• Tuberculosis and Respiratory Diseases
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• 제45권2호
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• pp.360-368
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• 1998

배 경: Endothelin(ET)은 혈관내피세포, 기도상피세포등에서 분비되고, 혈판 및 기도를 수축시키는 작용외에도 섬유아세포를 증식시키는 기능을 가지고 있다. 한편 미만성간질성폐질환은 염증세포의 침윤과 섬유화를 특정으로 하는 질환이며 이러한 질환을 가전 환자에서 혈장 및 기관지폐포세척액내의 ET 농도가 증가한다는 보고가 있었다. 또 폐혈관손상이 있는 경우 폐순환을 통한 ET의 제거율이 감소하기 때문에 ET의 동정맥비가 증가한다는 보고가 있었다. 이에 저자등은 미만성간질성폐질환 환자에서 혈장 ET 농도가 증가하는지, 또 증가한다면 어떠한 기전에 의하여 증가하는 지를 알고자 본 연구를 시행하였다. 방 법: 도플러심초음파상 폐동맥고혈압이 없는 미만성간질성폐질환 환자 17명과 정상대조군 11명을 대상으로 혈장, 요 중 및 기관지폐포세척액내의 ET 농도를 측정하였고, 또 이들의 ET 동-정맥 비와 요배설율을 구하였다. 성 적: 동맥혈, 정맥혈, 요 중 및 기관지폐포세척액내의 ET 농도는 미만성간질성폐질환군에서 대조군보다 유의하게 증가하였고 (P<0.05), ET의 동-정맥 비와 요배설율에는 유의한 차이가 없었다 (P>0.05). 결 론: 이상의 결과, 미만성간질성폐질환 환자의 혈장, 요 중 및 기관지폐포세척액내의 Endothelin농도는 대조군에 비해 유의하게 증가되어 있었고, 혈장 ET농도 증가의 기전은 폐실질에서의 분비증가로 사료되었다.

• The Journal of Korean Physical Therapy
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• 제20권3호
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• pp.53-59
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• 2008

Purpose: The non-receptor-type protein tyrosine kinase Syk (636 amino acids, 72 kDa) is ubiquitously expressed in hematopoietic stem cells and has been widely studied as a regulator and effector of B cell receptor signaling that occurs in processes such as differentiation, proliferation and apoptosis. However, the mechanism relating Syk and p38 mitogen-activated protein kinases (p38MAPK) by endothelin-1 (ET-1, 21 amino acids) stimulation in muscle cells, especially in the volume-dependent hypertensive state, remains unclear. Methods: In this study, we investigated the relationship between Syk and p38MAPK for isometric contraction and enzymatic activity by ET-1 from rat aortic smooth muscle cells and aldosterone-analogue deoxycorticosterone acetate (DOCA) hypertensive state rats (ADHR). Results: The systolic blood pressure was significantly increased in ADHR than in a control group of animals. ET-1 induced isometric contraction and phosphorylation of p38MAPK, which was increased in muscle strips from ADHR. Increased vasoconstriction and phosphorylation of p38MAPK induced by treatment with 30 nM ET-1 were inhibited by the use of 10${\mu}M$ SB203580, an inhibitor of p38MAPK from ADHR. Furthermore, ET-1 induced isometric contraction and phosphorylation of Syk and p38MAPK, which were increased in the aortic smooth muscle cells. Increased tension and phosphorylation of Syk and p38MAPK induced by ET-1 were inhibited by SB203580 from rat aortic smooth muscle cells. Conclusion: These results, suggest that the Syk activity affects ET-1-induced contraction through p38MAPK in smooth muscle cells and that the same pathway directly or indirectly is associated with volume dependent hypertension. The findings suggest the need to develop cardiovascular disease-specialized physical therapy.

• Clinical and Experimental Reproductive Medicine
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• 제31권4호
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• pp.235-244
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• 2004

Objective: The effects on spermatogenesis by expression of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were investigated. Materials and Methods: Testicular specimens were obtained from 40 infertile males due to primary testicular failure and from 10 fertile males with other urologic problems. The specimens of infertile males were devided into 4 groups according to histologic findings; Sertoli cell only syndrome (A), maturation arrest (B), hypospermatogenesis (C) and sloughing and disorganization (D). VEGF and ET-1 expression were detected with immunohistochemical stain. Results: VEGF expression on Leydig cell was detected in all cases. But, VEGF expression rates on germ cell were significantly higher in infertile group B, C, D compared to that of the control group (p<0.05). ET-1 expression rates on Leydig cell was significantly lower in all infertile group compared to that of the control group (p<0.05). But, ET-1 expression rates on Sertoli cell was significantly higher in all infertile group compared to that of the control group (p>0.05). In germ cell of infertile group, LH, FSH and prolactin were significantly decreased, and estradiol is increased in positive stain group on ET-1 immunohistochemical stain (p<0.05). VEGF and ET-1 expression were not correlated mean seminiferous tubule diameter (p>0.05). Conclusions: Abnormal spermatogenesis would be reflected in VEGF expression in germ cell.

• Asian-Australasian Journal of Animal Sciences
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• 제20권10호
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• pp.1503-1509
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• 2007

Endothelin-1 (ET-1) is an important factor in regulation of cardiovascular tone in humans and mammals, but the biological function of ET-1 in the avian vascular system has not been determined. The purpose of this study was to characterize the role of endogenous ET-1 in the vascular system of poultry by investigating the effect of endothelin A receptor ($ET_AR$) antagonist BQ123 on the femoral artery pressure (FAP) and the pulmonary artery pressure (PAP) in broiler chickens. First, we found that plasma and lung homogenate ET-1 levels were both increased with age over the seven weeks life cyccle of broiler chickens. Second, 60 min after intravenous injection, BQ123 ($0.4{\mu}g\;kg^{-1}$ and $2.0{\mu}g\;kg^{-1}$, respectively) induced a significant reduction in FAP and PAP (p<0.05). Third, chronic infusion of BQ123 ($2.0{\mu}g\;kg^{-1}$ each time, two times a day) into abdominal cavities led to significant decrease in systolic pressure of the femoral (p<0.05) and pulmonary arteries (p<0.01) in broiler chickens at 7 and 14 days after treatment. Taken together, the $ET_AR$ antagonist BQ123 lead to a significant reduction of FAP and PAP, which suggests that endogenous ET-1 may be involved in the maintenance and regulation of systemic and pulmonary pressure in broiler chickens.

• Journal of Oral Medicine and Pain
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• 제26권4호
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• pp.319-329
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• 2001

Endothelin-1 (ET-1) is a recently discovered potent vasoconstrictive peptide. It was first identified in vascular endothelial cells. ET-1 is a 21-amino acid peptide and elicits systemic effects such as stimulation of the production of atrial natriuretic peptide and release of aldosterone and corticosterone. In this study, to examine the role of ET-1 in the bone metabolism, effect of ET-1 on the proliferation and activity of osteoblastic cells was studied using HOS cells as osteoblast model. ET-1 dose-dependently increased the cell proliferation as determined by cell counting and MTT reduction assay after 48hr treatment. Alkaline phosphatase activity was inhibited by ET-1 and showed significant inhibition by 50 and 100 nM ET-1. ET-1 increased NBT reduction by HOS cells dose-dependently showing that ET-1 may increase the superoxide production by osteoblasts. Nitrite concentration in the media of HOS cell culture without cytokine stimulation was negligible and unaffected by ET-1 after 48hr treatment. Finally, after collection and concentration of conditioned media, gelatinase activity produced by HOS cells was determined by zymography. HOS cells can produce and secrete the gelatinase (gelatinase A type as determined by molecular weight of about 65,000) into culture media, however, ET-1 had no effect on the gelatinase activity. These findings suggest that ET-1 may have diverse effects on the proliferation and differentiation of osteoblasts, therefore, it may play an important role in bone metabolism.

• Biomolecules & Therapeutics
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• 제20권4호
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• pp.386-392
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• 2012

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 ($ET_A$) or type B ($ET_B$) was overexpressed by Adenoviral infection, and the twitch responses of infected ventricular myocytes were measured after ET-1 stimulation. Overexpression of $ET_A$ 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 $ET_B$ 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 $Ca^{2+}$ in response to ET-1. However, intracellular $Ca^{2+}$ did not change in proportion to the changes in contractility in myocytes overexpressing $ET_A$. Overexpression of $ET_A$ enhanced both systolic and diastolic contractility without parallel changes in $Ca^{2+}$. Differential regulation of this nature indicates that upregulation of $ET_A$ may contribute to diastolic myocardial dysfunction by selectively targeting myofilament proteins that regulate resting cell length, twitch duration and responsiveness to prevailing $Ca^{2+}$.

• Clinical and Experimental Pediatrics
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• 제52권6호
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• pp.689-695
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• 2009

목 적 : 폐동맥 고혈압은 지속적인 폐혈관 저항의 증가로 우심실 부전에 이르게 되는 질병 상태를 일컫는다. 폐동맥 고혈압의 기전으로 폐혈관의 내피세포로부터 endothelin 분비가 증가되어 세포 증식 촉진, 세포 자멸 억제, 혈관 수축, 염증 반응을 통해 폐혈관의 재형성에 관여함이 제시되었다. Bosentan은 endothelin 수용체에 결합하여 효과를 차단시키는 약물로 개발되었다. 이에 monocrotaline으로 폐고혈압을 유발시킨 동물에서 non-selective endothelin receptor blocker인 bosentan을 투여하였을 때 폐동맥 고혈압 발생에 미치는 효과를 알아보고자 본 연구를 시행하였다. 방 법 : 체중 250 g 내외의 4주령 가량 된 자성 Sprague-Dawley 백서를 대조군, monocrotaline군, bosentan군으로 나누었다. Monocrotaline군과 bosentan군에는 monocrotaline 수용액 60 mg/kg를 배부에 1회 피하 주사하고 대조군에는 동량의 생리식염수를 주사하였다. Bosentan군에는 bosentan ($20mg{\cdot}kg^{-1}{\cdot}day^{-1}$)을 monocrotaline 투여 직후부터 매일 1일 2회 위관 영양법으로 투여하였다. 7일, 14일, 28일에 각각 동물을 희생시켜 심장의 무게를 우심실벽, 좌심실벽, 심실간벽으로 나누어 기관의 무게를 측정하고 조직 검사를 위해 양측 폐를 포르말린 수용액에 고정하였다. 결 과 : 7일, 14일, 28일째 평균 체중은 대조군에 비해 monocrotaline군과 bosentan군이 유의하게 적었다. 우심실/(좌심실＋심실간벽)의 무게 비율은 28일째 monocrotaline군($0.71{\pm}0.10mg/g$)에 비해 bosentan군($0.49{\pm}0.09mg/g$)이 유의하게 적었다(P<0.05). 폐세동맥의 조직형태학적 분석 결과 실험 28일째 monocrotaline투여에 의해 유발된 중막 비후 소견이 bosentan 투여에 의해 현저하게 저하된 것으로 나타났다(monocrotaline군 $49.94{\pm}10.06$ vs bosentan군 $47.09{\pm}10.48$, P<0.05). 또한 호흡성 세기관지 이하의 폐포에 분포하는 근육성 폐세동맥의 숫자도 monocrotaline 투여에 의해 증가되었으나 14, 28일째 bosentan군에서는 현저하게 적은 것으로 나타났다. 결 론 : Monocrotaline으로 유도한 백서의 폐고혈압에서 bosentan을 투여하고 초기 경과를 관찰한 결과, 2주째부터 우심실 비대가 억제되었고 4주 이내 사망률도 낮아 endothelin receptor에 대한 길항 작용의 효과로 해석될 수 있겠다.

• Journal of Chest Surgery
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• 제33권3호
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• pp.221-229
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• 2000

Background: Thromboxane A2 and endothelin-1 are the potent vasoconstrictors affecting pulmonary pathophysiology in response to whole body inflammatin following CPB. Aprotinin, as an antiiflammatory agent, may decrease the release of such vasoactive substance from pulmonary tissues, preventing pulmonary hypertension after cardiopulmonary bypass. Material and Method: Ten mongrel dogs(Bwt. ac. 20kg) were subjected to cardioupulmonary bypass for 2 hours and postbypass pulmonary vascular resistance(0, 1, 2, 3 hours) were compared with prebypass level. The dogs were divided into 2 groups; control group(n-5) and aprotinin group(n=5). In the aprotinin group, aprotinin was administered as follows; 50,000 KIU/kg mixed in pump priming solution, 50,000 KIU/kg prebypass intravenous infusion over 30 minutes, 10,000 KIU/kg/hour postbypass continuous infusion. Prebypass and postbypass 0, 1, 2, 3 hour pulmonary vascular resistance were measured. At prebypass and postbypass 0, 90, 180 minutes, blood samples were obtained from pulmonary arterial and left atrial catherers for the assay of plasma thromboxane B2 a stable metabolite of thromboxane A2, and endothelin-1 concentrations. Result: The ratios of pustbypass over prebypass pulmonary vascular at postbypass 0, 1, 2, 3 hours were 1.28$\pm$0.20, 1.82$\pm$0.23, 1.90$\pm$0.19, 2.14$\pm$0.18 in control group, 1.58$\pm$0.18, 1.73$\pm$0.01, 1.66$\pm$0.10, 1.50$\pm$0.08 in aprotinin group ; the ratios gradually increased in control group while decreased or fluctuated after postbypass 1 hour in aprotinin group. There was statistically significant difference between control group and aprotinin group at postbypass 3 hours(P=0.014). Pulmonary arterial plasma concentration of thromboxane B2(pg/ml) at prebypass, postbypass 0, 90, 180 minutes were 346.4$\pm$61.9, 529.3$\pm$197.6, 578.3$\pm$255.8, 493.3$\pm$171.3 in control group, 323.8$\pm$118.0, 422.6$\pm$75.6, 412.3$\pm$59.9, 394.5$\pm$154.0 in aprotinin group. Left atrial concentrations were 339.3$\pm$89.2, 667.0$\pm$65.7, 731.2$\pm$192.7, 607.5$\pm$165.9 in control group, 330.0$\pm$111.2, 468.4$\pm$190.3, 425.4$\pm$193.6, 4.7.3$\pm$142.8 in aprotinin group. These results showed decrement of pulmonary thromboxane A2 generation in aprotinin group. Pulmonary arterial concentrations of endothelin-1(fmol/ml) at the same time sequence were 7.84$\pm$0.31, 13.2$\pm$0.51, 15.0$\pm$1.22, 16.3$\pm$1.73 in control group, 7.76$\pm$0.12, 15.3$\pm$0.71, 22.6$\pm$6.62, 14.9$\pm$1.11 in aprotinin group. Left atrial concentrations were 7.61$\pm$17.2, 57.1$\pm$28.4, 18.9$\pm$18.2, 31.5$\pm$20.5 in control group, 5.61$\pm$7.61, 37.0$\pm$26.2, 28.6$\pm$21.7, 37.8$\pm$30.6 in aprotinin group. These results showed that aprotinin had no effect on plasma endothelin-1 concentration after cardiopulmonary bypass. Conclusion: Administration of aprotinin during cardiopulmonary bypass could attenuate the increase in pulmonary vascular resistance after bypass. Inhibition of pulmonary thromboxane A2 generation was thought to be one of the mechanism of this effect. Aprotinin had no effect on postbypass endothelin-1 concentration.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.192-192
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• 1996

Endothelin has $ET_{A}$ type and $ET_{B}$ type receptors, and it has been thought that ET-1 proves vasoconstriction effect via $ET_{A}$ receptor and vasodilation via $ET_{B}$ receptor. Recently, it has been reported that $ET_{B}$ receptor is also related to the vaso-constriction. Bosentan is a $ET_{A+B}$ receptor antagonist, and proves it's effect on trauma and ischemia. We already announced that the level of Endothelin-1 increase in the brain and spinal cord of EAE-induced lewis rat and showed the origin of ET-1 is activated macrophages. Intracisternal injection of Bosentan, $ET_{A+B}$ receptor antagonist, (300nmol/body) was done for observing the role of endothelin-1 on the pathogenesis of EAE. Bosentan ameliorated the severity of clinical score of EAE and decreased the histologically observed inflammatory region. The blocking effect on the progression of EAE model suggests that Bosentan is a physiological antagonist in terms of development of the sign of multiple sclerosis.

• BMB Reports
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• 제46권7호
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• pp.364-369
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• 2013

Endothelin-1 (ET-1) plays an indispensable role in epidermal pigmentation in hyperpigmentary disorders due to a central role in melanogenesis. Nevertheless, precise mechanism involved in ET-1-induced hyperpigmentation is still undefined. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB) is a key element in melanosome formation. Therefore, we speculated that GPNMB was correlated with ET-1-induced pigmentation. After culturing with ET-1, melanin synthesis was significantly up-regulated, accompanying with increased expression of GPNMB and microphthalmia-associated transcription factor (MITF). Total number of melanosomes and melanin synthesis were sharply reduced via GPNMB-siRNA transfection, indicating ET-1-induced pigmentation by GPNMB-dependent manner. Furthermore, MITF-siRNA transfection strikingly inhibited GPNMB expression and the melanogenesis, and this suppression failed to be alleviated by ET-1 stimulation. All of these results demonstrated that ET-1 can trigger melanogenesis via the MITF-regulated GPNMB pathway. Taken together, these findings will provide a new explanation of how ET-1 induces hyperpigmentation, and possibly supply a new strategy for cosmetic studies.