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Background and purpose: Eisenmenger syndrome (ES) is a rare condition caused by a right-to-left cyanotic shunt. To date, only heart-lung transplant has been shown to be curative. Bosentan is the only medication studied with a double-blind placebo-controlled randomized trial for management of this condition. The intent of this article is to explore the literature surrounding bosentan in ES and assess its efficacy. Methods: A literature review was conducted with no limitation on date. Titles were scanned for applicability, and abstracts of those articles found to be pertinent were reviewed. Those articles considered relevant based on the abstract were read in entirety. Conclusions: Eisenmenger syndrome remains incurable except through heart-lung transplant. Although no specific medical treatment or algorithm exists, three pharmacological classes show promise in disease management: endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclins. Combined therapy with these agents may improve cardiopulmonary function. Bosentan has not been proven as a monotherapy for ES and is not appropriate in all patients as side effects are commonly reported. Implications for practice: Further study is required to assess efficacy of combination therapy and utilization as a bridge to transplant or surgical correction of the underlying defect. [ABSTRACT FROM AUTHOR]

Background--The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results--Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL⋅kg-1⋅min-1 (from 28.7 to 30.7 mL⋅kg-1⋅min-1) in the bosentan group compared with 0.6 mL⋅kg-1⋅min-1 (from 28.4 to 29.0 mL⋅kg-1⋅min-1) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; F=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (F=0.0()85). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. Conclusions--Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration--URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551. [ABSTRACT FROM AUTHOR]

Endothelin (ET)-1 is implicated in the development of hypertension and a role for endothelin receptor antagonists (ETRAs) in the management of hypertension is emerging. ETRAs are classified as selective or mixed depending on their degree of ET(A):ET(B) receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ET(B) blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ET(A) selective ETRA, on plasma ET-1 concentrations and ET(B)-mediated vasodilatation to ET-3. In a randomized, double-blind, 3-way crossover study, 10 healthy subjects received 7 days of placebo, bosentan 250 mg, and sitaxsentan 100 mg daily. Plasma ET-1 concentrations were measured at baseline and 3 hours on day 1 and predose on day 7. Subjects also underwent forearm blood flow measurements on day 7 of each period with brachial artery infusion of ET-3 (60 pmol/min for 5 minutes). Bosentan, but not placebo or sitaxsentan, significantly increased plasma ET-1 concentrations at day 7 (+0.70+/-0.20 pg/mL; P<0.005). Maximal ET-3-mediated vasodilatation was seen at 2 minutes following placebo (30+/-6%) and sitaxsentan (21+/-11%); however, this was abolished by bosentan, with a reduction in forearm blood flow of 8+/-3% (P<0.01 versus placebo and sitaxsentan). Bosentan but not sitaxsentan increases circulating plasma ET-1 levels and abolishes acute ET-3-mediated vasodilatation, confirming that the mixed ET(A/B) antagonist bosentan, but not the selective ET(A) antagonist sitaxsentan, causes functional ET(B) blockade at clinically relevant doses in healthy human subjects. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary arterial hypertension is a disease involving small muscular pulmonary arteries and arterioles. Treatment with prostacyclin analogs and endothelin receptor antagonists is the cornerstone of therapy in these patients. Recent evidence suggests that phosphodiesterase-5 inhibitors such as sildenafil may improve functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Despite these advances, pulmonary arterial hypertension remains a deadly and progressive disease and it has been suggested that combination therapy aimed at multiple targets may produce a greater improvement while minimizing adverse effects. We report three patients who declined after initial improvement on bosentan and subsequently showed an improvement in their functional capacity and brain natriuretic peptide (BNP) with the addition of sildenafil. This benefit has been sustained over a mean follow-up period of 19 (range 12-24) months. [ABSTRACT FROM AUTHOR]

Shows the cellular complexity in acute renal failure (ARF) and the role that endothelin-1 (ET-1) plays in ARF. Vasoconstrictor role of ET-1 in ARF; ET-1 inflammation in ARF; ET-1 antagonists in ARF treatment.

Competing Interests: The authors declare no conflict of interest.

Background: Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed., Methods: PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis., Results: Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment., Conclusions: Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs.

Rationale: Sildenafil, a phosphodiesterase-5-inhibitor and Bosentan, an endothelin-1-receptor antagonist combined therapy could have beneficial effect in systemic sclerosis (SSc) patients with peripheral artery disease., Patient Concerns: We report a case of a 48-year-old Black woman, who developed severe left limb claudication and walking limitation following a left femoropopliteal bypass occlusion in 2014. She was a heavy smoker and had a history of right middle cerebral artery ischemic stroke and bilateral Raynaud phenomenon., Diagnoses: According to the American College of Rheumatology/European League Against Rheumatism-2013 criteria, diagnosis of limited cutaneous SSc was retained with macrovascular lesions. She was referred for investigation of left limb claudication on treadmill using transcutaneous oxygen pressure measurement during exercise to argue for the vascular origin of the walking impairment. She had a severe left limb ischemia and the maximum walking distance (MWD) she reached was 118 m in March 2015 despite the medical optimal treatment and walking rehabilitation., Interventions: Sildenafil, 20 mg tid, was introduced due to active digital ulcers. In July 2015, the MWD increased to 288 m, then to 452 m in December 2015. Adding Bosentan to Sildenafil to prevent recurrent digital ulcers resulted in an MWD of 1576 m., Outcomes: Recently, the patient is treated with the combined therapy. She has no more pain during walking and his quality of life has improved., Lessons: Sildenafil and Bosentan combined therapy was associated in our case with an improvement of MWD without adverse effect. Further clinical trials are necessary to confirm our original observation.

The cornerstone of therapy in thromboangiitis obliterans (TAO) is complete abstinence from tobacco. In addition to discontinuation of cigarette smoking, very few pharmacological and surgical options of controversial efficacy are available to date. New therapeutic options with greater efficacy are clearly needed to properly manage these patients.In this preliminary study, we assessed the effectiveness and safety of bosentan in a case series of 8 adults with TAO and severe ischemic ulceronecrotic lesions who were treated with bosentan after inadequate response to platelet inhibitors, vasodilators, and intravenous alprostadil. Additionally, we reviewed 18 well-documented patients with refractory TAO treated with bosentan, which was previously reported (PubMed 1965-2015). These 26 patients formed the basis of our present analysis. All were current smokers.The median duration of bosentan treatment (SD) was 4.5 ± 4 months (range 3-16). Eleven patients (42%) were unable to completely abstain from smoking during their follow-up. With bosentan treatment, no new ischemic lesions were observed in the target extremities. A complete therapeutic response was achieved in 80% of patients, whereas a partial response was observed in 12%. Two patients (8%) ultimately required amputation despite treatment.After discontinuation of bosentan, patients were followed for a median of 20 ± 14 months (range 3-60). Two patients whose trophic lesions had healed relapsed.When comparing patients who gave up smoking with those who were unable to completely abstain from smoking during follow-up, no significant differences were found in efficacy outcomes. Four patients (15%) developed adverse events, requiring bosentan discontinuation in 1 case.These preliminary data suggest that bosentan may be considered a therapeutic option for treatment of cases of severe TAO refractory to conventional treatment, and merit further evaluation in larger controlled, randomized clinical studies., Competing Interests: The authors have no conflicts of interest to disclose

A 49-year-old man diagnosed with genotype 1 hepatitis C, CD5-positive marginal zone lymphoma, and mixed cryoglobulinemia type II developed skin ulcers and necrosis in his right foot. He was treated with amlodipine, corticosteroids, plasmapheresis, alprostadil, rituximab, and cyclophosphamide without a satisfactory response. For this reason, he required a partial amputation of the second, third, and fifth fingers of the right foot. To prevent ulcer deterioration of the first finger, bosentan was initiated. After 10 months of treatment, the ulcer completely healed and no adverse effects were experienced by the patient.

Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling., Methods and Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue., Conclusions: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.

Background: There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug., Methods: Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration., Results: Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL)., Conclusions: We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

Background and Purpose: Endothelin is considered to be a key mediator of vasospasm after subarachnoid hemorrhage. A meta-analysis of randomized trials on the effectiveness of endothelin receptor antagonists in subarachnoid hemorrhage has been published previously, but since then new major trials have been published. We present the results of a systematic review and meta-analysis update., Methods: We searched the Cochrane Library, the Cochrane Central Register of Controlled Trials, and PubMed with the following terms: subarachnoid hemorrhage AND (endothelin receptor antagonist OR clazosentan OR TAK-044 OR bosentan). All randomized, placebo-controlled trials investigating the effect of any endothelin receptor antagonists in patients with subarachnoid hemorrhage were included. Primary outcome was poor functional outcome (defined as death or dependency). Secondary outcomes were vasospasm, cerebral infarction as defined by investigators, and case fatality during follow-up. Data were pooled and effect sizes were expressed as risk ratio (RR) estimates with 95% confidence intervals (CI). We also calculated RR for several common complications., Results: in 5 trials with 2601 patients, endothelin receptor antagonists did not affect functional outcome (RR, 1.06: 95% CI, 0.93-1.22) despite a decreased incidence of angiographic vasospasm (RR, 0.58; 95% CI, 0.48-0.71). No effect was observed on vasospasm-related cerebral infarction (RR, 0.76; 95% CI, 0.53-1.11), any new cerebral infarction (RR, 1.04; 95% CI, 0.91-1.19), or case-fatality (RR, 1.04; 95% CI, 0.78-1.39). Endothelin receptor antagonists increased the risk of lung complications (RR, 1.79; 95% CI, 1.52-2.11), pulmonary edema (RR, 2.12; 95% CI, 1.32-3.39), hypotension (RR, 2.42: 95% CI, 1.78-3.29), and anemia (RR, 1.47; 95% CI, 1.19-1.83)., Conclusion: These results argue against the use of endothelin receptor antagonists in patients with subarachnoid hemorrhage.

Purpose of Review: Since the late 1990 s, when a more uniform definition of idiopathic pulmonary fibrosis (IPF) was proposed, more than 3000 patients have been enrolled in clinical studies exploring novel therapies. Some of the most relevant trials have been published only recently., Recent Findings: This review describes and comments on the randomized clinical trials in IPF published within the past 18 months, with emphasis on the studies evaluating pirfenidone, which at present is the only drug approved for IPF (at least in Europe and Japan), and bosentan. This latter represents the largest single trial performed in IPF so far., Summary: Despite multiple clinical trials, there is no strong, definitive evidence in favor of any agent to treat IPF. On the other hand, the placebo arms of these large trials have provided us with important critical information on the natural history of this disease. Clinical heterogeneity represents a critical issue to be taken into account in designing future clinical trials. The limited effectiveness of current treatment regimes has fuelled the search for a variety of new therapeutic approaches.

2-Methoxyestradiol (2ME) is a major nonestrogenic metabolite of estradiol. Our previous studies suggest that 2ME, in several models of cardiac and/or vascular injury, strongly inhibits cardiac and vascular remodeling. Furthermore, our most recent study shows that in male rats, 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH), and in female rats, 2ME eliminates the exacerbation of PAH and the increased mortality due to ovariectomy. The current standard of care of patients with PAH includes treatment with an endothelin receptor antagonist (eg, bosentan) or a phosphodiesterase5 inhibitor (eg, sildenafil). Moreover, combination therapy is often prescribed. Therefore, in the present study, we compared the efficacy of 2ME (10 μg · kg(-1) · h(-1), 2ME-10) to the effects of bosentan (200 mg/kg; BOS), sildenafil (50 mg/kg; SIL), and their respective combinations with 2ME-10 (2ME + BOS and 2ME + SIL groups, respectively). Treatments were initiated 12 days after administration of MCT (60 mg/kg). Twenty-eight days after MCT administration, right ventricular peak systolic pressure was measured and morphometric analysis was conducted. 2ME exhibited beneficial effects in pulmonary hypertensive animals and had efficacy comparable to that of BOS and SIL. Importantly, combination treatments had favorable effects on survival, vascular remodeling, and inflammatory response, and the 2ME + SIL combination was significantly more efficacious than any other treatment. These results indicate that 2ME is effective in experimental PAH and suggests that 2ME may provide additional therapeutic benefit over existing drugs used for the treatment of pulmonary hypertension.

We utilized human vascular smooth muscle cells to address the question if a G-protein-coupled receptor, the endothelin (ET) receptor, could transactivate a serine/threonine kinase receptor, specifically the transforming growth factor (TGF)-[beta] receptor, T[beta]RI. Functionality of the interaction was addressed by studying endothelin-1-stimulated proteoglycan synthesis. Signaling molecules were assessed by Western blotting and proteoglycan synthesis by [35S]sulfate and 35S-met/cys incorporation and molecular size by SDS-PAGE. Endothelin-1 treatment led to a time- and concentration-dependent increase in cytosolic phosphoSmad2C, which was inhibited by the mixed endothelin receptor antagonist bosentan and the T[beta]RI antagonist SB431542. Endothelin-1 treatment led to a time-dependent increase in nuclear phosphoSmad2C. Endothelin-1-stimulated proteoglycan synthesis was partially inhibited (40%) by SB431542 and completely blocked by bosentan. The effect of endothelin-1 to stimulate an increase in glycosaminoglycan size on biglycan was also blocked in a concentration-dependent manner by SB431542. These data extend the current paradigm of G-protein coupled receptor signaling to include the transactivation of the serine kinase receptor for TGF-[beta] (T[beta]RI). This response should be considered in the context of response to endothelin-1, and the options for therapeutically targeting endothelin-1 are accordingly broadened to include downstream signaling otherwise associated with TGF-[beta] receptor activation.

Purpose of Review: We intend to update the data of various clinical features and management of sarcoidosis in the aged., Recent Findings: Subclinical or inapparent systemic involvement of sarcoidosis was found at autopsy in elderly patients who died from sarcoidosis, complication of malignancy, or cerebrovascular accidents. Sarcoidosis in the aged presents with unusual intrathoracic and extrapulmonary clinical features. Occasionally, these features may masquerade as malignancy. Sarcoidosis may appear or reactivate in patients receiving treatment with tumor necrosis factor antagonists or antiviral treatment. In elderly patients, antitumour necrosis factor treatment is effective for refractory sarcoidosis, methylphenidate hydrochloride for fatigue, and bosentan for sarcoidosis-associated pulmonary hypertension. Inhaled prostacyclin has been found to be effective in some patients with pulmonary hypertension. Sarcoidosis and malignancy can coexist., Summary: Autopsy studies revealed that both apparent and subclinical or inapparent systemic involvement of sarcoidosis might exist in aged patients with sarcoidosis. Aged sarcoidosis patients often present with unusual clinical features of sarcoidosis. Occasionally, these features resemble malignancy. New treatment with tumor necrosis factor antagonists for intractable sarcoidosis, methylphenidate hydrochloride for fatigue, and bosentan for sarcoidosis-associated pulmonary hypertension may be effective in sarcoidosis in the aged. Sarcoidosis and malignancy may coexist.

Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly affects treatment and prognosis. The most commonly affected CTD is scleroderma, although lupus, inflammatory myopathies such as poly and dermatomyositis, and mixed CTD are also associated with PAH. The manifestations of PAH have both similarities and differences when occurring in the setting of CTD as compared with idiopathic PAH. These differences are most notable in scleroderma. In this section we will discuss the features of PAH as they appear in CTDs, and in particular, scleroderma. The focus of this article is an approach to the diagnosis and treatment of PAH in CTD, and how this setting might differ from idiopathic and other forms of PAH.

Purpose of Review: Literature about thoracic surgery in patients with pulmonary hypertension is scarce. Perceived high risk has appropriately discouraged any unnecessary operation. However, the medical therapy for pulmonary hypertension has made great advances during the last decade. It is likely that future advances in survival and possibly the need for diagnostic procedures will increase the anesthesiologist's exposure to such patients. Understanding the unique physiology as well as new therapeutic agents will facilitate safe care for these challenging patients., Recent Findings: Since 1998, there have been three World Heath Organization symposiums on pulmonary hypertension. The most recent meeting in 2008 at Dana Point included revisions of the classification scheme and updates on new trials and therapies. New drugs have been utilized in cardiac, lung, or liver transplant operations to treat pulmonary hypertension. It is also recognized that one-lung ventilation presents unique problems for the patient with pulmonary hypertension. Inhalation use of the new pulmonary vasodilator drugs represents a new frontier for intraoperative pharmacology., Summary: Here, the various types of pulmonary hypertension, physiologic changes, and new drug therapies are reviewed. Clinical experience with patients with pulmonary hypertension undergoing both nonthoracic and thoracic procedures is also reviewed. By identifying potential problem areas and application of new pharmacology, an approach to the patient with pulmonary hypertension is synthesized.

Background: Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway., Methods and Results: In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing., Conclusions: In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

Reduced cardiac output is one of the consequences of myocarditis. Bosentan, an endothelin-1 receptor (ET1R) antagonist, could be useful to reduce cardiac afterload, preserving cardiac output. In this study, we investigated the potential therapeutic use of bosentan in an animal model of viral myocarditis. Using a mouse model of coxsackievirus B3 (CVB3)-induced myocarditis, we demonstrated preserved ejection fraction (EF) and fractional shortening (FS) by treatment with bosentan (68+/-5.8% EF and 40+/-3.7% FS for treated versus 48+/-2.2% EF and 25+/-2.6% FS for controls; P=0.028). However, bosentan enhanced cardiac viral load (10.4+/-6.7% in the bosentan group versus 5.0+/-5.5% in control group; P=0.02), likely through enhancement of p38 mitogen-activated protein kinase (MAPK) phosphorylation (0.77+/-0.40% ATF2 activation in the bosentan group versus 0.03+/-0.02% in controls; P=0.0002), mediated by endothelin receptor type-A. We further demonstrate that a water soluble inhibitor of p38 MAPK, SB203580 HCl, is a potent inhibitor of virus replication in the heart (0.28% antisense viral genome stained area for 3 mg/kg dose versus 2.9% stained area for controls; P=0.01), attenuates CVB3-induced myocardial damage (blinded cardiac histopathologic scores of 1.8+/-1.6 and 2.05+/-1.2 for the 3 mg/kg and 10 mg/kg doses, respectively, versus 3.25+/-1.2 for the controls), and preserves cardiac function (69+/-3.5% EF for 3 mg/kg dose and 71+/-6.7% EF for 10 mg/kg dose versus 60+/-1.5% EF control; P=0.038 and P=0.045, as compared to control, respectively). Bosentan, a prescribed vasodilator, improves cardiac function but enhances viral load and myocarditis severity through ETRA mediated p38 MAPK activation; p38 MAPK is a desirable antiviral target. Caution must be exercised during treatment of suspected infectious myocarditis with supportive vasoactive remedies.

Pulmonary arterial hypertension (PAH) is a progressive albeit rare long-term complication of HIV infection, which has gained importance following the improved survival of HIV-infected patients with the use of HAART. The clinical and pathological findings in PAH associated with HIV infection (HIV-PAH) share many features with the idiopathic form of the disease. HIV-PAH is associated with a particularly poor prognosis and decreased survival compared with HIV-infected patients without this complication, and patients with HIV-PAH tend to die from the effects of PAH rather than as a result of their HIV infection. Prompt diagnosis and effective treatment of PAH in HIV-infected patients is therefore essential. There are currently only limited data regarding the efficacy of PAH therapies in HIV-PAH. Treatment with epoprostenol has been reported to provide benefit in some cases, but is associated with a range of problems linked to the need for continuous intravenous infusion. The dual endothelin receptor antagonist bosentan has proved to be effective in HIV-PAH without affecting the control of HIV infection, and has the benefit of oral administration. Other PAH therapies including prostacyclin analogs, phosphodiesterase type 5 inhibitors and selective endothelin receptor antagonists have yet to be trialed in this setting. Taking into account currently available data and clinical experience, a treatment algorithm for HIV-PAH based on that defined in treatment guidelines for other forms of PAH is suggested.

Sepsis causes changes in vascular resistance and hypovolemia. Previous studies have demonstrated that the spleen regulates blood volume via atrial natiuretic peptide (ANP). We hypothesized that LPS alters extrasplenic responses to ANP via endothelial-dependent mechanisms and studied the role of NO and endothelin 1 (ET-1). Isolated extrasplenic arteries and veins (vessels in mesentery adjoining spleen) were obtained from male Wistar rats weighing 200 to 280 g (n = 102) and mounted on a pressure myograph to determine intraluminal diameter for 4 h. Isolated vessels constricted in response to the half-maximum response of ANP (veins, 30% +/- 1.7%; arteries, 34.5 +/- 1.7%; P < 0.05), and this was abolished by the NO donor S-nitroso-N-acetylpenicillamine (SNAP 75 microM). Arteries and veins incubated with LPS (50 microg mL(-1) for 4 h) were unresponsive to ANP, and constriction was not restored by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 100 microM). However, venular constriction returned in the presence of the ET-1 antagonist Bosentan, increasing from -1.5 +/- 1.2 (10 min) to -10 +/- 2.5% (4 h) with LPS + Bosentan (3 x 10(-6) M) compared with -2.3 +/- 1.2 and 0% with LPS alone. In conclusion, LPS abolished endothelial-dependent extrasplenic venular constriction to ANP partially due to increased ET-1, whereas NO seemed to modulate vascular responses to ANP.

Pulmonary arterial hypertension represents an absolute contraindication for heart transplantation. We report the case of a 30-year-old man with end-stage heart failure due to restrictive cardiomyopathy and pulmonary arterial hypertension. A complex multidrug therapy improved pulmonary haemodynamics to the point that orthotopic heart transplantation could be carried out. At 18-month follow-up after heart transplantation, the patient's cardiac function made a full recovery. Larger prospective studies are warranted to support these results.

Background: The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude-associated hypoxia., Methods and Results: In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21+/-7 versus 31+/-7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100+/-200 versus 1610+/-590 mL; -6.7+/-3.5 versus -1.8+/-4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration., Conclusions: The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

Background: Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone and pathological states such as ischemia/reperfusion (I/R) injury, coronary vasospasm, and cardiac allograft vasculopathy. We assessed the effects of elevated ET-1 levels as seen after I/R to determine if ET-1 modulates nitric oxide (NO) production via the translocation of specific protein kinase C (PKC) isoforms., Methods and Results: Human saphenous vein endothelial cells (HSVECs) (n=8) were incubated with ET-1 or phosphate-buffered saline (PBS) for 24 hours. NO production was determined in the supernatant by measuring nitrate/nitrite levels. Protein expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), caveolin-1 and PKC were determined. Lastly, PKC translocation and activity were assessed after exposure to the drug of interest. HSVECs exposed to ET-1 displayed decreased NO production. PKC inhibition reduced NO production, whereas PKC activation increased production. NO production was maintained when HSVECs exposed to ET-1 were treated with the PKC agonist, PMA. eNOS protein expression was reduced after ET-1 treatment. PKC inhibition also downregulated eNOS protein expression, whereas PMA upregulated expression. ET-1 exposure led to a significant increase in PKCdelta and PKCalpha translocation compared with control, whereas translocation of PKClambda was inhibited. ET-1 exposure significantly reduced overall PKC activity compared with control., Conclusions: Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. ET-1 antagonism with bosentan stimulates translocation of PKClambda and leads to increased PKC activity and NO production. ET-1 antagonism may provide a novel therapeutic strategy to improve vascular homeostasis.

Background: Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia., Methods and Results: The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, -0.7 to 2.8), demonstrating that bosentan did not worsen oxygen saturation. Compared with placebo, bosentan reduced pulmonary vascular resistance index (-472.0 dyne.s.cm(-5); P=0.0383). The mean pulmonary arterial pressure decreased (-5.5 mm Hg; P=0.0363), and the exercise capacity increased (53.1 m; P=0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the bosentan group and 2 (12%) in the placebo group., Conclusions: In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.

The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3+/-1.8, CION 32.4+/-5.3s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET(A) (atrasentan, 3-10 mg/kg) or ET(B) (A-192621, 5-20 mg/kg) receptors caused significant inhibitions lasting 1-2.5h (peaks approximately 65-90%). Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Endothelin-1 (ET-1) receptor antagonists increase plasma immunoreactive ET-1 levels. However, their effect on preproendothelin-1 (PPE-1) mRNA levels is still controversial. Few studies have found a decrease in PPE-1 mRNA levels in endothelial cells treated with the nonselective ETA/B receptor antagonist, and others demonstrated that an ETB blockade by the selective antagonist BQ788 increases PPE-1 mRNA levels. We studied the effect of ETA and ETB selective receptor antagonists on PPE-1 transcription, both in vitro and in vivo. Endothelial cells, transiently transfected with PPE-1 luciferase plasmid, were treated with ET-1 receptor antagonists. Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control. In contrast, the ETA receptor antagonist, BQ123, had no effect on luciferase activity. Transgenic mice that express the luciferase gene under the control of PPE-1 promoter were treated with Bosentan. Luciferase activity, PPE-1 mRNA levels, and plasma immunoreactive ET-1 levels were increased by 1.6-fold to 2.0-fold in the Bosentan-treated group compared with the untreated, control group. ET-1 receptor blockade increased PPE-1 transcription both in vitro and in vivo. The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription.

Endothelin-1 (ET-1) has been shown to regulate the expression of various genes in addition to its vasoconstrictor role in the liver. Elevated levels of ET-1 during cirrhosis play an important role in the observed microcirculatory dysfunction; however, its role as a transcription regulator remains unclear. This study aimed to determine the role of ET-1 in the hepatic gene expression of vasomediators after cirrhosis in response to LPS. Cirrhosis was induced by bile duct ligation (BDL) for 1 or 3 weeks in male Sprague-Dawley rats. Following 1 or 3 weeks of BDL or sham operation (sham), rats received an intravenous (i.v.) injection of bosentan, a dual-selective ETA/B receptor antagonist (30 mg/kg bw) or saline, and an intraperitoneal (i.p.) injection of LPS (1 mg/kg bw). Plasma alanine aminotransferase (ALT) levels were significantly elevated in 1- and 3-week BDL animals. Six hours following LPS, the elevated ALT levels were markedly exacerbated in 3-week BDL animals, which were significantly ameliorated with bosentan treatment. LPS resulted in increased ET-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 mRNA expressions in both sham and BDL rats. Bosentan significantly inhibited the up-regulations of ET-1, iNOS, and COX-2 mRNA. Our data strongly suggest that ET-1 plays an important role in up-regulating the expression of iNOS, COX-2, and ET-1 itself in hepatic tissue following LPS challenge, which may contribute to the observed hepatocellular injury during endotoxemia in cirrhosis. Thus, due to significant increases in ET-1 levels during cirrhosis, ET-1 receptor blockade may prove to be of great therapeutic value in the treatment of cirrhotic patients exposed to secondary injuries such as endotoxemia.

Pulmonary arterial hypertension (PAH) is a term used to classify a variety of conditions that share in common an injury to the pulmonary vasculature that produces elevations in pulmonary arterial pressure. However, it is the integrity of right ventricular function, rather than the degree of vascular injury, that is the major determinant of symptoms and survival in PAH. The article will review the normal structure and function of the right ventricle and summarize the impact of PAH and its treatments on right ventricular function.

The binding affinities of YM598, a novel endothelin-A (ETA) receptor antagonist, for native human ETA receptors expressed in human coronary artery smooth muscle cells and endothelin-B (ETB) subtypes in the human melanoma cell line SKMel- 28 were compared with those of atrasentan and bosentan. The in vivo ETA receptor antagonist activities of YM598 and atrasentan were also evaluated in pithed rats. The inhibitory dissociation constant values of YM598, atrasentan and bosentan were 0.772, 0.0551 and 4.75 nM, respectively, for native human ETA receptors, and 143, 4.80 and 40.9 nM, respectively, for native human ETB subtypes. The calculated selectivity ratios of YM598, atrasentan and bosentan for ETA versus ETB receptors were 222, 136 and 13.0, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner, after both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but those of both agents were comparable when orally administered. These results suggest that YM598 has a high selectivity for native human ETA receptors against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist, with regard to pharmacological bioavailability in rats.

The aim of the present study was to investigate the putative role of endothelin (ET) in mediating ischemia/hypoxia-induced ANP release utilizing exogenous ET-1 or ET receptor antagonists (BQ-123 or Bosentan). Isolated rat hearts with non-distended atria were perfused using a Langendorff apparatus and heart rate maintained constant via atrial pacing. Global ischemia was induced either by direct reduction in perfusion or by infusion of exogenous ET-1 (5 x 10(-10) M) for 30 minutes. Perfusion with the ET receptor antagonists, BQ-123 (10(-6) M) or Bosentan (10(-5) M) was initiated 10 minutes before onset of ischemia. Moderate or severe ischemia was induced by reduction (52-61% and 70-82%, respectively) in perfusate flow. Thirty minutes of ischemia/hypoxia (5% O2) was followed by 30 minutes of reperfusion/re-oxygenation. Both moderate and severe ischemia increased ANP release. BQ-123 and Bosentan did not affect basal or ischemia-induced ANP release. Exogenous ET-1 perfusion induced a late increase in ANP release (P < 0.01) that did not exceed the increase in ANP release associated with equivalent direct flow reduction. Hypoxia induced an 8-fold increase in ANP release rate. The ANP release rate returned toward basal levels after re-oxygenation. Bosentan, but not BQ-123, significantly attenuated (P < 0.01) hypoxia-induced ANP release. In conclusion, in this system, ANP release is stimulated by moderate (or severe) ischemia and severe hypoxia independent of change in atrial distension; endogenous ET does not mediate basal and ischemia-induced ANP release; and hypoxia-induced ANP release is partially modulated via interaction with endogenous ET.

The mechanisms of coronary artery dysfunction in coxsackievirus B3 (CVB3)-mediated viral myocarditis are poorly understood. We used pressure myography of mouse septal coronary arteries to determine the early and late effects of CVB3 infection on vascular function. Male CD-1 mice (age 6-7 weeks) were infected with CVB3 (1.75 x 10(10) pfu, i.p.). Control mice were injected with PBS. Mice were killed at 3, 7, and 42 days post infection, and the ventricular septal artery was dissected and mounted on a pressure myograph. Pressure-induced myogenic tone was similar in CVB3-infected and sham-infected mice at 3 and 7 days post infection. However, at 42 days post infection constriction of septal arteries to pressures equal to or less than 60 mm Hg was enhanced in CVB3-infected mice compared with sham controls. Agonist-induced vasodilation, as assessed by response to acetylcholine (1 nM-3 microM), was unaltered at early time points (days 3 and 7) in CVB3-infected mice. At later time points (day 42), there was a significant decrease in ACh-induced vasodilation in CVB3-infected mice. Bosentan, an ET-1 (ETA and ETB) receptor antagonist, did not completely ameliorate the reduced ACh-induced vasodilation in 42-day infected mice, indicating that ET-1 does not contribute to vascular dysfunction. Smooth muscle function, as measured by constriction to KCl or dilation to sodium nitroprusside, was unchanged in infected mice at early and late time points. Immunohistochemistry and ET-1 immunoassay were then performed to assess ET-1 levels in CVB3- and sham-infected hearts. There were no differences in ET-1 protein localization or levels at 42 days post infection in sham- and CVB3-infected animals. Finally, in situ hybridization and TUNEL staining were performed to assess viral localization and cell death in CVB3-infected hearts. There was no detectable CVB3 or TUNEL positivity in the endothelium of coronary arteries. Therefore, late impairment of endothelial-dependent vasorelaxation of coronary resistance vessels in CVB3-induced myocarditis does not appear to involve altered ET-1 expression but may be secondary to decreased stimulated NO secretion by the endothelium.

Recent studies indicate that cardiac T-type Ca2+ current (ICaT) reappears in hypertrophied ventricular cells. The aim of this study was to investigate the role of angiotensin II (Ang II), a major inducer of cardiac hypertrophy, in the reexpression of T-type channel in left ventricular hypertrophied myocytes. We induced cardiac hypertrophy in rats by abdominal aorta stenosis for 12 weeks and thereafter animals were treated for 2 weeks with losartan (12 mg/kg per day), an antagonist of type 1 Ang II receptors (AT1). In hypertrophied myocytes, we showed that the reexpressed ICaT is generated by the CaV3.1 and CaV3.2 subunits. After losartan treatment, ICaT density decreased from 0.40+/-0.05 pA/pF (n=26) to 0.20+/-0.03 pA/pF (n=27, P<0.01), affecting CaV3.1- and CaV3.2-related currents. The amount of CaV3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of CaV3.2 mRNA was unaffected by stenosis. In cultured newborn ventricular cells, chronic Ang II application (0.1 micromol/L) also increased ICaT density and CaV3.1 mRNA amount. UO126, a mitogen-activated protein kinase kinase-1/2 (MEK1/2) inhibitor, reduced Ang II-increased ICaT density and CaV3.1 mRNA amount. Bosentan, an endothelin (ET) receptor antagonist, reduced Ang II-increased ICaT density without affecting the amount of CaV3.1 mRNA. Finally, cotreatment with bosentan and UO126 abolished the Ang II-increased ICaT density. Our results show that AT1-activated MEK pathway and autocrine ET-activated independent MEK pathway upregulate T-type channel expression. Ang II-increased of ICaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca2+ overload and arrhythmias seen in cardiac pathology.