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The Effects of Diltiazem and Pentoxifylline on Apoptosis of Irradiated Rat Salivary Gland (흰쥐 침샘의 방사선조사시 Apoptosis에 대한 Diltiazem과 Pentoxifylline의 효과)

  • Yang, Kwang-Mo;Suh, Hyun-Suk
    • Radiation Oncology Journal
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    • v.16 no.4
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    • pp.367-375
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    • 1998
  • Purpose : Xerostomia is a complication met by almost all patients who have radiotherapy for cancers of head and neck. Many studies for prevention of xerostomia will be necessary. Radiation-induced acute response of salivary glands has been defined as interphase death or apoptosis. Increased intracellular calcium level have an important role in radiation-induced apoptosis. Calcium channel blocker may prevent radiation-induced apoptosis of salivary glands. This study was designed to evaluate the effectiveness of diltiazem known as calcium channel blocker and pentoxifylline with inhibition of inflammatory response on the apoptosis as an acute response of radiation in rat salivary glands. Materials and Methods : Sprague-Dawley rats with about body weight 200-250 g were divided into 5 study groups : control, radiation alone, diltiazem with radiation, pentoxifylline with radiation, and diltiazem and pentoxifylline with radiation. The diltiazen and pentoxifylline were injected intraperitoneally 20 mg/kg and 50 mg/kg, 30 and 20 mimute before irradiation. respectively. Irradiation was given with a 4 MV linear accelerator. The 1600 cGy of radiation was delivered in a single fraction through a single anterior portal encompassing the entire neck. After 24 h of irradiation, rats were sacrificed and parotid and submandibular glands were removed and stained with hematoxylin and eosin. The quantification of apoptosis was performed by microscopic examination of stained tissue sections at a magnification of 200X and the percentage of apoptotic cell was calculated. Results : On parotid glands, the percentage of apoptosis by radiation alone, diltiazem with radiation, pentoxifylline with radiation, and diltiazem and pentoxifylline with radiation were 1.72$\%$ (8.35/486), 0.64$\%$ (2.9/453), 0.23$\%$ (1.2/516), and 0.28$\%$ (1.1/399), respectively. The apoptosis was markedly reduced in the groups receiving drugs compared with groups receivinge, radiation alone (p<0.05). In serous cell of submandibular glands, the percentages of apoptosis of radiation alone, diltiazem with radiation, pentoxifylline with radiation, and diltiazem and pentoxifylline with radiation were 1.94$\%$ (l1/567), 0.34$\%$ (1.9/554), 0.28$\%$ (1.8/637), and 0.22$\%$ (1.3/601), respectively. In the mucus cell of submandibular glands, the percentages of apoptosis were 0.92$\%$ (5.1/552), 0.41$\%$ (2.5/612), 0.29$\%$ (1.3/455), and 0.18$\%$ (1.0/562), respectively. The apoptosis was markedly reduced in the serous glands (p<0.05), but there was no difference in development of apoptosis in each group of mucus gland. Conclusion : These results suggest that radiation-induced apoptosis of serous cells of salivary glands may be decreased by diltiazem and pentoxifylline administration.

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$H_2$ Receptor-Mediated Relaxation of Circular Smooth Muscle in Human Gastric Corpus: the Role of Nitric Oxide (NO)

  • Lee, Sang Eok;Kim, Dae Hoon;Kim, Young Chul;Han, Joung-Ho;Choi, Woong;Kim, Chan Hyung;Jeong, Hye Won;Park, Seon-Mee;Yun, Sei Jin;Choi, Song-Yi;Sung, Rohyun;Kim, Young Ho;Yoo, Ra Young;Park, Hee Sun;Kim, Heon;Song, Young-Jin;Xu, Wen-Xie;Yun, Hyo-Yung;Lee, Sang Jin
    • The Korean Journal of Physiology and Pharmacology
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    • v.18 no.5
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    • pp.425-430
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    • 2014
  • This study was designed to examine the effects of histamine on gastric motility and its specific receptor in the circular smooth muscle of the human gastric corpus. Histamine mainly produced tonic relaxation in a concentration-dependent and reversible manner, although histamine enhanced contractility in a minor portion of tissues tested. Histamine-induced tonic relaxation was nerve-insensitive because pretreatment with nerve blockers cocktail (NBC) did not inhibit relaxation. Additionally, $K^+$ channel blockers, such as tetraethylammonium (TEA), apamin (APA), and glibenclamide (Glib), had no effect. However, $N^G$-nitro-L-arginine methyl ester (L-NAME) and 1H-(1,2,4)oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), did inhibit histamine-induced tonic relaxation. In particular, histamine-induced tonic relaxation was converted to tonic contraction by pretreatment with L-NAME. Ranitidine, the $H_2$ receptor blocker, inhibited histamine-induced tonic relaxation. These findings suggest that histamine produced relaxation in circular smooth muscle of human gastric smooth muscle through $H_2$ receptor and NO/sGC pathways.

The Influence of Several Drugs Affecting $Ca^{2+}$ Influx on Frequency-tension Curve of Rat Left Atrium (쥐의 좌심방에서 세포막을 통한 $Ca^{2+}\;Flux$에 영향을 주는 약물이 자극빈도-장력 곡선에 미치는 영향)

  • Kim, Chan-Yun;Ahn, Sok-Kyun;Suh, Chang-Kook;Kang, Doo-Hee
    • The Korean Journal of Physiology
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    • v.23 no.2
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    • pp.329-337
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    • 1989
  • Cardiac muscles show stimulation frequency-dependent tension changes i.e. Bowditch phenomenon and Woodworth phenomenon, the former is an increase of tension with the increase of stimulation frequency, whereas the latter is an increase of tension with a decrease of stimulation frequency. Bowditch phenomenon is seen in the range of frequency 1.0 cps and above, and Woodworth phenomenon below the frequency 1.0 cps in the most of mammalian cardiac atrium. To throw some light on the possible mechanism of both phenomena in rat atrium, influences of drugs affecting $Ca^{2+}$ influx through the plasma membrane $(verapamil,\;La^{3+},\;norepinephrine)$ and $Ca^{2+}$ release from sarcoplasmic reticulum (SR) on frequency-tension curve were studied. The results obtained are summarized as follows: 1) At low temperature $(27.5^{\circ}C)$, both Bowditch and Woodworth phenomenon were demonstrated. But Bowditch phenomenon disappeared at the temperature above $(32.5^{\circ}C)$. 2) At $(27.5^{\circ}C)$, in the presence of verapamil, a $Ca^{2+}$ channel blocker, a time course of change in the frequency-tension was studied. It was found that Bowditch phenomenon was affected before the Woodworth phenomenon, then the former was completely disappeared. At $(32.5^{\circ}C)$, where no Bow-ditch is seen in normal atrial muscle, Bowditch phenomenon was reappeared by an administration of norepinephrine suggesting again that slow inward current of such as $Ca^{2+}$ channel is closely related to Bowditch phenomenon. 3) At $27.5^{\circ}C$, in the presence of $La^{3+}$, although tensions were decreased at all stimulation frequencies, Bowditch and Woodworth phenomenon were still demonstrated. However in the presence of both $La^{3+}$ and verapamil, Bowditch phenomena was disappeared suggesting that $La^{3+}$ is less effective in blocking $Ca^{2+}$ channel than verapamil. 4) At $27.5^{\circ}C$, in the presence of ryanodine, an inhibitor of calcium release from SR, Woodworth phenomenon was disappeared, which was consistent with previous reports of others, suggesting that $Ca^{2+}$ release from SR is closely related to Woodworth phenomenon. From the above findings, it may be concluded that Bowditch phenomenon is dependent on the magnitude of $Ca^{2+}$ influx through slow channel and Woodworth phenomenon is dependent on the amount of $Ca^{2+}$ stored in SR.

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Inhibitory mechanism of α1-adrenergic stimulation on the release of thyroxine in mouse thyroids (Mouse 갑상선에서 α1-adrenoceptor 자극에 의한 thyroxine 유리 억제기전)

  • Kang, Hyung-sub;Kim, Song-kyu;Kang, Chang-won;Kim, Jin-sang;Lee, Ho-il
    • Korean Journal of Veterinary Research
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    • v.38 no.4
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    • pp.712-719
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    • 1998
  • Thyroid function is mainly regulated through cAMP and phophatidylinositol, and it is well known that TSH-stimulated thyroxine ($T_4$) release is inhibited by catecholamine from mouse thyroids via the ${\alpha}_1$-adrenoceptor stimulation. Previous study has established that the inhibition of $T_4$ release by ${\alpha}_1$-adrenoceptor stimulation results in activated protein kinase C (PKC). The purpose of this study was to determine if ion transport systems are involved in the inhibition of $T_4$ release elicited by ${\alpha}_1$-adrenergic agonist in mouse thyroids. TSH-, IBMX- and cAMP analogue-stimulated $T_4$ release were significantly inhibited by methoxamine, R59022 (diacylglycerol kinase inhibitor), and MDL (adenylate cyclase inhibitor). TSH-stimulated $T_4$ release could be inhibited by Bay K 8644 and cyclopiazoic acid, but not by verapamil and tetrodotoxin. The addition of nifedipine ($Ca^{2+}$ channel blocker), tetrodotoxin and lidocaine ($Na^+$ channel blockers), but not amiloride (EIPA) and ryanodine, completely blocked the inhibitory effects of methoxamine on $T_4$ release. TSH-stimulated $T_4$ release was also inhibited by benzamil ($Na^+-Ca^{2+}$ exchange inhibitor). TSH-, IBMX- and cAMP-stimulated $T_4$ release were inhibited by methoxamine or R59022, these effects were reversed by nifedipine. but not by verapamil. Furthermore, nifedipine reversed the inhibitory effects of benzamil and R59022 on TSH-stimulated $T_4$ release. These data suggest that the observed ${\alpha}_1$-adrenoceptor-mediated inhibition of $T_4$ release in mouse thyroids is the result of an increase in intracellular $Na^+$ or $Ca^{2+}$ effected via activation of fast $Na^+$ or nifedipine-sensitive $Ca^{2+}$ channels, and that $Na^+-Ca^{2+}$ exchange may play an important role in reducing thyroid hormone by increasing intracellular $Ca^{2+}$.

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The effect of octanol on the intracellular Ca2+ increase in submandibular acinar cells evoked by β-adrenergic activation (악하선 선포세포에서 β-아드레날린계 활성화 후 세포내 Ca2+ 농도 증가에 미치는 옥탄올의 효과)

  • Choi, Jeong-Iee
    • Journal of dental hygiene science
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    • v.2 no.1
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    • pp.47-51
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    • 2002
  • The concentration of intracellular $Ca^{2+}$ was measured by spectrofluorometer after rat submandibular acinar cells were loaded with fura-2/AM(fura-2). After isoproterenol and octanol were administered while letting submandibular gland acinar cell placed in a perfusion chamber flow through a standard solution, the changes of $Ca^{2+}$ concentration were measured. When they were administered separately, there showed little changes of intracellular $Ca^{2+}$ concentration. When they were administered at the same time, however the concentration of intracellar $Ca^{2+}$ was shown to increase. When forskolin, an adenylate cyclase activater, was administerd together with octanol the response looked similar to the response of isoproterenol. In case of the extracellular $Ca^{2+}$ was removed by omitting $Ca^{2+}$ in standard solution and treating EGTA, isoproterenol and forskolin does not affect to the concentration of intracellular $Ca^{2+}$. Therefore, it was certified that the increase of intracellular $Ca^{2+}$ was caused from outside the cell. In order to know that the $Ca^{2+}$ influx is related with capacitative entry pathway, godolinium, blocker of that pathway was treated. With the result of that experiment there was no complete control of the increase in the concentration of intracellular $Ca^{2+}$. However, speed and amount of $Ca^{2+}$ increase was comparatively diminished.

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Hydrogen peroxide attenuates refilling of intracellular calcium store in mouse pancreatic acinar cells

  • Yoon, Mi Na;Kim, Dong Kwan;Kim, Se Hoon;Park, Hyung Seo
    • The Korean Journal of Physiology and Pharmacology
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    • v.21 no.2
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    • pp.233-239
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    • 2017
  • Intracellular calcium ($Ca^{2+}$) oscillation is an initial event in digestive enzyme secretion of pancreatic acinar cells. Reactive oxygen species are known to be associated with a variety of oxidative stress-induced cellular disorders including pancreatitis. In this study, we investigated the effect of hydrogen peroxide ($H_2O_2$) on intracellular $Ca^{2+}$ accumulation in mouse pancreatic acinar cells. Perfusion of $H_2O_2$ at $300{\mu}M$ resulted in additional elevation of intracellular $Ca^{2+}$ levels and termination of oscillatory $Ca^{2+}$ signals induced by carbamylcholine (CCh) in the presence of normal extracellular $Ca^{2+}$. Antioxidants, catalase or DTT, completely prevented $H_2O_2$-induced additional $Ca^{2+}$ increase and termination of $Ca^{2+}$ oscillation. In $Ca^{2+}$-free medium, $H_2O_2$ still enhanced CCh-induced intracellular $Ca^{2+}$ levels and thapsigargin (TG) mimicked $H_2O_2$-induced cytosolic $Ca^{2+}$ increase. Furthermore, $H_2O_2$-induced elevation of intracellular $Ca^{2+}$ levels was abolished under sarco/endoplasmic reticulum $Ca^{2+}$ ATPase-inactivated condition by TG pretreatment with CCh. $H_2O_2$ at $300{\mu}M$ failed to affect store-operated $Ca^{2+}$ entry or $Ca^{2+}$ extrusion through plasma membrane. Additionally, ruthenium red, a mitochondrial $Ca^{2+}$ uniporter blocker, failed to attenuate $H_2O_2$-induced intracellular $Ca^{2+}$ elevation. These results provide evidence that excessive generation of $H_2O_2$ in pathological conditions could accumulate intracellular $Ca^{2+}$ by attenuating refilling of internal $Ca^{2+}$ stores rather than by inhibiting $Ca^{2+}$ extrusion to extracellular fluid or enhancing $Ca^{2+}$ mobilization from extracellular medium in mouse pancreatic acinar cells.

The Influence of Heart Rate and Coronary Calcification on the Diagnostic Accuracy of 64-slice Multidetector Cardiac CT in Coronary Artery Disease (심박동수 및 관상동맥 석회화가 64 절편 다중검출기 심장 CT의 관상동맥 질환 진단일치도에 미치는 영향)

  • Kang, Yeong-Han;Park, Jong-Sam
    • The Journal of the Korea Contents Association
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    • v.9 no.12
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    • pp.339-347
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    • 2009
  • Purpose : This study was to investigate the influence of heart rate and coronary calcification on diagnostic accuracy of 64-slice multidetector CT(MDCT) in coronary artery disease. Methods : 178 patients(84 men, 94 women) undergoing cardiac CT were included in this study. 3 coronary arteries(LAD, LCX, RCA) were assessed the presence of significant stenosis($\geq50%$) and the results compared with those of coronary angiography. Results : On a patient-based analysis, the diagnostic accuracy of 64-slice MDCT was 96.6%. The diagnostic accuracy on left anterior descending, left circumflex, right coronary artery were 86.5%, 84.3%, 92.1% respectively. Body mass index and blood pressure were not influenced on diagnostic accuracy of 64-slice MDCT. In less than 60/min of heart rate, accuracy was 90.1% and $\kappa$ value was 0.78. While in more than 70/min of heart rate, accuracy was 75.8% and $\kappa$ value was 0.52. In less than 100 of coronary calcification, accuracy was 91.3% and $\kappa$ value was 0.81. While in more than 400, accuracy was 68.6% and $\kappa$ value was 0.33. Conclusion : 64-slice MDCT shows similar diagnostic accuracy as coronary angiography. But in the context of more than 70/min of heart rate and 400 of coronary calcification, diagnostic accuracy was decreased. So there needs to identify heart rate and coronary calcification in cardiac CT, and if heart rate shows more than 70/min, use beta-blocker to regulate it.

Occurrence of EDC/PPCPs in Influent and Effluent of a Wastewater Treatment Plant (하수처리장 유입.유출수 내 EDC/PPCPs의 발생 특성)

  • Lee, Min-Ju;Ryu, Jae-Na;Oh, Je-Ill;Kim, Hyun-Bae
    • Journal of Korean Society of Environmental Engineers
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    • v.31 no.9
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    • pp.783-792
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    • 2009
  • This study investigated 31 selected EDCs(Endocrine Disrupting Compounds) and PPCPs(Pharmaceutical and Personal Care Products) in the influent and effluent of a wastewater treatment plant(WWTP) nearby Seoul metropolitan area. The chemical compounds of EDC/PPCPs detected from the plant influent sample include stimulant, X-ray contrast media and fire retardant. The total amount of each compound class were 59.67%, 20.20% and 9.00% respectively. However, in the effluent sample, the major micropolutants detected were oral beta-blocker(30.54%), fire retardant(20.49%), X-ray contrast media(18.17%). The EDC/PPCPs occurrence levels of this study were somewhat lower than previous domestic studies'. When compared to those of overseas, the values were even lower. Some pharmaceutical compound levels particularly measured in European studies were even several thousand times high. This study then compared PECs(Predicted Environmental Concentration) and MECs(Measured Environmental Concentration) of 9 selected pharmaceuticals compounds. The calculated PECs were substantially different with the MECs, while the occurrence order between the PECs and MECs in terms of concentrations of the compounds were similar.

Influence of Cilnidipine on Catecholamine Release in the Perfused Rat Adrenal Medulla

  • Woo, Seong-Chang;Baek, Young-Joo;Lim, Dong-Yoon
    • The Korean Journal of Physiology and Pharmacology
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    • v.8 no.5
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    • pp.265-272
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    • 2004
  • The present study was attempted to investigate the effect of cilnidipine (FRC-8635), which is a newly synthesised novel dihydropyridine (DHP) type of organic $Ca^{2+}$ channel blockers, on secretion of catecholamines (CA) evoked by acetylcholine (ACh), high $K^+$, DMPP and McN-A-343 from the isolated perfused rat adrenal gland. Cilnidipine $(1{\sim}10{\mu}M)$ perfused into an adrenal vein for 60 min produced relatively dose- and time-dependent inhibition in CA secretory responses evoked by ACh $(5.32{\times}10^{-3}M),\;DMPP\;(10^{-4}M\;for\;2\;min)$ and McN-A-343 $(10^{-4}M\;for\;2\;min)$. However, lower dose of cilnidipine did not affect CA secretion by high $K^+\;(5.6{\times}10^{-2}\;M)$, higher dose of it reduced greatly CA secretion of high $K^{+}$. Cilnidipine itself did fail to affect basal catecholamine output. In the presence of cilnidipine $(10{\mu}M)$, the CA secretory responses evoked by Bay-K-8644 $(10{\mu}M)$, an activator of L-type $Ca^{2+}$ channels and cyclopiazonic acid $(10{\mu}M)$, an inhibitor of cytoplasmic $Ca^{2+}$-ATPase were also inhibited. Moreover, ${\omega}-conotoxin\;GVIA\;(1{\mu}M)$, a selective blocker of the N-type $Ca^{2+}$ channels, given into the adrenal gland for 60 min, also inhibited time-dependently CA secretory responses evoked by Ach, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid. Taken together, these results demostrate that cilnidipine inhibits CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors from the isolated perfused rat adrenal gland without affecting the basal release. However, at lower dose, cilnidipine did not affect CA release by membrane depolarization while at larger dose inhibited that. It seems likely that this inhibitory effect of cilnidipine is exerted by blocking both L- and N-type voltage-dependent $Ca^{2+}$ channels (VDCCs) on the rat adrenomedullary chromaffin cells, which is relevant to inhibition of both the $Ca^{2+}$ influx into the adrenal chromaffin cells and intracellular $Ca^{2+}$ release from the cytoplasmic store. It is thought that N-type VDCCs may play an important role in regulation of CA release from the rat adrenal medulla.

Inhibitory Effects of Potassium Channel Openers on the Oxytocin-induced Contraction of the Rat Uterus in vitro (쥐자궁근의 운동성에 대한 $K^+$채널 개방제의 이완 작용)

  • Kim, Hee-Jeong;Lee, Mun-Han;Ryu, Pan-Dong
    • The Korean Journal of Pharmacology
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    • v.30 no.2
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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.

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