혈관내피세포 유무에 따른 돼지 관동맥에서의 Endothelin에 대한 반응

홍명기,김재중,이철환,박성욱,박승정 대한순환기학회 1998 Korean Circulation Journal Vol.28 No.12

양 태아의 산소 환기 중 Endothelin B 수용체 차단제가 폐동맥 확장에 미치는 영향

김나연,이동석,Ivy, D. Dunbar 東國大學校醫學硏究所 2004 東國醫學 Vol.11 No.2

Endothelin-1 (ET-1)은 정상 양 태아와 주산기 폐동맥 고혈압 모델에서 폐혈관 긴장도를 유지하는데 관여하고 있다. ET-1의 효과는 적어도 두개의 수용체 아형인 ET_(A)와 ET_(B)의 균형에 의한다. ET_(A) 수용체는 주로 평활근 세포에 존재하며 혈관의 수축과 평활근 세포의 증식에 기여한다. 혈관 내피 세포에 존재하는 ET_(B) 수용체의 자극은 산화질소의 분비를 통해 혈관을 확장시키고 혈중의 ET-1을 제거하는 역할을 한다. 그러나 출생 시 ET_(B) 수용체의 자극이 폐혈관 긴장도의 감소를 유도하는지에 대하여서는 잘 알려져 있지 않다. 출생과 관련된 자극에서 단기간 동안의 ET_(B) 수용체 차단제의 사용이 폐혈관 저항에 미치는 영향을 알아보기 위하여 출산이 임박한 만삭 양 태아에게 저농도(FiO₂<10%)와 고농도(FiO₂100%)로 기계적 환기를 시키는 동안, 선택적인 ET_(B) 수용체 차단제인 BQ-788가 혈류역학에 미치는 영향을 알아보기로 하였다. 정상적인 양 태아에서 BQ-788의 투여는 기저 좌폐동맥 혈류량과 폐혈관저항에는 영향을 미치지는 않았다. 대조군과 비교하여 저농도와 고농도의 산소 호흡중 BQ-788의 투여는 좌 폐동맥 혈류량의 증가를 현저하게 약화시켰다(P<0.01). 폐혈관 저항은 저농도와 고농도의 기계적산소 환기시 양군에서 모두 점차적으로 감소하였으나, BQ-788의 투여는 실험 기간 동안 내내 폐혈관저항을 높게 유지시켰다(P<0.01). 본 실험의 결과로 미루어 볼 때 선택적인 ET_(B) 수용체의 차단은 분만시 폐혈관 확장을 약화시키며, 선택적인 ET_(B) 수용체의 자극은 양 태아의 분만 시 폐혈관 확장에 기여하리라 생각된다. Endothelin-1 (ET-1) contributes to regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In utero, the effects of ET-1 depend on the balance of at least two receptor subtypes: ET_(A) and ET_(B). ET_(A) receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ET_(B) receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ET_(B) receptors contributes to the fall in pulmonary vascular tone at birth is unknown. To determine the role of acute ET_(B) receptor blockade in pulmonary vasodilation to birth related stimuli, we studied the hemodynamic effects of selective ET_(B) receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO₂(100%) in near term fetal sheep. Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. Comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO₂ ventilation (P<0.01). PVR progressively decreased during mechanical ventilation with low and high FiO₂in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (P<0.01). We conclude that selective ET_(B) receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ET_(B) receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

Influence of Nitric Oxide Synthesis Inhibition on Endothelin-1 and Its Receptor Expression in Rat Kidney

Lee, Jong Un,Kim, Soo Wan,Kim, Sun Mi,Oh, Yoon Wha,Li, Ying Shun,Kim, Nam Ho,Choi, Ki Chul 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.2

배 경 : 본 연구는 산화질소 합성억제 흰쥐 모델에서신장 endothelin(ET)계의 변화를 알아보고자 하였다. 방 법 : 수컷 Sprague-Dawley 흰쥐를 이용하여 실험하였다. 실험군은 내인성 산화질소 합성을 억제하고자 NG-nitro-L-arginine methyl ester(L-NAME, 100mg/L)을 4주간 음용수로 공급하였다. 대조군은 약물이 포함되지 않은 수돗물을 공급하였다. 신장에서 ET-1,ETA 및 ETB 수용체 mRNA 발현 변화는 역전사-중합효소 연쇄반응을 이용하였다. 혈장 및 신장에서 산화질소 대사물 함량을 측정하였다. 결 과 : 산화질소 합성억제제인 L-NAME 투여군에서 유의한 혈압의 상승을 보였으며, 혈장 및 신장에서 산화질소 대사물은 감소하였다. ET-1 mRNA 발현은 신피질에서 증가하였으나, 신수질에서는 유의한 변화를 보이지 않았다. 신장에서 ETA 및 ETB 수용체 발현 또한 유의한 차이를 보이지 않았다. L-NAME(200 μg/kg per min, iv)를 60분간 주사한 흰쥐에서 유의한 혈압의 증가와 함께 혈장 ET-1 농도가 증가하였다. 또한, 이때 신피질 ET-1 mRNA 발현은 증가하였으나, ETA 및 ETB 수용체 발현 또한 유의한 차이를 보이지 않았다. 결 론 : 이상의 결과는 산화질소 합성 억제에 의한 고혈압의 발생에 ET계의 활성증가가 일부 관여함을 시사한다. Background : The present study was aimed to evaluate the influence of nitric oxide( NO) synthesis inhibition on endothelin(ET) expression in rat kidney. Methods : Male Sprague-Dawley rats were treated with NG-nitro-L-arginine methyl ester(L-NAME, 100 mg/L drinking water) for 4 weeks to inhibit the endogenous synthesis of NO. The tissue expression of ET-1, ETA receptor, and ETB receptor mRNA in the kidney was determined by reverse transcription-polymerase chain reaction. Results : Tissue levels of NO metabolites were significantly decreased in the plasma and the kidney, along with the increased blood pressure. The expression of ET-1 mRNA was increased in the cortex, but not in the medulla. The expression of ETA and ETB receptor mRNA was not significantly altered either in the cortex or in the medulla. The plasma level of ET-1 peptide was significantly increased, along with the increased blood pressure, when L-NAME(200 μg/kg per min, iv) was administered in an acute preparation of animals. Accordingly, the expression of ET-1 mRNA was increased in the cortex, whereas that of ETA and ETB receptor mRNA was not altered. Conclusion : These results suggest that enhanced activity of ET system induced by NO synthesis inhibition may be associated with hypertension although direct association between two factors is not confirmed. (Korean J Nephrol 2002;21(2):205-212)

SM709, Ingredient of Antimelanogenic Bamboo Extract, Blocks Endothelin-1-induced [Ca<SUP>2⁢</SUP>]<SUB>i</SUB> Increase in Human Melanocytes

Shin-Hee Kim,Ki-Mu Lee,Hyo Shin Kim,Gyu Seung Lee,Byeong Hwa Jeon,Kwang Jin Kim,Jin Bong Park 대한생리학회-대한약리학회 2003 The Korean Journal of Physiology & Pharmacology Vol.13 No.4

Endothelins secreted from keratinocytes are intrinsic mitogens and melanogens of human melanocytes in UVB-induced hyperpigmentation. To elucidate the cellular mechanism of antimelanogenic activity of bamboo extract, the effects of three ingredients of bamboo extract on endothelin 1 (ET-1)-induced Ca<SUP>2⁢</SUP> mobilization were investigated in cultured human melanocytes. ET-1 receptors in human melanocytes were characterized by using specific antagonist, and ET-1 was found to increase intracellular Ca<SUP>2⁢</SUP> concentration ([Ca<SUP>2⁢</SUP>]<SUB>i</SUB>) by activating ET-B receptor. SM709 (1,2-O-diferulyl-glycerol), an ingredient of bamboo extract, inhibited ET-1-induced [Ca<SUP>2⁢</SUP>]<SUB>i</SUB> increase in a concentration- and time-dependent manner, although another ingredients SM707 and SM708 had no effect on ET-1-induced [Ca<SUP>2⁢</SUP>]<SUB>i</SUB> increase in human melanocytes. SM709 (100<FONT FACE= 바탕 >μM), however, did not affect [Ca<SUP>2⁢</SUP>]<SUB>i</SUB> increase induced by thapsigargin and caffeine, suggesting that SM709 has no effect on the Ca<SUP>2⁢</SUP> store in melanocytes. Furthermore, SM709 did not affect [Ca<SUP>2⁢</SUP>]<SUB>i</SUB> increase induced by LPA or ATP, known as G protein-mediated PLC activators like ET-1. Taken together, it is suggested that SM709 antagonizes ET-1-induced transmembrane signaling through ET-B receptor, which maybe a possible underlying mechanism of antimelanogenic activity of bamboo extract in human melanocytes.

SM709, Ingredient of Antimelanogenic Bamboo Extract, Blocks Endothelin-1-induced $[Ca^{2+}]_i$ Increase in Human Melanocytes

Kim, Shin-Hee,Lee, Ki-Mu,Kim, Hyo-Shin,Lee, Gyu-Seung,Jeon, Byeong-Hwa,Kim, Kwang-Jin,Park, Jin-Bong The Korean Society of Pharmacology 2003 The Korean Journal of Physiology & Pharmacology Vol.7 No.6

Endothelins secreted from keratinocytes are intrinsic mitogens and melanogens of human melanocytes in UVB-induced hyperpigmentation. To elucidate the cellular mechanism of antimelanogenic activity of bamboo extract, the effects of three ingredients of bamboo extract on endothelin 1 (ET-1)-induced $Ca^{2+}$ mobilization were investigated in cultured human melanocytes. ET-1 receptors in human melanocytes were characterized by using specific antagonist, and ET-1 was found to increase intracellular $Ca^{2+}$ concentration ($[Ca^{2+}]_i$) by activating ET-B receptor. SM709 (1,2-O-diferulyl-glycerol), an ingredient of bamboo extract, inhibited ET-1-induced $[Ca^{2+}]_i$ increase in a concentration- and time-dependent manner, although another ingredients SM707 and SM708 had no effect on ET-1-induced $[Ca^{2+}]_i$ increase in human melanocytes. SM709 ($100{\mu}M$), however, did not affect $[Ca^{2+}]_i$ increase induced by thapsigargin and caffeine, suggesting that SM709 has no effect on the $Ca^{2+}$ store in melanocytes. Furthermore, SM709 did not affect $[Ca^{2+}]_i$ increase induced by LPA or ATP, known as G protein-mediated PLC activators like ET-1. Taken together, it is suggested that SM709 antagonizes ET-1-induced transmembrane signaling through ET-B receptor, which maybe a possible underlying mechanism of antimelanogenic activity of bamboo extract in human melanocytes.

Endothelin Receptor Overexpression Alters Diastolic Function in Cultured Rat Ventricular Myocytes

( Misuk Kang1 ),( Jeffery W. Walker ),( Ka Young Chung ) 한국응용약물학회 2012 Biomolecules & Therapeutics(구 응용약물학회지) Vol.20 No.4

The endothelin (ET) signaling pathway controls many physiological processes in myocardium and often becomes upregulated in heart diseases. The aim of the present study was to investigate the effects of ET receptor upregulation on the contractile function of adult ventricular myocytes. Primary cultured adult rat ventricular myocytes were used as a model system of ET receptor overexpression in the heart. Endothelin receptor type A (ETA) or type B (ETB) was overexpressed by Adenoviral infection, and the twitch responses of infected ventricular myocytes were measured after ET-1 stimulation. Overexpression of ETA exaggerated positive inotropic effect (PIE) and diastolic shortening of ET-1, and induced a new twitch response including twitch broadening. On the contrary, overexpression of ETB increased PIE of ET-1, but did not affect other two twitch responses. Control myocytes expressing endogenous receptors showed a parallel increase in twitch amplitude and systolic Ca2+ in response to ET-1. However, intracellular Ca2+ did not change in proportion to the changes in contractility in myocytes overexpressing ETA. Overexpression of ETA enhanced both systolic and diastolic contractility without parallel changes in Ca2+. Differential regulation of this nature indicates that upregulation of ETA may contribute to diastolic myocardial dysfunction by selectively targeting myofi lament proteins that regulate resting cell length, twitch duration and responsiveness to prevailing Ca2+.

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

Li-qun Peng,Ping Li,Qiu-li Zhang,Lan Hong,Li-ping Liu,Xun Cui,Bai-ri Cui 대한생리학회-대한약리학회 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.1

Adenosine 3 ,5 -cyclic monophosphate (cAMP) participates in the regulation of numerous cellular functions, including the Na⁺-K⁺-ATPase (sodium pump). Ouabain, used in the treatment of several heart diseases, is known to increase cAMP levels but its effects on the atrium are not understood. The aim of the present study was to examine the effect of ouabain on the regulation of atrial cAMP production and its roles in atrial endothelin-1 (ET-1) secretion in isolated perfused beating rabbit atria. Our results showed that ouabain (3.0 μmol/L) significantly increased atrial dynamics and cAMP levels during recovery period. The ouabainincreased atrial dynamics was blocked by KB-R7943 (3.0 μmol/L), an inhibitor for reverse mode of Na⁺-Ca²⁺ exchangers (NCX), but did not by L-type Ca²⁺ channel blocker nifedipine (1.0 μmol/L) or protein kinase A (PKA) selective inhibitor H-89 (3.0 μmol/L). Ouabain also enhanced atrial intracellular cAMP production in response to forskolin and theophyline (100.0 μmol/L), an inhibitor of phosphodiesterase, potentiated the ouabain-induced increase in cAMP. Ouabain and 8-Bromo-cAMP (0.5 μmol/L) markedly increased atrial ET-1 secretion, which was blocked by H-89 and by PD98059 (30 μmol/L), an inhibitor of extracellular-signal-regulated kinase (ERK) without changing ouabain-induced atrial dynamics. Our results demonstrated that ouabain increases atrial cAMP levels and promotes atrial ET-1 secretion via the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. These findings may explain the development of cardiac hypertrophy in response to digitalis-like compounds.

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

Peng, Li-qun,Li, Ping,Zhang, Qiu-li,Hong, Lan,Liu, Li-ping,Cui, Xun,Cui, Bai-ri The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.1

Adenosine 3',5'-cyclic monophosphate (cAMP) participates in the regulation of numerous cellular functions, including the $Na^+-K^+$-ATPase (sodium pump). Ouabain, used in the treatment of several heart diseases, is known to increase cAMP levels but its effects on the atrium are not understood. The aim of the present study was to examine the effect of ouabain on the regulation of atrial cAMP production and its roles in atrial endothelin-1 (ET-1) secretion in isolated perfused beating rabbit atria. Our results showed that ouabain ($3.0{\mu}mol/L$) significantly increased atrial dynamics and cAMP levels during recovery period. The ouabain-increased atrial dynamics was blocked by KB-R7943 ($3.0{\mu}mol/L$), an inhibitor for reverse mode of $Na^+-Ca^{2+}$ exchangers (NCX), but did not by L-type $Ca^{2+}$ channel blocker nifedipine ($1.0{\mu}mol/L$) or protein kinase A (PKA) selective inhibitor H-89 ($3.0{\mu}mol/L$). Ouabain also enhanced atrial intracellular cAMP production in response to forskolin and theophyline ($100.0{\mu}mol/L$), an inhibitor of phosphodiesterase, potentiated the ouabain-induced increase in cAMP. Ouabain and 8-Bromo-cAMP ($0.5{\mu}mol/L$) markedly increased atrial ET-1 secretion, which was blocked by H-89 and by PD98059 ($30{\mu}mol/L$), an inhibitor of extracellular-signal-regulated kinase (ERK) without changing ouabain-induced atrial dynamics. Our results demonstrated that ouabain increases atrial cAMP levels and promotes atrial ET-1 secretion via the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. These findings may explain the development of cardiac hypertrophy in response to digitalis-like compounds.

패혈증에서 혈중 Endothelin-1 및 Interleukin-8의 임상적 의의

박광주 ( Park Gwang Ju ),최영인 ( Choe Yeong In ),오윤정 ( O Yun Jeong ),최영화 ( Choe Yeong Hwa ),황성철 ( Hwang Seong Cheol ),이이형 ( Lee I Hyeong ) 대한결핵 및 호흡기학회 2001 Tuberculosis and Respiratory Diseases Vol.50 No.3

대황이 당뇨병 백서의 신장 및 혈관에 미치는 효과

남상규,김형구,김혜윤,이정섭,정현애,고영철,신선호,장통영,Nam, Sang-Kyu,Kim, Hyeong-Gu,Kim, Hye-Yoon,Lee, Jung-Sup,Jung, Hyun-Ae,Ko, Young-Chul,Shin, Sun-Ho,Jang, Tong-Young 대한한방내과학회 2006 大韓韓方內科學會誌 Vol.27 No.4

Objectives : This study aimed at investigating whether aqueous extract of Radix et Rhizoma Rhei (AR) ameliorates renal and vascular complications in diabetic rats. Methods : The experiment operated for 6 weeks. The rats were divided into 4 groups: normal group, diabetic group (control group), diabetic group treated with AR (100 mg/kg/day) for the last 3 weeks, and diabetic group treated with AR (200 mg/kg/day) for the last 3 weeks. Results : There were no significant changes in the renal functional parameters by treatment of AR in the diabetic rats. Aorta segment in the diabetic rats revealed a thickening of intima and media, which was ameliorated by treatment with AR. The aortic expression level of endothelin-1 was also significantly attenuated by treatment with AR. Conclusions : Treatment with AR could not ameliorate renal functional defects, but improved vascular complication in diabetic rats.