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Bupivacaine과 ropivacaine이 Xenopus oocyte에 발현된 HERG 전류에 미치는 영향
김국성,이규승,김효신,손숙진,이상도,김광진,전병화,김윤희,박진봉 충남대학교 의과대학 의학연구소 2003 충남의대잡지 Vol.30 No.1
Bupivacaine is an amide-type local anesthetic widely used for regional anesthesia. Ropivacaine is developed as a less cardiotoxic alternatives to bupivacaine. In the present study, we have analyzed the effects of bupivacaine and ropivacaine on HERG currents expressed in Xenopus oocytes. Bupivacaine and ropivacaine(3∼1,000μM) blocked HERG currents in a concentration dependent manner. EC_(50) was 26.1±3.1μM(n_(R) 0.65±0.04) and 43.5±7.9μM(n_(H) 0.99±0.13) in bupivacaine and ropivacaine, respectively. Bupivacaine and ropivacaine did not affect the activation and deactivation kinetics of HERG channels. However, the drugs decreased the slope conductance measured from fully activated current-voltage relationship curves. These results suggest that bupivacaine and ropivacaine have a similarinhibitory effect on HERG channels, which could be a possible cellular mechanism of LQT or ventricular arrythmia by the drugs.
Analysis of Blood Flow-dependent Blood Nitric Oxide Level and Half-life of Nitric Oxide in Vivo
Kim Cuk-Seong,Kim Hyo-Shin,Lee Young-Jun,Park Jin Bory,Ryoo Sung-Woo,Chang Seok-Jang,Jeon Byeong-Hwa Biomedical Engineering Society for Circulation 2003 International Journal of Vascular Biomedical Engin Vol.1 No.2
Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. To estimate the blood flow-dependent nitric oxide level and half-life (T1/2) of nitric oxide in vivo state, we investigated the change of aortic NO currents during the change of aortic blood flow rate using NO-selective electrode system and electromagnetic flowmeter in the aorta of anesthetized rats. Resting mean aortic blood flow rate was $49.6{\pm}5.6ml/min$ in the anesthetized rats. NO currents in the aorta were increased by the elevation of blood pressure and/or blood flow rate. When the aortic blood flow was occluded by the clamping, aortic NO currents were decreased. The difference of NO concentration between resting state and occluded state was $1.34{\pm}0.26{\mu}M$ (n=7). This NO concentration was estimated as blood flow-dependent nitric oxide concentration in the rats. Also, while the aortic blood flow was occluded, NO currents were decreased with exponential pattern with $12.84{\pm}2.15$ seconds of time constant and $7.70{\pm}1.07$ seconds of half-life. To summarize, this study suggested that blood flow-dependent NO concentration and half-life of nitric oxide were about $1.3{\mu}M$ and 7.7 seconds, respectively, in the aorta of anesthetized rats. The nitric oxide-selective electrode system is useful for the direct and continuous measurement of NO in vivo state.
P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc
Kim, Cuk-Seong,Jung, Saet-Byel,Naqvi, Asma,Hoffman, Timothy A.,DeRicco, Jeremy,Yamamori, Tohru,Cole, Marsha P.,Jeon, Byeong-Hwa,Irani, Kaikobad Ovid Technologies Wolters Kluwer -American Heart A 2008 Circulation research Vol.103 No.12
<P>The transcription factor, p53, and the adaptor protein, p66shc, both play essential roles in promoting oxidative stress in the vascular system. However, the relationship between the two in the context of endothelium-dependent vascular tone is unknown. Here, we report a novel, evolutionarily conserved, p53-mediated transcriptional mechanism that regulates p66shc expression and identify p53 as an important determinant of endothelium-dependent vasomotor function. We provide evidence of a p53 response element in the promoter of p66shc and show that angiotensin II-induced upregulation of p66shc in endothelial cells is dependent on p53. In addition, we demonstrate that downregulation of p66shc expression, as well as inhibition of p53 function in mice, mitigates angiotensin II-induced impairment of endothelium-dependent vasorelaxation, decrease in bioavailable nitric oxide, and hypertension. These findings reveal a novel p53-dependent transcriptional mechanism for the regulation of p66shc expression that is operative in the vascular endothelium and suggest that this mechanism is important in impairing endothelium-dependent vascular relaxation.</P>
Yu, Jae-Hyeon,Kim, Cuk-Seong,Yoo, Dae-Goon,Song, Yun-Jeong,Joo, Hee-Kyoung,Kang, Gun,Jon, Ji-Yoon,Park, Jin-Bong,Jeon, Byeong-Hwa The Korean Society of Pharmacology 2006 The Korean Journal of Physiology & Pharmacology Vol.10 No.4
Atherosclerosis is considered as a chronic inflammatory process. However, the nature of the oxidant signaling that regulates monocyte adhesion and its underlying mechanism is poorly understood. We investigated the role of reactive oxygen species on the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion in the cultured endothelial cells. $TNF-{\alpha}$ at a range of $1{\sim}30\;ng/ml$ induced VCAM-1 expression dose-dependently. BCECF-AM-labeled U937 cells firmly adhered on the surface of endothelial cells when the endothelial cells were incubated with $TNF-{\alpha}$ (15 ng/ml). Ten $\;{\mu}mol/L$ of SB203580, an inhibitor of p38 MAPK, significantly reduced $TNF-{\alpha}-induced$ VCAM-1 expression, compared to the JNK inhibitor ($40\;{\mu}mol/L$ of SP60015) or ERK inhibitor ($40\;{\mu}mol/L$ of U0126). Also, SB203580 significantly inhibited $TNF-{\alpha}-induced$ monocyte adhesion in HUVEC. Superoxide production was minimal in the basal condition, however, treatment of $TNF-{\alpha}$ induced superoxide production in the dihydroethidineloaded endothelial cells. Diphenyleneiodonium (DPI, $10\;{\mu}mol/L$), an inhibitor of NADPH oxidase, and rotenone $(1\;{\mu}mol/L)$, an inhibitor of mitochondrial complex I inhibited $TNF-{\alpha}-induced$ superoxide production, VCAM-1 expression and monocyte adhesion in the endothelial cells. Taken together, our data suggest that NADPH oxidase and mitochondrial ROS were involved in $TNF-{\alpha}-induced$ VCAM-1 and monocyte adhesion in the endothelial cells.
Redox Factor-1 Inhibits Cyclooxygenase-2 Expression via Inhibiting of p38 MAPK in the A549 Cells
Yoo, Dae-Goon,Kim, Cuk-Seong,Lee, Sang-Ki,Kim, Hyo-Shin,Cho, Eun-Jung,Park, Myoung-Soo,Lee, Sang-Do,Park, Jin-Bong,Jeon, Byeong-Hwa The Korean Society of Pharmacology 2010 The Korean Journal of Physiology & Pharmacology Vol.14 No.3
In this study, we evaluated the role of apurinic/apyrimidinic endonuclease1/redox factor-1 (Ref-1) on the tumor necrosis factor-$\alpha$ (TNF-$\alpha$) induced cyclooxygenase-2 (COX-2) expression using A549 lung adenocarcinoma cells. TNF-$\alpha$ induced the expression of COX-2 in A549 cells, but did not induce BEAS-2B expression. The expression of COX-2 in A549 cells was TNF-$\alpha$ dose-dependent (5~100 ng/ml). TNF-$\alpha$-stimulated A549 cells evidenced increased Ref-1 expression in a dose-dependent manner. The adenoviral transfection of cells with AdRef-1 inhibited TNF-$\alpha$-induced COX-2 expression relative to that seen in the control cells ($Ad{\beta}gal$). Pretreatment with $10\;{\mu}M$ of SB203580 suppressed TNF-$\alpha$-induced COX-2 expression, thereby suggesting that p38 MAPK might be involved in COX-2 expression in A549 cells. The phosphorylation of p38 MAPK was increased significantly after 5 minutes of treatment with TNF-$\alpha$, reaching a maximum level at 10 min which persisted for up to 60 min. However, p38MAPK phosphorylation was markedly suppressed in the Ref-1-overexpressed A549 cells. Taken together, our results appear to indicate that Ref-1 negatively regulates COX-2 expression in response to cytokine stimulation via the inhibition of p38 MAPK phosphorylation. In the lung cancer cell lines, Ref-1 may be involved as an important negative regulator of inflammatory gene expression.
Role of Mitochondrial Oxidative Stress in Sepsis
Harsha Nagar,Shuyu Piao,Cuk-Seong Kim 대한중환자의학회 2018 Acute and Critical Care Vol.33 No.2
Mitochondria are considered the power house of the cell and are an essential part of the cellular infrastructure, serving as the primary site for adenosine triphosphate production via oxidative phosphorylation. These organelles also release reactive oxygen species (ROS), which are normal byproducts of metabolism at physiological levels; however, overproduction of ROS under pathophysiological conditions is considered part of a disease process, as in sepsis. The inflammatory response inherent in sepsis initiates changes in normal mitochondrial functions that may result in organ damage. There is a complex system of interacting antioxidant defenses that normally function to combat oxidative stress and prevent damage to the mitochondria. It is widely accepted that oxidative stress-mediated injury plays an important role in the development of organ failure; however, conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction is lacking. Nevertheless, it has been suggested that antioxidant therapy delivered specifically to the mitochondria may be useful.
Kyoung Sook Park,Cuk Seong Kim,Sang Won Kang,Jin Bong Park,Kwang-Jin Kim,Seok Jong Chang,Byeong Hwa Jeon 대한생리학회-대한약리학회 2000 The Korean Journal of Physiology & Pharmacology Vol.4 No.3
<P> To evaluate the involvement of nitric oxide production on the endothelium-dependent relaxation in diabetes, we have measured vascular and endothelial function and nitric oxide concentration, and the expression level of endothelial nitric oxide synthase in the streptozotocin-induced diabetic rats. Diabetic rats were induced by the injection of streptozotocin (50 mg/kg i.v.) in the Sprague-Dawley rats. Vasoconstrictor responses to norepinephrine (NE) showed that maximal contraction to norepinephrine (10<SUP>5 </SUP>M) was significantly enhanced in the aorta of diabetic rats. Endothelium-dependent relaxation induced by acetylcholine was markedly impaired in the aorta of diabetic rats, these responses were little improved by the pretreatment with indomethacin. However, endothelium-independent relaxation induced by nitroprusside was not altered in the diabetic rats. Plasma nitrite and nitrate (NO<SUB>2</SUB>/<SUB>3</SUB>) levels in diabetic rats were significantly lower than in non-diabetic rats. Western blot analysis using a monoclonal antibody against endothelial cell nitric oxide synthase (eNOS) revealed that the protein level was lower in the aorta of diabetic rats than in non-diabetic rats. These data indicate that nitric oxide formation and eNOS expression is reduced in diabetes, and this would, in part, account for the impaired endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats.