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ETA Receptor Antagonist (eta + receptor_antagonist)
Selected AbstractsEquine pulmonary and systemic haemodynamic responses to endothelin-1 and a selective ETA receptor antagonistEQUINE VETERINARY JOURNAL, Issue 4 2001A. E. BENAMOU Summary Based on previous in vitro studies, we hypothesised that endothelin (ET) would induce vasoconstriction in the pulmonary circululation of the horse and that this action would be mediated via ETA receptors. Pulmonary and systemic haemodynamic responses to endothelin-1 (ET-1), a potent vasoactive endogenous peptide, were investigated in 6 conscious, nonsedated horses at rest. Bolus i.v. injections of exogenous ET-1 (0.1, 0.2 and 0.4 ,g/kg bwt) caused significant increases in pulmonary (PAP) and carotid (CAP) artery pressures, with peak increases of 79% and 51% for mean PAP and CAP, respectively. The effect of ET-1 on PAP and CAP was rapid and transient for PAP (,10 min) but prolonged for CAP (up to 60 min). ET-1 significantly decreased cardiac output by up to 35% and significantly increased systemic vascular resistance (SVR) by up to 104%. Pulmonary vascular resistance (PVR) showed a trend (P>0.05) to increase with 0.2 and 0.4 ,g/kg bwt ET-1. Infusion of a selective ETA receptor antagonist (TBC11251) completely inhibited the responses to a subsequent bolus of 0.2 ,g/kg bwt ET-1. We conclude that exogenous ET-1 exerts a potent vasoconstrictive action on the pulmonary and systemic circulations of the horse. These effects appear to be mediated largely through ETA receptors in both circulations. Endothelin may play a role in hypertensive conditions in the horse. [source] Effects of endothelin-1 on portal-systemic collaterals of common bile duct-ligated cirrhotic ratsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2004C.-C. Chan Abstract Background/Aims, Endothelin-1 (ET-1) may induce intrahepatic vasoconstriction and consequently increase portal pressure. Endothelin-1 has been shown to exert a direct vasoconstrictive effect on the collateral vessels in partially portal vein-ligated rats with a high degree of portal-systemic shunting. This study investigated the collateral vascular responses to ET-1, the receptors in mediation and the regulation of ET-1 action by nitric oxide and prostaglandin in cirrhotic rats with a relatively low degree of portal-systemic shunting. Methods, The portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10,10,10,7 m) with or without BQ-123 (ETA receptor antagonist, 2 × 10,6 m), BQ-788 (ETB receptor antagonist, 10,7 m) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of N, -nitro-L-arginine (NNA, 10,4 M), indomethacin (INDO, 10,5 M) or in combination were assessed. Results, Endothelin-1 significantly increased the perfusion pressures of portal-systemic collaterals. The ET-1-induced constrictive effects were inhibited by BQ-123 or BQ-123 plus BQ-788 but not by BQ-788 alone. The inhibitory effect was greater in the combination group. Pretreatment of NNA or NNA plus INDO equivalently enhanced the response of ET-1 while pretreatment of INDO alone exerted no effect. Conclusion, Endothelin-1 has a direct vasoconstrictive effect on the collaterals of BDL cirrhotic rats, mainly mediated by ETA receptor. Endogenous nitric oxide may play an important role in modulating the effects of ET-1 in the portal-systemic collaterals of BDL cirrhotic rats. [source] Vasoactive factors in sickle cell disease: In vitro evidence for endothelin-1-mediated vasoconstrictionAMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2004Sitki Ergul Abstract While systemic plasma endothelin-1 (ET-1) levels are increased during acute crisis in sickle cell disease, the relative levels of potent vasoactive factors that contribute to the regulation of vascular function, such as ET-1, NO, and cell-free hemoglobin, during the course of periodic vaso-occlusive episodes remain unclear. Moreover, whether and to what extent sickling-induced release of ET-1 alters vascular tone is not completely understood. To investigate the sequential changes in circulating vasoactive factors, we measured plasma ET-1, NO metabolites (NOx), and cell-free hemoglobin (Hb) before (steady-state), during (crisis), and after a vaso-occlusive (post-crisis) episode. Steady-state ET-1 levels (fmol/mL) increased from 2.3 ± 0.4 to 11.0 ± 1.4 and 4.2 ± 1.0 during crisis and post-crisis periods, respectively. There was no significant difference in plasma NOx levels. Cell-free Hb levels were significantly higher in sickle cell patients in all phases as compared to the control group, and especially during crisis cell-free Hb levels were elevated by 4-fold (209,000 ± 31,000 vs. 46,000 ± 5,300 ng/mL in steady-state). Conditioned medium from human pulmonary artery endothelial cells exposed to sickled erythrocytes prepared by deoxygenation induced contraction of aortic rings, and this effect was blocked by an ETA receptor antagonist. These findings indicate that ET-1 is the predominant contractile factor released by cultured endothelial cells upon exposure to deoxygenated sickled SS erythrocytes and ET-1,NO,NO scavenger balance is altered in favor of vasoconstriction during an acute episode in SCD. Am. J. Hematol. 76:245,251, 2004. © 2004 Wiley-Liss, Inc. [source] Contractile Changes of the Clitoral Cavernous Smooth Muscle in Female Rabbits with Experimentally Induced Overactive BladderTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2008Soon-Chul Myung MD ABSTRACT Introduction., Recently, growing clinical evidence has suggested that sexual dysfunction is more prevalent in women with overactive bladder (OAB). Aims., However, there has been no basic research to clarify the relationship between OAB and female sexual dysfunction. Therefore, we investigated this issue using a rabbit model of OAB. Methods., Twenty-seven New Zealand white female rabbits were randomly divided into the OAB and control groups. Main Outcome Measures., The contractile responses of clitoral cavernous strips to K+, phenylephrine (PE), Bay K 8644, and endothelin (ET)-1, and the relaxation responses of acetylcholine (ACh), sodium nitroprusside (SNP), and Y-27632 to PE-induced contraction by measuring isometric tension. Results., The contractile responses to K+, PE, Bay K 8644, and ET-1 were significantly more increased in the OAB group in a dose-dependant manner than in the control group (P < 0.05), and the responses to ET-1 were more prominent than those to the remaining substances (P < 0.01). The increased contractile responses to ET-1 were blocked by BQ123 (ETA receptor antagonist) but not by BQ788 (ETB receptor antagonist). Clitoral cavernosal strips from the OAB group were more difficult to relax than those from the control group in terms of ACh- and SNP-induced relaxation (P < 0.05). The Y-27632-induced relaxant responses to PE- and ET-1-induced contraction were less prominent in the OAB group than in the control group. Conclusions., The results of this study provide evidence that female OAB may deteriorate clitoral engorgement, which is associated with a greater force generation by increased calcium sensitization and subsequently decreased of relaxation. The activation of ET and Rho-kinase system may be crucial to negatively effect the clitoral smooth muscle relaxation in experimentally induced OAB animal model. But whether these vasomotor effects are revived in human clitoris is still debatable. Myung S-C, Lee M-Y, Lee S-Y, Yum S-H, Park S-H, and Kim S-C. Contractile changes of the clitoral cavernous smooth muscle in female rabbits with experimentally induced overactive bladder. J Sex Med 2008;5:1088,1096. [source] Dual ETA/ETB vs. selective ETA endothelin receptor antagonism in patients with pulmonary hypertensionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006C. F. Opitz Abstract Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ETA/ETB and selective ETA receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ETA receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ETB receptors has been more complex. It has been shown that there is a subpopulation of ETB receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ETB receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ETA receptor antagonism. [source] Endothelin receptors blockade blunts hypoxia-induced increase in PAP in humansEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2010I. Pham Eur J Clin Invest 2010; 40 (3): 195,202 Abstract Background, Activation of the endothelin-1 (ET-1) pathway may be involved in hypoxia-induced pulmonary vasoconstriction, increase in pulmonary pressure and high altitude pulmonary oedema. Thus, we investigated the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects (n = 10). Design, We used a double-blind, placebo-controlled, randomized, cross-over design to study the effects of a single oral dose of bosentan (250 mg) on PASP after 90-min-exposure to normobaric hypoxia (FiO2 = 0·12). We measured PASP and cardiac output by echocardiography, systolic arterial blood pressure, arterial O2 saturation (SaO2), and blood gases at rest and during a sub-maximal exercise. Results, PASP in normoxia at rest was 23·5 ± 2·7 and during exercise 39·8 ± 11·6 mmHg (P < 0·0001). During the placebo period, hypoxia induced a significant decrease in SaO2, PaO2 and PCO2 and increase in pH. PASP at rest increased significantly: 32·1 ± 3·5 mmHg (P < 0·001 vs. normoxia). Bosentan significantly blunted the hypoxia-induced increase in PASP: bosentan: 27·0 ± 3·3 mmHg, P = 0·002 vs. placebo at rest, but not during exercise: bosentan 39·8 ± 11·6 vs. placebo 43·0 ± 8·5 mmHg, ns. Bosentan had no effect on the hypoxia-induced changes in blood gases, or on cardiac output and systolic arterial blood pressure, which were not modified by hypoxia. Conclusion, A single oral dose of bosentan blunted an acute hypoxia-induced increase in PASP in healthy subjects, without altering cardiac output or systemic blood pressure. [source] Bosentan treatment of portopulmonary hypertension related to liver cirrhosis owing to hepatitis CEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006W. Grander Abstract Pulmonary arterial hypertension (PAH) with coexisting portal hypertension has been defined as portopulmonary hypertension (PPHTN). It is often related to liver cirrhosis of various aetiologies and is associated with a high mortality rate. Endothelin-1 (ET) is supposed to play an important role in the pathogenesis of PAH as well as portal hypertension. Therefore, therapy with an ETA/ETB receptor antagonist might be of use in the treatment of PPHTN. We report the case of a 76-year-old male with liver cirrhosis owing to chronic hepatitis C virus infection and PPHTN who was treated with the dual ETA/ETB receptor antagonist bosentan. The patient showed remarkable improvement of 6-min walking distance from 300 to 480 m after 2 weeks and to 540 m after 14 weeks, respectively. In addition, a significant decline of N-terminal pro B-type natriuretic peptide fraction (NT-proBNP) from 4928 ng mL,1 to 640 ng mL,1 was observed. Bosentan might be a promising new therapeutical option for patients suffering from PPHTN. [source] Bosentan therapy for pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006D. Bonderman Abstract Hereditary haemorrhagic telangiectasia (HHT) is a disorder of arteriovenous malformations and telangiectases. In rare cases affected individuals may develop typical pulmonary arterial hypertension (PAH). Vasodilator therapy has not been recommended because of a potential increase in arteriovenous shunt volume. This report is on two patients with severe HHT-associated PAH who were treated with bosentan, an oral endothelin ETA/ETB receptor antagonist. After 1 year, symptomatic and functional improvements were confirmed by haemodynamic evaluation demonstrating a significant decrease of mean pulmonary artery pressures and an increase in cardiac index, without evidence for an increase in effective shunt volume. [source] | ||||||||||