• 제목/요약/키워드: endothelin-1

검색결과 93건 처리시간 0.022초

개심술 환자에서 술전및 술후의 폐동맥 고혈압및 혈역학적 변수들과 ET-1치와의 관계에 대한 연구 (Endothelin-1 Levels in Patients with Heart Disease Associated with Pulmonary Hypertension ; Potential role of Endothelin-1 in genesis of pulmonary artery vasospasm)

  • 박형주
    • Journal of Chest Surgery
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    • 제25권6호
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    • pp.650-660
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    • 1992
  • To elucidate a potential contribution of endotheline-1[ET-1] to the genesis of pulmonary hypertension and postoperative pulmonary hypertensive crisis in the patients with heart disease, we measured plasma levels of the ET-1 during perioperative period of open heart surgery. In addition, we examined changes of ET-1 during perioperative period and correlations between ET-1 levels and hemodynamic variables. 12 patients including 5 acquired heart disease and 7 congenital heart disease patients were selected randomly as a study group, Group A and B, respectively. 6 patients proved not having heart or hemodynamic problem were selected as a control, Group C. 110 blood samples from pulmonary artery[ET-P] and radial artery[ET-S] were taken and assayed by Sep-pak extraction and RIA. ET-1 levels of Group A were ET-P, 3.94$\pm$5.31pg /ml, ET-S, 3.10$\pm$2.90pg/ml[p>0.05], Group B were ET-P, 1.63$\pm$0.62pg/ml, ET-S, 1.99$\pm$2.45pg/ml[p>0.05], Group C were ET-P, 1.97$\pm$2.02pg/ml, ET-S, 1.72$\pm$0.77pg/ml[p>0.05]. There were no statistically significant differences of ET-1 levels among the Group A, B, C[p>0.05]. There was no correlation between pulmonary artery pressure[PAP] and ET-1 level[p>0.05], and ET-1 levels were not increased even in the cases of pulmonary hypertensive criwis or low cardiac output syndrome, whereas significant correlation between ET-S and pulmonary vascular res-istance[Rp] [r=0.36, p<0.05], and negative correlation between ET-S and OS saturation of pulmonary artery[OS-P][r= -0.49, p<0.01] were identified. Another significant finding was peak increase of ET-1 levels in the postoperative period 1 hour[p<0.05] and then gra-dualy decrease through the postoperative period. In conclusion, ET-1 has no correlation with PAP, whereas correlation with Rp, and inverse correlation with OS-P. It is suggested that ET-1 is neither the direct causative substance of pulmonary hypertension nor pulmonary vasospasm but there must be increased production of ET-1 in chronic pulmonary hypertensive state. Counter-regulatory mechanism to ET-1 is speculated during the pulmonary vasospasm.

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Changes in the Endothelin-1-induced Contraction of Aorta in Streptozotocin-induced Diabetic Rats

  • Cheong, Hyun-Joo;Kim, Eun-Jin;Kim, Su-Jin;Lee, Sun-Hee;Rhim, Byung-Yong
    • The Korean Journal of Physiology and Pharmacology
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    • 제4권3호
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    • pp.185-195
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    • 2000
  • Vascular diseases are significant complications of diabetes mellitus (DM), and the endothelial cells may play a pivotal role in the development of vascular disease in DM. Endothelin-1 (ET-1) released from endothelium is a potent vasoconstrictor peptide and circulating level of ET-1 is increased in a variety of disease states. The purpose of this study was to determine the changes of responsiveness to ET-1 in DM, and we experimented on the changes in the ET-1-induced contraction, levels of nitrite and lipid peroxidation, and ET-1 immunoreactivity in aorta from streptozotocin-induced DM rats. DM was induced by single injection of streptozotocin (55 mg/kg, i.p.). The immunoreactive ET-1 levels in endothelial layer of thoracic aorta were much higher in DM rats than control rats. Nitrite in tissue homogenate was decreased and plasma nitrite was increased in DM rats. Malondialdehyde (MDA) was significantly increased in DM rats and cGMP was not significantly different between control and DM rats. ET-1 produced concentration- dependent contractile responses that are significantly attenuated in DM rats compared to controls. In the presence of selective $ET_A$ receptor antagonist BQ610, the maximum contraction was decreased and the concentration ratios for BQ610 yielded $pA_2$ values of 7.3 (slope, 0.65) in control rats, whereas BQ610 had no antagonistic effect on ET-1-induced contraction in DM rats. However, pretreatment with BQ788, an $ET_B$ receptor antagonist, maximum response was decreased and the dose-response curves for ET-1 were shifted to the right in both groups and $pA_2$ values were 7.9 and 7.7 (slope, 1.05 in control and DM rats), respectively. IRL 1620 and sarafotoxin S6c, $ET_B$ agonists, induced relaxation in control rats but not in DM rats. These results indicate that endothelial cell dysfunction and enhanced immunoreactivity of ET-1 have been found in DM rat and ET-1-induced contraction was attenuated in DM rat. These attenuated responses might be at least in part caused by the alteration of $ET_A$ receptor properties (e.g. desensitization), and partly related with an alteration in intracellular mechanism for contraction to ET-1.

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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 Journal of Physiology and Pharmacology
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    • 제20권1호
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    • pp.9-14
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    • 2016
  • 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.

Endothelin-1이 유발하는 stereotyped behavior과 arterial blood pressure 상승에 NMDA receptor와 NO의 관련성

  • 류정수;방준석;허인회
    • 한국응용약물학회:학술대회논문집
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    • 한국응용약물학회 1997년도 춘계학술대회
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    • pp.92-92
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    • 1997
  • Stereotaxic apparatus를 이용하여 흰쥐의 두개골을 천공하여 periaqueductal gray matter에 정확히 cannula를 삽입하여 1일 이상의 방치후 여기로 약물을 투여하여 일군의 동물들은 행동의 변화를 관찰하고, 일군의 동물들은 경동맥에서의 혈압과 심박수의 변화를 관찰한다. 결과: ET-1에 의해 유발된 barrel-rolling은 NMDA receptor-selective antagonist인 MK-801에 의해 유의성있게 억제되었으며, NOS antagonist인 L-NAME과 NO scavenger인 Hemoglobin에 의해서도 유의성 있게 억제되었다.

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NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria

  • Wu, Cheng-zhe;Li, Xiang;Hong, Lan;Han, Zhuo-na;Liu, Ying;Wei, Cheng-xi;Cui, Xun
    • The Korean Journal of Physiology and Pharmacology
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    • 제25권2호
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    • pp.159-166
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    • 2021
  • Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 μM) and BQ788 (0.3 μM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 μM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 μM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxia-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 μM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 μM) and LY294002 (10.0 μM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria.

Expression of Nitric Oxide Synthase and Endothelin-1 in Human Uterine Artery from Full-Term Pregnancies

  • Choi, Ook-Hwan;Lee, Sun-Hee;Kim, Eun-Jin;Kim, Koan-Hoi;Rhim, Byung-Yong
    • The Korean Journal of Physiology and Pharmacology
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    • 제9권3호
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    • pp.165-172
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    • 2005
  • The aim of this study was to determine the roles of ET-1 and NO on uterine blood flow in pregnancy. Uterine arteries were isolated from 17 nonpregnant and 12 pregnant women. Nonpregnant group included patients with median age of $48.6{\pm}2.3$ years who underwent hysterectomy, because of myoma. Pregnant group included patients with median age of $31.3{\pm}1.4$ years undergoing cesarean delivery. ET-1 and ET-2 induced concentration-dependent contraction in isolated nonpregnant and pregnant uterine arteries. The contractile response and maximal contraction were increased in pregnant uterine arteries. In nonpregnant uterine arteries, there was no contraction in response to ET-3, whereas pregnancy induced concentration-dependent contraction by ET-3. Tissue nitrite/nitrate level and immunohistochemical staining of eNOS and iNOS were increased in pregnant uterine arteries, compared with nonpregnant uterine arteries. In addition, the expressions of eNOS and iNOS mRNA were significantly increased in pregnancy. Moreover, contractions by ET isopeptides, including ET-1, were enhanced, and immunohistochemical staining of ET-1 and ET-1 mRNA expression was increased in pregnant uterine arteries. These results suggest that NO production by increased NOS activity, especially eNOS activity, is related to placental and uterine blood flow. Furthermore, ET-1 appears to play a pathophysiological role in pregnant complications such as hypertension.

급성 천식발작시 혈장 및 요중 Endothelin 농도 변동 (Changes in Plasma and Urine Endothelin Levels During Acute Exacerbation of Asthma)

  • 장중현;신태림;우가은;김종선;홍은순;서기열;차주현;김미선;김영선;조영주
    • Tuberculosis and Respiratory Diseases
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    • 제44권4호
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    • pp.844-852
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    • 1997
  • 연구배경 : 최근의 기관지천식 병인과 관련한 여러 연구에서 천식 발작중에 폐장에서 과도하게 유리된 endothelin(ET)이 기관지 수축을 유발시키는 주요한 펩티드임이 확인되었다. 이 연구의 목적은 급성발작의 경과에 따른 혈장 몇 요중치의 변동 및 상호 연관성을 관찰함에 있다. 방 법 : 연구대상은 16명의 급성 천식악화로 입원한 환자에서 내원당일과 치료 2주후의 2회의 혈장 및 24시간 요를 채취하였다. 정상대조군은 신체건강한 성인 10명으로 정하였다. 모든 천식환자는 입원당시 부신피질호르몬제, 베타-2 교감신경작동제, 아미노필린 제제를 투약받았다. ET은 방사면역측정법에 외해 측정되었으며 교차반응성에 있어 ET-1과는 100%, ET-2와 67%, ET-3와 84%, Big-ET과 8% 이었다. 결 과 : 혈장 ET은 천식환자의 및대조군의 수치와 비교하여 천식악화시 유의하게 증가하였다. 그러나 요중 ET은 천식악화시 및 치료후에 유의한 감소가 관찰되지 않았으나 정상대조군에 비해서는 둘다 유의하게 증가되어 있었다. 혈중 및 요중 ET치는 폐기능 및 저산소혈증 등과 유의한 상관관계는 없었다. 결 론 : 천식의 급성악화시에 증가한 혈장의 ET은 폐장에서의 ET 유리의 증가에 기인한 것으로 사료된다. 천식발작 환자는 정상인에 비해 요중 ET의 배설이 증가하여 있었으나 치료 2주후까지는 유의한 감소가 관찰되지 않았다. 따라서 천식발작시의 요중 ET의 변동을 관찰하기 위해서는 좀더 긴 관찰기간 및 많은 환자를 대상으로 포괄적인 연구가 되어야 할 것으로 생각된다.

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An inhibitory effect of tumor necrosis factor-alpha antagonist to gene expression in monocrotaline-induced pulmonary hypertensive rats model

  • Kwon, Jung Hyun;Kim, Kwan Chang;Cho, Min-Sun;Kim, Hae Soon;Sohn, Sejung;Hong, Young Mi
    • Clinical and Experimental Pediatrics
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    • 제56권3호
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    • pp.116-124
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    • 2013
  • Purpose: Tumor necrosis factor (TNF)-${\alpha}$ is thought to contribute to pulmonary hypertension. We aimed to investigate the effect of infliximab (TNF-${\alpha}$ antagonist) treatment on pathologic findings and gene expression in a monocrotaline-induced pulmonary hypertension rat model. Methods: Six-week-old male Sprague-Dawley rats were allocated to 3 groups: control (C), single subcutaneous injection of normal saline (0.1 mL/kg); monocrotaline (M), single subcutaneous injection of monocrotaline (60 mg/kg); and monocrotaline + infliximab (M+I), single subcutaneous injection of monocrotaline plus single subcutaneous injection of infliximab (5 mg/kg). The rats were sacrificed after 1, 5, 7, 14, or 28 days. We examined changes in pathology and gene expression levels of TNF-${\alpha}$, endothelin-1 (ET-1), endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase (MMP) 2, and tissue inhibitor of matrix metalloproteinase (TIMP). Results: The increase in medial wall thickness of the pulmonary arteriole in the M+I group was significantly lower than that in the M group on day 7 after infliximab treatment (P<0.05). The number of intraacinar muscular arteries in the M+I group was lower than that in the M group on days 14 and 28 (P<0.05). Expression levels of TNF-${\alpha}$, ET-1, ERA, and MMP2 were significantly lower in the M+I group than in the M group on day 5, whereas eNOS and TIMP expressions were late in the M group (day 28). Conclusion: Infliximab administration induced early changes in pathological findings and expression levels of TNF-${\alpha}$, and MMP2 in a monocrotaline-induced pulmonary hypertension rat model.

Novel Genome-Wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm

  • Eun Pyo Hong;Dong Hyuk Youn;Bong Jun Kim;Jae Jun Lee;Sehyeon Nam;Hyojong Yoo;Heung Cheol Kim;Jong Kook Rhim;Jeong Jin Park;Jin Pyeong Jeon
    • Journal of Korean Neurosurgical Society
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    • 제66권4호
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    • pp.409-417
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    • 2023
  • Objective : The association between boule (BOLL) and endothelin receptor type A (EDNRA) loci and intracranial aneurysm (IA) formation has been reported via genome-wide association studies. We sought to identify genome-wide interactions involving BOLL and EDNRA loci for IA in a Korean adult cohort. Methods : Genome-wide pairwise interaction analyses of BOLL and EDNRA involving 250 patients with IA and 296 controls were performed using the additive effect model after adjusting for confounding factors. Results : Among 512575 single-nucleotide polymorphisms (SNPs), 23 and 11 common SNPs suggested a genome-wide interaction threshold (p<1.25×10-8) involving rs700651 (BOLL) and rs6841581 (EDNRA). Rather than singe SNP effect of BOLL or EDNRA on IA development, they showed a synergistic effect on IA formation via multifactorial pair-wise interactions. The rs1105980 of PTCH1 gene showed the most significant interaction with rs700651 (natural log-transformed odds ratio [lnOR], 1.53; p=6.41×10-11). The rs74585958 of RYK gene interacted strongly with rs6841581 (lnOR, -19.91; p=1.64×10-9). Although, there was no direct interaction between BOLL and EDNRA variants, two EDNRA-interacting gene variants of TNIK (rs11925024 and rs1231) and FTO (rs9302654), and one BOLL-interacting METTL4 gene variant (rs549315) exhibited marginal interaction with BOLL gene. Conclusion : BOLL or EDNRA may have a synergistic effect on IA formation via multifactorial pair-wise interactions.

Regulation of Adenosine-activated GIRK Channels by Gq-coupled Receptors in Mouse Atrial Myocytes

  • Cho, Ha-Na
    • The Korean Journal of Physiology and Pharmacology
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    • 제14권3호
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    • pp.145-150
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    • 2010
  • Adenosine (Ado) is an important mediator of the endogenous defense against ischemia-induced injury in the heart. The action of Ado is mediated by activation of G protein-gated inwardly rectifying $K^+$ (GIRK) channels. In turn, GIRK channels are inhibited by reducing phosphatidylinositol 4,5-bisphosphate ($PIP_2$) through Gq protein-coupled receptors (GqPCRs). We previously found that GIRK channels activated by acetylcholine, a muscarinic M2 acetylcholine receptor agonist, are inhibited by GqPCRs in a receptor-specific manner. However, it is not known whether GIRK channels activated by Ado signaling are also regulated by GqPCRs. Presently, this was investigated in mouse atrial myocytes using the patch clamp technique. GIRK channels were activated by $100\;{\mu}M$ Ado. When Ado was repetitively applied at intervals of 5~6 min, the amplitude of second Ado-activated GIRK currents ($I_{K(Ado)}$) was $88.3{\pm}3.7%$ of the first $I_{K(Ado)}$ in the control. Pretreatment of atrial myocytes with phenylephrine, endothelin-1, or bradykinin prior to a second application of Ado reduced the amplitude of the second $I_{K(Ado)}$ to $25.5{\pm}11.6%$, $30.5{\pm}5.6%$, and $96.0{\pm}2.7%$, respectively. The potency of $I_{K(Ado)}$ inhibition by GqPCRs was different with that observed in acetylcholine-activated GIRK currents ($I_{K(ACh)}$) (endothelin-1>phenylephrine>bradykinin). $I_{K(Ado)}$ was almost completely inhibited by $500\;{\mu}M$ of the $PIP_2$ scavenger neomycin, suggesting low $PIP_2$ affinity of $I_{K(Ado)}$. Taken together, these results suggest that the crosstalk between GqPCRs and the Ado-induced signaling pathway is receptor-specific. The differential change in $PIP_2$ affinity of GIRK channels activated by Ado and ACh may underlie, at least in part, their differential responses to GqPCR agonists.