라 생각된다. 본 연구는 강력한 $K^+$ 통로개방제의 하나인 pinacidil이 Tl-201을 이용한 종양의 국소화에 어떠한 영향을 미치는 가를 알아보기 위하여, 종양을 가진 생쥐에서 pinacidil에 의한 Tl-201의 체내분포 변화를 알아보았다. 대상 및 방법: 생쥐 유방암세포주를 이식받은 Balb/c 생쥐를 3주간 사육한 후 실험에 이용하였다. Tl-201 185 KBq를 꼬리정맥을 통해 주입한 후 일정시간에 실험동물을 희생시켜 Tl-201의 체내 분포를 알아 보았으며, pinacidil $100{\mu}g$ 투여에 따른 분포 변화를 알아보았다. 또한 Tl-201 3.7 MBq를 꼬리정맥을 통해 주입하여 Tl-201의 시간에 따른 전신 잔류율을 측정하였고, pinacidil 투여에 의한 전신 잔류율 변화를 구하였다. 결과: pinacidil 투여시 대조군에 비해 혈액 내 Tl-201의 방사능치를 약간 감소시키나 신장에서는 현저한 감소를 일으켰다. 또한 간, 근육, 및 장관의 방사능은 pinacidil 투여에 의해 변하지 않았다. 종양 내 Tl-201 섭취율 및 종양조직/혈액 무게당 섭취비는 대조군에 비해 pinacidil 투여군에서 낮았으며, Tl-201의 24시간 전신 잔류율도 pinacidil 투여군에서 낮았다. 결론: $K^+$ 통로개방제는 Tl-201의 체외 배설을 촉진시키고, 신장 섭취를 감소시켜나, 종양 섭취량도 감소시켰다. 그러므로 Tl-201 종양영상 판독시 $K^+$ 통로개방제를 사용하는 경우에는 오히려 Tl-201 종양영상의 질이 향상되기 보다는 저하될 수 있다는 사실을 고려하여야 할 것으로 생각된다.

• Biomolecules & Therapeutics
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• 제10권3호
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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.