Effects Of Bosentan Research Articles

What is the role of bosentan in healing of femur fractures in a rat model?

The purpose of this study was to examine the effects bosentan (which is a strong vasoconstrictor) on bone fracture pathophysiology, and investigate the roles of the nonselective endothelin1 receptor blocker bosentan on the bone fractures formed in rats through radiographic, histopathologic, and immunohistochemical methods. The rats were divided into three groups (six rats in each group): a femoral fracture control group, a femoral fractureplus bosentan at 50mg/kg group, and a femoral fracture plus bosentan at 100mg/kg group. The femoral fracture model was established by transversely cutting the femur at the midsection. After manual reduction, the fractured femur was fixed with intramedullary Kirschner wires. The radiographic healing scores of the bosentan 100 and 50mg/kg groups were significantly better that those of the fracture control group. The fracture callus percent of new bone in the bosentan 100mg/kg group was significantly greater than that in the control group. Also, semiquantitative analysis showed higher positive vascular endothelial growth factor and osteocalcin staining and lower positive endothelinreceptor typeA staining in the treatment groups than in the control group. Bosentan treatment also decreased tissue endothelin1 expression relative to that in the fracture control group. As a result of our study, the protective effect of bosentan was shown in experimental femoral fracture healing in rats by radiographic, histopathologic, and molecular analyses.

Does bosentan protect diabetic brain alterations in rats? The role of endothelin-1 in the diabetic brain.

Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non-diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET)-1 in brain damage formed in a streptozocin (STZ)-induced diabetes model, and the effect of bosentan, which is the non-specific ET1 receptor blocker in the prevention of the diabetes-induced brain damage. To examine the effects of bosentan (50 mg/kg and 100 mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: the sham group (n = 10), the diabetic control group (n = 10), the group of diabetic rats given bosentan 50 mg/kg (n = 10) and the group of diabetic rats given bosentan 100 mg/kg (n = 10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cytoretraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes-induced cerebral complications.

Effect of Bosentan and Sildenafil Combination Therapy on Morbidity and Mortality in Pulmonary Arterial Hypertension (PAH): Results From the COMPASS-2 Study

Effect of Bosentan and Sildenafil Combination Therapy on Morbidity and Mortality in Pulmonary Arterial Hypertension (PAH): Results From the COMPASS-2 Study

Determination of the effects of pulmonary arterial hypertension and therapy on the cardiovascular system of rats by impedance cardiography.

AimTo evaluate the effects of bosentan, sildenafil, and combined therapy on the cardiovascular system using impedance cardiography (ICG) in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH).MethodsSeventy male Wistar-albino rats were randomized into five groups. A single dose of MCT was given to all rats, except to the control group. After 4 weeks, bosentan, sildenafil, and combined treatment was started and lasted for 3 weeks. The last group that developed PAH did not receive any medication. Echocardiographic evaluation was performed to determine the PAH development. Thoracic fluid content index (TFCI), stroke volume index (SI), heart rate (HR), cardiac index (CI), and myocardial contractility index (IC) were determined. All procedures were performed at the baseline and after 4 and 7 weeks.ResultsEchocardiographic parameters showed that the all MCT-injected rats developed PAH. There were no significant inter- and intra-group differences in TFCI, SI, and IC (P > 0.05), but at the 7th week, CI value in the sildenafil-treated PAH rats was significantly higher than in other groups and HR of PAH rats with combined therapy was significantly lower than in other groups.ConclusionPAH did not have an effect on LV function of rats, or if it did, the effect was compensated by physiological processes. Also, sildenafil treatment deteriorated the LV cardiac index.

Endothelin receptor inhibition with bosentan delays onset of liver injury in streptozotocin-induced diabetic condition.

This study was designed to investigate the protective effects of bosentan an orally active non-peptide mixed ETA/ETB receptor antagonist, on liver injury in streptozotocin-induced diabetic rats. 24 Albino-Wistar rats were randomly divided into 4 groups: healthy (Group 1), diabetic (Group 2) (60 mg/kg of streptozotocin i.p.), diabetic treated with bosentan 50 mg/kg (Group 3) and diabetic treated with bosentan 100 mg/kg (Group 4). The treatment of bosentan was initiated after streptozocin injection and continued for 60 days. Liver from diabetic rats showed significant increase in malondialdehyde (MDA) level and significant decrease in glutathione (GSH), and superoxide dismutase (SOD) activity. Endothelin (ET-1), tumor necrosis factor (TNF-α) and transforming growth factor beta (TGF-β) gene expression significantly increased in the diabetic groups in the rat liver tissue. Bosentan treatment showed a significant up-regulatory effect on ET-1, TNF-α and TGF-β mRNA expression. Results from histopathological evaluation of the liver were in accordance with our biochemical and molecular results. These data provide clear evidence that bosentan treatment is associated with promising hepatoprotective effect against diabetes-induced liver damage via reduction of cell inflammation and oxidative damage. These data suggest that ET receptors may be an important actor in diabetes-related liver damage, and blockage of these receptors may become a target for preventing diabetic complications in the future.

The ocular endothelin system: a novel target for the treatment of endotoxin-induced uveitis with bosentan.

We compared the anti-inflammatory effects of bosentan and dexamethasone in endotoxin-induced uveitis (EIU). Endotoxin-induced uveitis was induced by subcutaneous injection of lipopolysaccharide (LPS, 200 μg) in Wistar rats. Rats were divided randomly into 10 groups (n = 6). Bosentan at doses of 50 and 100 mg/kg were administered orally 1 hour before and 12 hours after LPS injection, and dexamethasone was administered by intraperitoneally 30 minutes before and 30 minutes after LPS injection at a dose of 1 mg/kg. Data were collected at two time points for each control and treatment; animals were killed at either 3 or 24 hours after LPS injection. Histopathologic evaluation and aqueous humour measurements of TNF-α level were performed, and endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS), and endothelin receptor A and B (EDNRA and B) expression were analyzed. The group treated with 100 mg/kg bosentan at 24 hours displayed significantly milder uveitis and fewer inflammatory cells compared to LPS-injected animals, and there were similar findings in the dexamethasone-treated group at 24 hours. The TNF-α levels in the dexamethasone treatment group were lower than those in the LPS-induced uveitis control group (P < 0.05); however, there was no difference between the dexamethasone and bosentan treatment groups at 3 and 24 hours after LPS administration. Bosentan treatment at doses of 50 and 100 mg/kg significantly decreased iNOS expression compared to LPS-injected animals (P < 0.001). The ET-1 expression was suppressed significantly by bosentan and dexamethasone at 3 and 24 hours after LPS administration (P < 0.001). The EDNRA expression in the bosentan treatment groups was statistically significantly lower than that in the LPS-induced uveitis control group at 3 and 24 hours after LPS administration (P < 0.05). Bosentan reduces intraocular inflammation and has similar effects as dexamethasone in a rat model of EIU.

Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats

Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal fibrosis by inhibiting RhoA/ROCK axis in DOCA-salt rats. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 4 weeks: vehicle, ABT-627 (endothelin-A receptor inhibitor) and A192621 (endothelin-B receptor inhibitor). DOCA-salt was characterized by increased blood pressure, decreased renal function, increased proteinuria, increased glomerulosclerosis and tubulointerstitial fibrosis with myofibroblast accumulation, increased renal endothelin-1 levels and RhoA activity along with increased expression of connective tissue growth factor at both mRNA and protein levels as compared with uninephrectomized control male Wistar rats. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone, ameliorated proteinuria. Impaired renal function and histological changes were overcome by treatment with ABT-627, but not with A192621. The beneficial effects of bosentan, a nonspecific endothelin receptor blocker, on proteinuria, RhoA activity, and connective tissue growth factor levels were similar to ABT-627. Furthermore, in an isolated perfuse kidney, a RhoA inhibitor, C3 exoenzyme, and two ROCK inhibitors, fasudil and Y-27632, significantly attenuated connective tissue growth factor levels. These results indicate that DOCA-salt elevates renal endothelin-1 levels and RhoA activity via activation of mineralocorticoid receptor, resulting in renal fibrosis and proteinuria. Endothelin-A receptor blockade can attenuate DOCA-salt-induced renal fibrosis probably through the inhibition of RhoA/ROCK activity and connective tissue growth factor expression.

Influence of St. John’s wort on the steadystate pharmacokinetics and metabolism of bosentan

We assessed the effect of St. John's wort (SJW) on bosentan pharmacokinetics at steady-state in different CYP2C9 genotypes in healthy volunteers. Nine healthy extensive metabolizers of CYP2C9 and 4 poor metabolizers received therapeutic doses of bosentan (125 mg q.d. on study day 1; 62.5 mg b.i.d. on study day 2, 125 mg b.i.d. on study days 3 - 20) for 20 days and SJW (300 mg t.i.d.) concomitantly for the last 10 days. Bosentan pharmacokinetics was assessed on days 1, 10, and 20. Concurrently, we repeatedly quantified changes of CYP3A activity using low dosed midazolam (3 mg p.o.) as a probe drug. Due to auto-induction of its metabolism, Cl/F increased by 67%, thus significantly lowering bosentan exposure (AUC) to 60% after 10 days of bosentan administration (n = 13, p < 0.05). Concurrently, midazolam clearance (CYP3A activity) increased by 224% (n = 13, p < 0.05) and further increased after SJW by 374% compared to baseline (n = 13, p < 0.05). SJW increased midazolam clearance by 47% (n = 13, p < 0.05) but failed to alter bosentan exposure and clearance consistently. No significant differences in bosentan exposure and clearance changes were observed in CYP2C9 poor metabolizers. SJW increased CYP3A activity but had no consistent effect on bosentan clearance. However, inter-individual changes of the interaction were large, suggesting that close monitoring of bosentan effects may be advisable. The contribution of CYP2C9 to this interaction seems to be minor.

Effect of bosentan therapy on ventricular and atrial function in adults with Eisenmenger syndrome. A prospective, multicenter study using conventional and Speckle tracking echocardiography

The effect of bosentan on the ventricular and atrial performance in patients with Eisenmenger syndrome is unclear. In adult patients with Eisenmenger syndrome, we aimed to evaluate the midterm effect of bosentan on physical exercise, ventricular and atrial function, and pulmonary hemodynamics. Forty adult patients before and after 24 weeks bosentan therapy underwent 6 min walk test, two-dimensional speckle tracking echocardiography, plasma NT-proBNP measurement and cardiac catheterization. After 24 weeks, bosentan therapy an improvement was observed regarding the 6 min walk distance from a median (quartile 1-quartile 3) of 382.5 (312-430) to 450 (390-510) m (p = 0.0001), NT-proBNP from 527.5 (201-1,691.25) to 369 (179-1,246) pg/ml (p = 0.021), right ventricular mean longitudinal systolic strain from 18 (13-22) to 19 (14.5-25) % (p = 0.004), left ventricular mean longitudinal systolic strain from 16 (12-21) to 17 (16-22) % (p = 0.001), right atrial mean peak longitudinal strain from 26 (18-34) to 28 (22-34) % (p = 0.01) and right atrial mean peak contraction strain from 11 (8-16) to 13 (11-16) % (p = 0.005). The invasively obtained Qp:Qs and Rp:Rs did not significantly change under bosentan therapy. In adult patients with Eisenmenger syndrome, bosentan therapy improves ventricular and atrial functions resulting in enhancement of physical exercise and reduction in the NT-proBNP level, while the pulmonary vascular resistance does not change substantially.

Effects of bosentan on pulmonary fibrosis

Objective To investigate the effects of bosentan on pulmonary fibrosis.Methods Forty-eight male Wistar rats were randomly and equally divided into control groups (C2,C4),model groups (F2,F4) and drug groups (D1,D2).Bleomycin was used to create pulmonary fibrosis model,while rats in D1 and D2 groups were treated by bosentan from day 2 and day 15.Plasma endothelin-I (ET-1),matrix metalloproteinase-9 (MMP-9) and tissue inhibitorof metalloproteinase (TIMP)-1 were measured.Alveolitis and fibrosis scores were assessed after 2 and 4 weeks.Results (1) The levels of ET-1 in F4 group were highest,followed by F2,C4 and C2 groups [(0.41 ±0.13),(0.28 ±0.08),(0.11 ±0.04),and (0.10 ±0.05) μg/L].Compared to F4 group,the levels of ET-1 in D1 group was reduced,but no significant difference was found between D2 and F4 groups; (2) Pathological assessment showed that alveolar structure was destroyed,and numerous inflammatory cells and fibroblasts could be seen in F2 group as well as collagen,most significantly in F4 group,and those were significantly reduced in D1 group as compared with F4 ; (3) The levels of ET-1 were positively associated with alveolitis and fibrosis scores,but MMP-9/TIMP-1 were negatively with them.Conclusion Bosentan can protect against the bleomycin-induced pulmonary fibrosis,and the improvement is more significant in early stage. Key words: Bosentan; Bleomycin ; Pulmonary fibrosis ; Endothelin-1

Effect of bosentan on intimal hyperplasia of carotid artery anastomoses in rabbits

We investigated the effect of bosentan on intimal hyperplasia of carotid artery anastomoses in rabbits. Eighteen New Zealand male rabbits were randomized into two groups, as drug (Group B) and non-drug (Group A). The right carotid artery of all the subjects was transected and anastomosed end-to-end with 10/0 polypropylene suture. The left carotid artery was left intact. Group B subjects received 30 mg/kg/day oral bosentan for 21 days, starting 3 days before the operation. Group A subjects did not receive any medication. After 28 days, the anastomoses site and the contralateral control site were removed, and samples were investigated histomorphometrically. Significant intimal hyperplasia was observed at all anastomoses compared to the non-anastomotic left side. Bosentan decreased significantly the intimal area [Group A: 48.3 µm(2) (37.1 µm(2)-65.7 µm(2)), Group B: 31.4 µm(2) (12.2 µm(2)-63.2 µm(2)), (p=0.04)] and intima/media area ratio [Group A: 0.49 (0.13-0.74), Group B: 0.22 (0.09-0.37), (p=0.024)] compared to the non-drug group. According to our investigation, bosentan decreased the intimal hyperplasia developed in a rabbit carotid artery model. Further investigations are needed to support the potential clinical utilization of bosentan after vascular interventions.

Beyond Vasodilator: Anti-Apoptotic Effect of Endothelin Receptor Antagonist

Refer to the page 97-104 Treatment of pulmonary arterial hypertension (PAH) has changed with development of PAH targeted therapy, which includes use of specific vasodilator in pulmonary arterial system. Bosentan is an endothelin receptor antagonist (ERA) and vasodilator that was the first approved oral drug for PAH treatment. The clinical benefit of bosentan has been established in several multicenter clinical trials1),2) and shown to develop slowly over several months. Therefore, beyond its vasodilator effect, the effect of ERA on PAH progression has been investigated. Pathology of pulmonary artery in PAH patients shows vascular smooth muscle proliferation and obliteration of pulmonary vessels. Endothelial dysfunction is commonly found, and inflammatory response and endothelial cell apoptosis have also been reported. After apoptosis of normal endothelial cell line, surviving cells proliferate. This abnormal proliferation forms unique plexiform lesions that obliterate arterioles and capillaries at the end stage of disease. Vascular smooth muscle cells are prone to hyperplasia and unbalanced apoptosis (decreased apoptosis) leads to hypertrophy of the vessel wall. Endothelin (ET) is produced in endothelial cells of various tissues. Especially, ET-1 is predominantly expressed in pulmonary circulation. ET-2 mainly expressed in the kidney and ET-3 in the brain and intestine.3) ET is secreted from the abluminal side of the cells towards the adjacent vascular smooth muscle cells. There are two types of ET receptor including ETA and ETB. ETA is located in pulmonary vascular smooth muscle cells where it mediates vasoconstriction through inositol trisphosphate (IP3) formation and release of intracellular calcium. The ETA receptor is associated with proliferation of vascular smooth muscle cells in pulmonary arteries. In PAH patients, expression of the ETA receptor is increased and is associated with vasoproliferation. Inflammation also plays an important role in PAH patients and ETA is elevated in this setting. Imbalance between proliferation and apoptosis in vascular smooth muscle cells is associated with vascular hypertrophy in PAH.4) However, before initiation of vascular hypertrophy, inflammation of endothelial cells is observed and is associated with apoptosis of endothelial cells. Therefore, apoptosis of endothelial cells can trigger the initial event for progression of PAH. Vascular endothelial growth factor receptor blockade has been noted as a possible mechanism for endothelial cell apoptosis, followed by the selection of apoptosis-resistant clones, which lead to the formation of plexiform lesions with severe angio-obliterating lesions.5) The article by Hong et al.6) suggests a role for bosentan in attenuating apoptosis and inflammation of endothelial cells. Their results indicate decreases in both caspase-3 and vascular endothelial growth factor in the bosentan-treated group. The proinflammatory cytokine, interleukin-6, was decreased and mRNA expressions of tumor necrosis factor (TNF)-α were decreased. Potential effects of bosentan to reduce apoptosis have been also reported in neuronal cells through the up-regulation of bcl-2 gene expression and decreased expression of the apoptotic protein, caspase.7) These observations suggest that bosentan may prevent disease progression in an early stage by preventing endothelial apoptosis and inflammatory response. Another interesting suggestion is the expanding indication of bosentan to other diseases. Overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling doxorubicin-induced cardiomyopathy. Bien et al.8) reported that bosentan inhibits doxorubicin-induced cardiomyopathy in a mouse model. Pretreatment with bosentan resulted in reduction of TNF-α and Bax expression. Interestingly, ET antagonists are proapoptotic and antiproliferative in human colon cancer cells.9) Therefore, beyond its role as a vasodilator, bosentan has the potential to attenuate apoptotic cells, and this property can be applied to other disease associated with cell apoptosis.

Apoptosis and Inflammation Associated Gene Expressions in Monocrotaline-Induced Pulmonary Hypertensive Rats after Bosentan Treatment

Background and ObjectivesVascular wall remodeling in pulmonary hypertension can be caused by an aberration in the normal balance between proliferation and apoptosis of endothelial cell in the pulmonary artery. The objective of this study was to evaluate the effect of bosentan on apoptosis in monocrotaline (MCT)-induced pulmonary hypertension.Materials and MethodsSprague-Dawley rats were divided into three groups: control (C) group, M group (MCT 60 mg/kg) and B group (MCT 60 mg/kg plus bosentan 20 mg/day orally). Gene expressions of Bcl (B cell leukemia/lymphoma)-2, caspase-3, complement component (C)-6, vascular endothelial growth factor (VEGF), interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were analyzed by real time polymerase chain reaction and western blot analysis.ResultsThe messenger ribonucleic acid (mRNA) expressions of caspase-3 and VEGF were significantly increased in the M group compared with the C group, and significantly decreased in the B group compared with the M group in week 4. mRNA expression of IL-6 was significantly decreased in weeks 1, 2, and 4 in the B group compared with the M group. mRNA expression of TNF-α was significantly decreased on day 5 and in weeks 1 and 2 in the B group compared with the M group.ConclusionBosentan may have potential for preventing apoptosis and inflammation.

Bosentan, a mixed endothelin receptor antagonist, induces antidepressant-like activity in mice

Endothelins are peptides described initially as potent vasoactive mediators. Recently, studies reported that endothelins can modulate the production and release of cytokines by immune cells. In turn, cytokines are involved in depression disorders and also in the effectiveness of some antidepressants. Therefore, we investigated the effects of treating mice with bosentan, a mixed endothelin receptor antagonist, in widely used models for assessing antidepressant activity of compounds, the forced swimming (FST) and the tail suspension tests (TST). Moreover, the influence of bosentan treatment on circulating IL-6 levels was also addressed after FST. The results show that bosentan treatment induced a bell shaped dose-dependent antidepressant-like effect with increase in circulating IL-6 levels in animals exposed to FST. Bosentan also presented antidepressant-like effect in TST. Similar results were obtained with nortriptyline treatment in the FST and TST. Possible anxiogenic effect of bosentan was excluded using the elevated plus maze test. Therefore, this is the first study to demonstrate the antidepressant-like activity of bosentan in mice, unveiling a previous unrecognized role of endothelin in depression and its possible relation with increased circulating IL-6 levels.

Effects of bosentan on digital ulcers in patients with systemic sclerosis

Effects of bosentan on digital ulcers in patients with systemic sclerosis

Effect of bosentan on exercise capacity in patients with pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension

Effect of bosentan on exercise capacity in patients with pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension

Effect of Bosentan on Pulmonary Hypertension Secondary to Systolic Heart Failure

Objectives: The dual endothelin receptor antagonist bosentan improves pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension (PH). The effects of bosentan on secondary PH due to systolic heart failure (HF) are not well defined. This study evaluates the effect and tolerability of bosentan in patients with PH secondary to HF. Methods: Seventeen adult HF patients with PH and New York Heart Association class III-IV symptoms were treated with bosentan, 62.5 mg twice daily, for 1 month, which was gradually increased to 125 mg twice daily thereafter. Right heart catheterization (RHC), a clinical evaluation and echocardiographic measurements were performed at baseline and at 4 ± 3 (mean ± SD) months of follow-up. Response to bosentan was defined as an improvement in clinical, echocardiographic and RHC parameters. Results: Six patients did not complete the study (therapy was discontinued due to hypotension, elevated liver enzymes or acute decompensation of HF), 11 patients completed the follow-up; 9 patients responded to therapy. Systemic arterial pressures, pulmonary pressures, PVR and the transpulmonary gradient significantly decreased compared with baseline levels in 9 responders (p = 0.05, 0.05, 0.01 and 0.004, respectively), and 4 became eligible for heart transplantation and 3 for left ventricular assist device implantation. Conclusions: Bosentan decreased pulmonary pressures and PVR in the majority of patients with PH secondary to systolic HF, thereby allowing them to be considered candidates for heart transplantation.

Combination of Sildenafil and Bosentan for Pulmonary Hypertension in a Human Ex Vivo Model

Both sildenafil and bosentan have been used clinically to treat pulmonary arterial hypertension. As these substances target different pathways to modulate vasoconstriction, we investigated the combined effects of both drug classes in isolated human pulmonary vessels. Segments of pulmonary arteries (PA) and veins (PV) were harvested from 51 patients undergoing lobectomy. Contractile force was determined isometrically in an organ bath. Vessels were constricted with norepinephrine (NE) to determine effects of sildenafil. They were constricted with ET-1 to assess effects of bosentan, and with NE and ET-1 to evaluate the combination of both substances. Sildenafil (1E-5 M) significantly reduced maximum constriction by NE of both PA (13.0 ± 11.1 vs. 34.9 ± 7.6% relative to KCl induced constriction; n = 6; p < 0.001) and PV (81.2 ± 34.2 vs 121.6 ± 20.8%; n = 6; p < 0.01) but did not affect basal tones. Bosentan (1E-5 M) significantly reduced maximum constriction of PV (56.6 ± 21.5 vs. 172.1 ± 30.0%; n = 6; p < 0.01) by ET-1 and led to a small but insignificant decrease of basal tone (p = 0.07). Bosentan almost completely abolished constriction of PA (1.0 ± 0.9 vs. 74.7 ± 25.7 %; n = 6; p < 0.001) by ET-1, but did not affect basal tone. Bosentan (1E-7 M) significantly attenuated combined ET-1/NE dose-response curves in PA (93.1 ± 47.4 vs. 125.3 ± 41.0%; n = 12; p < 0.001) whereas the effect of sildenafil (1E-5 M) was less pronounced (103.6 ± 20.2%; p < 0.05). Simultaneous administration of both substances showed a significantly greater reduction of maximum constriction in PA compared to individual administration (64.6 ± 26.3 %; p < 0.001). Sildenafil only at its highest concentration was effective in suppressing NE induced pulmonary vessel contraction. Bosentan was able to completely suppress ET-1 induced contraction of PA and strongly attenuated contraction of PV. The present data suggest a benefit of sildenafil/bosentan combination therapy as they affect different pathways and may allow lower dosages.

Recurrent Gastrointestinal Bleeding in a Patient with Eisenmenger Syndrome Using Bosentan

Eisenmenger syndrome is associated with irreversible increase in pulmonary vascular resistance causing reduced survival. Bosentan, a non-selective endothelin receptor antagonist is the commonly used specific pulmonary arterial hypertension drug in Eisenmenger syndrome. In this paper, we present a case of recurrent gastrointestinal bleeding in a 23-year-old female with Eisenmenger syndrome who was only under bosentan treatment, which has not been reported previously. Most common adverse effect of bosentan is elevation in the liver enzymes however, bleeding complication is very rare. On the contrary, it was proposed that bosentan might be a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress. Although the mechanistic relationship of bleeding tendency and role of Eisenmenger syndrome concomitant with bosentan treatment is far from conclusive statement for now, this association warrants and should draw attention of clinicians and researches in this field.

Effect of Bosentan on Exercise Capacity in Patients with Pulmonary Arterial Hypertension or Inoperable Chronic Thromboembolic Pulmonary Hypertension

Endothelin receptor antagonists (ERA) improve the prognosis of patients with pulmonary arterial hypertension (PAH). However, only limited data are available on the effect of treatment with the ERA bosentan on exercise capacity assessed with cardiopulmonary exercise testing (CPX) in patients with PAH or inoperable chronic thromboembolic pulmonary hypertension (CTEPH).