BOSENTAN - endothelin receptor antagonist
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Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH (Pulmonary Artery Hypertension) patients. Although it is not clear if the increases in endothelin plasma levels are a cause or a consequence of PH (Pulmonary Hypertension), the data supports a prominent role for the endothelin system in the pathogenesis of PAH. Bosentan is an endothelin receptor antagonist used in the treatment of Primary pulmonary hypertension (PPH) which is a progressive disease with high mortality and administration of the orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.International Journal of Human and Health Sciences Vol. 03 No. 01 January’19. Page : 10-13Keywords:
Endothelin receptor antagonist
Pathogenesis
Background : Endothelins have been implicated in gastric mucosal damage in a variety of animal models. Exogenous ET‐1 and ET‐3 are causally associated with experimental gastric ulcers. Furthermore, clinical reports also show elevated plasma and gastric mucosal endothelin‐1 levels in patients suffering from peptic ulcers. Aim : To study the possibility that endothelin receptor antagonists may have beneficial effects and prevent the development of gastric ulcers. We have tested in rats the orally‐active endothelin antagonist bosentan (Ro 47‐0203) and Ro 48‐5695, which is 10–30 times more potent than bosentan on endothelin receptors. Methods : Water immersion restrained stress (WIRS) and indomethacin were used to provoke gastric mucosal damage. Endothelin receptor antagonists were administered orally prior to the induction of gastric damage. The gastric lesion index (mm), assessed macroscopically, and myeloperoxidase (MPO) activity were used as markers of the extent of mucosal injury. Results : Bosentan at 100 and 30 mg/kg administered orally caused attenuation of gastric damage in the WIRS model by 58% and 42%, respectively. Bosentan also caused complete reduction of MPO activity. In indomethacin‐induced gastric damage, 100 mg/kg bosentan attenuated gastric damage by 45% and 61% as measured by the gastric lesion index and MPO activity respectively. Ro 48‐5695 was at least 30 times more potent than bosentan in reducing indomethacin‐induced mucosal damage and at 3 mg/kg, caused a decrease of 49% in the gastric lesion index and a reduction in MPO activity of 41%. Bosentan and Ro 48‐5695 possess weak antisecretory properties as tested in the mouse gastric gland assay, than cannot, alone, account for their anti‐ulcer properties. Conclusions : Both endothelin receptor antagonists prevented the development of gastric mucosal injury in the rat. Disturbances in the gastric microcirculation are responsible for the development of experimental gastric ulcers. The anti‐ulcer properties of these two endothelin antagonists suggest possible new therapeutic approaches to controlling gastric inflammation.
Endothelin receptor antagonist
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Activation of the endothelin-1 system plays a key role in the pathogenesis of pulmonary arterial hypertension (PAH). The endothelin-1 receptor antagonist bosentan inhibits the action of endothelin-1 at both receptor subtypes (ET(A) and ET(B) receptors) and has been approved for PAH therapy since 2001. Recent data were presented at an international symposium in Barcelona in February 2006.
Endothelin receptor antagonist
Pathogenesis
Ambrisentan
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Objective:To investigate the effects of endothelin receptor antagonist Bosentan on the endothelin system in diabetic SD rat.Methods:SD rats were divided into 3 groups at random: untreated diabetic group (DM), Bosentan treated diabetic group (DM-B) and normal control group (SD). Diabetic rats were induced by one dose intraperitoneal injection of Streptozotocin. The DM-B group was treated with Bosentan 100 mg·kg -1 ·d -1 through stomach perfusion for 4 weeks, while the DM and SD groups were treated with sterile water only. The concentrations of circulating and renal endothelin in 3 rats groups were then detected. Furthermore, the kidney expressions of endothelin-1(ET-1), endothelin A receptor (ET-AR) and endothelin B receptor (ET-BR) were measured by reverse transcription-polymerase chain reaction and immuno-histochemistry.Results:There are only a few expressions of ET-1, ET-AR and ET-BR in SD rats kidneys. Elevated level of renal ET-1 was observed in two diabetic groups through RT-PCR ( P 0.01 vs SD group) and no significant difference between the two groups were observed. Notable more renal expressions of ETAR were detected in DM compared with SD group. Bosentan can decrease the elevated of ET-AR expressions( P 0.01 vs DM group). However, there is no significant difference of ET-BR expressions in the three groups.Conclusion:Endothelin has a high activity in diabetic rats. Bosentan can not only interfere with the effects of ET-1, but also down-regulate the elevated renal expressions of ETAR in diabetic rats, so it is useful in keeping kidney from injury in diabetes mellitus.
Endothelin receptor antagonist
Intraperitoneal injection
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Bosentan is a specific competitive dual endothelin receptor antagonist of low molecular weight. It inhibits ET-1 action through combination with both ETA and ETB receptors. It is indicated to treat type Ⅲ and Ⅳ pulmonary hypertension in WHO functional group. The pharmacology, pharmacokinetics,and clinical applications of bosentan are reviewed in this paper.
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Endothelin receptor antagonist
Mediator
Pathogenesis
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Objective: To investigate whether endothelin receptor antagonist Bosentan could reduce the nitroglycerin(NTG) tolerance in rats . Methods: Twenty-eight wistar rats were divided into control group(n=10),Nitroglycerin(NTG) group(n=6), Bosentan group (n=6)and NTG+Bosentan group(n=6).The hypotensive response to sodium nitroprusside(SNP) in different group rats,and the relaxation effect of different concentrations of SNP on isolated aortic rings from different group rats were observed .The endothelin-1 (ET-1) contents of plasma and vascular tissue were measured by the radioimmuno assay method. Results: The hypotention response to SNP was significantly attenuated in NTG group,compared with control group. The hypotensive response to SNP was improved in NTG+Bosentan group, compared with NTG group .The relaxation effect of SNP on isolated rat aortic ring was obviously restored in NTG+Bosentan group,compared with NTG group. The ET-1 contents of plasma and vascular tissue were markedly increased in both NTG+Bosentan group and NTG group compared with control group. Conclusion: Endothelin receptor antagonist Bosentan can prevent against the NTG tolerance .
Endothelin receptor antagonist
Sodium nitroprusside
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Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH (Pulmonary Artery Hypertension) patients. Although it is not clear if the increases in endothelin plasma levels are a cause or a consequence of PH (Pulmonary Hypertension), the data supports a prominent role for the endothelin system in the pathogenesis of PAH. Bosentan is an endothelin receptor antagonist used in the treatment of Primary pulmonary hypertension (PPH) which is a progressive disease with high mortality and administration of the orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.International Journal of Human and Health Sciences Vol. 03 No. 01 January’19. Page : 10-13
Endothelin receptor antagonist
Pathogenesis
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Abstract The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.
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The peptide endothelin plays a significant role in a wide array of pathological conditions, including primary pulmonary hypertension and pulmonary arterial hypertension associated with collagen vascular disease. These are life-threatening conditions that can severely compromise the function of the lungs and heart. Inhibiting the actions of endothelin by blockade of its receptors provides a new and effective approach to therapy for patients with these conditions. Bosentan (Tracleer™) is the first orally-active dual endothelin receptor antagonist and has recently been approved in the US, Canada, Switzerland and the EU for the treatment of pulmonary arterial hypertension. Bosentan significantly improves exercise capacity, symptoms and functional status in patients with this disease and also slows clinical deterioration, which may be indicative of a delay of disease progression. Results from large-scale studies of bosentan in patients with pulmonary arterial hypertension and chronic heart failure have established its long-term safety and tolerability profiles. The introduction of the dual endothelin receptor antagonist bosentan has provided an essential treatment for pulmonary arterial hypertension and ongoing trials are evaluating its potential role in the management of other endothelin-mediated disease states.
Endothelin receptor antagonist
Tolerability
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