Endothelin Antagonists Research Articles

Cerebral Vasospasm: A Review.

Cerebral vasospasm is a prolonged but reversible narrowing of cerebral arteries beginning days after subarachnoid hemorrhage. Progression to cerebral ischemia is tied mostly to vasospasm severity, and its pathogenesis lies in artery encasement by blood clot, although the complex interactions between hematoma and surrounding structures are not fully understood. The delayed onset of vasospasm provides a potential opportunity for its prevention. It is disappointing that recent randomized, controlled trials did not demonstrate that the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate improve patient outcome. Minimizing ischemia by avoiding inadequate blood volume and pressure, administering the calcium antagonist nimodipine, and intervention with balloon angioplasty, when necessary, constitutes current best management. Over the past two decades, our ability to manage vasospasm has led to a significant decline in patient morbidity and mortality from vasospasm, yet it still remains an important determinant of outcome after aneurysm rupture.

Efficacy of inhaled iloprost on top of other targeted therapies for patients with pulmonary hypertension and severe right heart failure

To investigate the efficacy and safety of inhaled iloprost on top of other pulmonary hypertension (PH) specific therapies for patients with PH and severe right heart failure. We consecutively enrolled WHO functional class IV patients with PH and chronic thromboembolic pulmonary hypertension (CTEPH) in Shanghai Pulmonary Hospital from January 2011 to January 2013. Inhaled iloprost was administrated to all enrolled patients, oral endothelin antagonist receptors (ERAs) and/or type 5 phosphodiasterase inhibitors (PDE5-I) were also used as basis therapies. The in-hospital outcomes and the changes of right heart functional parameters were observed. Twenty-four patients with PH and 5 patients with CTEPH were enrolled. After a mean treatment duration of (23 ± 13) days, 3 patients dead and significant improvement was observed in the remaining 26 patients. Compared with the baseline, heart rate decreased from (99 ± 14) to (91 ± 12) bpm (P = 0.001), plasma NT-proBNP level decreased from 5 823 (3 029-13 248) to 3 220 (1 678-6 720) ng/L (P < 0.001), tricuspid annular plane systolic excursion (TAPSE) increased from (1.3 ± 0.4) to (1.4 ± 0.3) cm (P = 0.018), right ventricular diameter decreased (left-to-right diameter from (57 ± 11) to (53 ± 10) mm, P = 0.040, and superoinferior diameter from (69 ± 11) to (64 ± 16) mm, P = 0.027), Tbil also decreased from (41 ± 34) to (26 ± 17) µmol/L (P < 0.001). No severe side effects were observed. The strategy of inhaled iloprost on top of other PAH-specific target therapy medications is effective and safe for PH patients with severe right heart failure.

Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases.

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11β-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.

Angiotensin 2 Type 1 Receptor Blockade with Neprilysin Inhibition for Chronic Heart Failure: A New Paradigm?

A new treatment for heart failure (HF) combining angiotensin 2 type 1 receptor blockade with inhibition of the widespread membrane-bound enzyme, neprilysin (NEP), seems likely to take treatment of chronic heart failure (CHF) a major step forward. Neurohormonal pathways are central to the evolution and progression of HF irrespective of the exact initial triggering cardiac injury or overload, and our current evidence-based treatments for this condition depend upon antagonism of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous (SNS) systems through prescription of angiotensin converting enzyme inhibitors (ACEIs), angiotensin 2 type 1 receptor blockers (ARBs), mineralocorticoid antagonists (MRAs) and blockers of beta-adrenoceptors (beta blockers). Properly deployed, these therapies reduce 1-year mortality to less than half than that suffered by patients with HF in the pre-1980s era. 1,2 However, despite this clear impact upon the outcome of this deadly syndrome, 5-year mortality in CHF remains greater than 50%. This poor outlook plus the continuing high prevalence of HF mandates an ongoing search for more effective treatments. 3 The therapeutic advances outlined above were established by the turn of the 21st century and until now, trials of new neurohormonal interventions over the last 15 years have been largely disappointing. Examples include therapeutic trials, all based on impeccable rationales and supported by encouraging preclinical data and positive phase 1 and 2 clinical data of endothelin 1 antagonists, arginine vasopressin blockers and direct renin inhibitors. 4-6 When subjected to the test of full phase 3 randomised controlled clinical trials, none of these approaches has proven to reduce cardiovascular or all-cause mortality in HF, although some secondary end-points such as readmission with recurrent, acute decompensated HF may show a benefi cial trend and useful niche applications have developed such as the use of endothelin antagonists in pulmonary hypertension and of AVP blockers in accelerating correction of hyponatraemia complicating HF. In the 1990s, an effort was made to add enhancement of benefi cial endogenous adaptive responses

Current Concepts in Management of Pulmonary Hypertension: Fighting the Old Demon with Modern Weapons.

Pulmonary hypertension in children is a rare disease associated with high morbidity and mortality. The pathogenesis is not fully understood. Diagnostic evaluation focuses on ruling out other etiologies of pulmonary hypertension and prognosticating the disease. Congenital heart disease and left sided heart disease associated pulmonary hypertension are more common in children. Therapies for idiopathic pulmonary hypertension have evolved over the past decade. Phosphodiesterase 5 inhibitors (sildenafil, tadalafil), endothelin antagonists (Bosentan and ambrisentan) and prostanoids are the classes of drugs shown to be useful in pulmonary hypertension. However, use of these drugs in children is based on extrapolation of adult usage and on expert consensus rather than based on randomized controlled trial evidence. Despite these advances, the outcomes of various forms of pulmonary hypertension remain poor, especially in India, where some forms of therapy are not available and children often are diagnosed at an advanced stage of disease.

The UK National Pulmonary Hypertension Service, Registry and Research Collaboration.

[first paragraph of article] The advent of targeted therapies for idiopathic pulmonary hypertension, with an initial focus on prostaglandins and endothelin antagonists, mandated the planning and development of a service that could evaluate and manage patients with this orphan disease in the United Kingdom (UK). Accordingly, a small group of interested physicians met to debate the model of service delivery that was best suited to the UK and its National Health Service (NHS) at the Royal College of Physicians in London. There was a uniform view, given the rarity of the disorder, its complexity and the anticipated cost of therapy to the NHS, that a model of a limited number of specialist centres working in a collaborative way would offer best value and quality care for patients.

A systematic review of pharmacological treatment options used to reduce ischemia reperfusion injury in rat liver transplantation.

BackgroundAlthough animal studies models are frequently used for the purpose of attenuating ischemia reperfusion injury (IRI) in liver transplantation (LT), many of pharmacological agents have not become part of clinical routine.MethodsA search was performed using the PubMed database to identify agents, from which 58 articles containing 2700 rat LT procedures were selected. The identified pharmacological agents were categorized as follows: I - adenosine agonists, nitric oxide agonists, endothelin antagonists, and prostaglandins, II – Kupffer cell inactivator, III - complement inhibiter, IV - antioxidant, V - neutrophil inactivator, VI -anti-apoptosis agent, VII - heat shock protein and nuclear factor kappa B inducer, VIII - metabolic agent, IX - traditional Chinese medicine, and X - others. Meta-analysis using 7-day-survival rate was also performed with Mantel-Haenszel's Random effects model.ResultsThe categorization revealed that the rate of donor-treated experiments in each group was highest for agents from Group II (70%) and VII (71%), whereas it was higher for agents from Group V (83%) in the recipient-treated experiments. Furthermore, 90% of the experiments with agents in Group II provided 7-day-survival benefits. The Risk Ratio (RR) of the meta-analysis was 2.43 [95% CI: 1.88-3.14] with moderate heterogeneity. However, the RR of each of the studies was too model-dependent to be used in the search for the most promising pharmacological agent.ConclusionWith regard to hepatic IRI pathology, the categorization of agents of interest would be a first step in designing suitable multifactorial and pleiotropic approaches to develop pharmacological strategies.

Defining, Treating, and Understanding Chronic Kidney Disease--A Complex Disorder.

Chronic kidney disease (CKD) is prevalent in more than 20 million people in the United States. The majority of care provided to patients with this disease comes from primary care physicians, although it is often poorly understood. After an extensive literature review, it is clear that it can be difficult to classify and there are many barriers to care. Risk factors for both incident CKD and disease progression include hypertension, poor glycemic control, sociodemographic factors, acute kidney injury, metabolic acidosis, and possibly hyperuricemia and dietary factors. Treatment of patients with CKD should focus on mitigating risk factors, as well as common comorbidities such as cardiovascular disease, anemia, and bone mineral disease. Novel therapies such as pirfenidone, pentoxifylline, and endothelin-1 antagonists are being investigated with promising results.

Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions.

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator‐activated receptor‐gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke.

Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity

A series of phenoxybutanoic acid derivatives were synthesized and tested for their antagonistic activity on the contraction of the rat thoracic aortic ring induced by endothelin-1. Preliminary screening results showed that 6e and 6g with benzoheterocycles demonstrated significant antagonistic activities when compared to the reference compound BQ123. The results from additional assays for the binding affinity and selectivity for endothelin receptors showed that 6e was a selective ETA antagonist with a nanomolar IC50. Moreover, 6e was effective in relieving hypoxia-induced pulmonary arterial hypertension and right ventricular weight ratio. Therefore, 6e may have potential for further development as a therapeutic agent for the treatment of cardiovascular diseases.

Number and frequency of albuminuria measurements in clinical trials in diabetic nephropathy.

Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits. This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements. Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone. Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Preventive role of endothelin antagonist on kidney ischemia: Reperfusion injury in male and female rats

Background:Renal ischemia/reperfusion injury (RIRI) is the most common cause of acute kidney injury. We tested the protective role of endothelin-1 receptor blocker; bosentan (BOS) in animal model of RIRI in two different genders.Methods:Male and female Wistar rats were assigned as sham operated (sham), control group (ischemia), and case group (ischemia + BOS) treated with BOS (50 mg/kg) 2 h before bilateral kidney ischemia induced by clamping renal vessels for 45 min followed by 24 h of renal reperfusion.Results:The RIRI significantly increased the serum levels of blood urea nitrogen and creatinine in both genders (P < 0.05). These values were significantly decreased by BOS in both genders. In male rats, the serum levels of malondialdehyde in the ischemia + BOS group were decreased significantly when compared with ischemia group (P < 0.05).Conclusions:BOS can be used in both genders to attenuate kidney ischemia injury possibly due to its effect in the renal vascular system.

Role of endothelin-1 antagonist; bosentan, against cisplatin-induced nephrotoxicity in male and female rats

Background:Cisplatin (CP) is a chemotherapy drug, with the major side effect of nephrotoxicity. The level of endothelin-1 (ET-1) increases during nephrotoxicity, which is accompanied with vasoconstrictive properties. Bosentan (BOS) is a nonselective ET-1 receptor antagonist, having vasodilatory and anti-hypertension effects. The purpose of this study was to investigate the renoprotective effect of BOS against CP-induced nephrotoxicity in male and female rats.Materials and Methods:Male and female rats were divided into six groups; groups 1–3 and 4–6 were male and female rats, respectively. Animals in groups 1 and 4 were considered as negative control and groups 2 and 5 considered as positive control groups received BOS (30 mg/kg/day) alone and CP (2.5 mg/kg/day) alone, respectively, for 1-week. The animals in groups 3 and 6 were treated with both CP and BOS. Finally, serum parameters were measured, and the kidney tissue was subjected to staining to evaluate tissue damage.Results:The serum levels of blood urea nitrogen and creatinine, kidney tissue damage score and kidney weight elevated, and body weight significantly decreased in both CP alone and in CP plus BOS-treated groups when compared with the control groups (P < 0.05), while BOS did not ameliorate these parameters neither in males nor in females. No significant differences were observed in serum levels of nitrite and malondialdehyde between the groups, but kidney tissue level of nitrite decreased significantly in CP alone and CP plus BOS-treated groups (P < 0.05).Conclusion:Renoprotective effect of BOS, as ET-1 blocker, was not observed against CP-induced nephrotoxicity neither in male nor in female rats. This is while BOS promoted the severity of injuries in females.

Aspects of the endothelin system in colorectal cancer

Endothelin system members including endothelin-1, endothelin-2, endothelin-3, endothelin receptors, and endothelin converting enzyme are considered major regulating factors in cancer cell biology and cancer microenvironment. Endothelins are members of the matrix metalloproteinase superfamily of proteases, which are released from pre-proteins, bind to their receptors with differential affinity, and are degraded following cellular uptake. For their structural similarity, endothelin-2 and endothelin-3 can be regarded as natural competitors for the endothelin-1 receptors and as natural antagonists of endothelin-1. Endothelin-1 is regulated at several levels, primarily at the level of transcription. Remarkably, endothelin-1 is overexpressed in colorectal cancer, and elevated plasma levels were found in colorectal cancer patients. Endothelin receptor type A has an unequal distribution in the colon, as it is over-expressed in the proximal and distal segments of the colon. Compared with normal mucosal tissue, there is high expression of endothelin receptor type A and low expression of endothelin receptor type B in colorectal cancer at all Dukes stages. By binding to endothelin receptor type A, endothelin-1 leads to down-regulation of epithelial and increased expression of mesenchymal markers. Also, endothelin-1 acts as anti-apoptotic factor through multiple pathways like PI3K-dependent AKT activation or NF-κB signaling. Members of the endothelin system might be used as cancer biomarker and from a therapeutic point of view, targeting the endothelin axis is a promising aim. In effect, potential drugs may include endothelin converting enzyme inhibitors as well as selective and non-selective antagonists of endothelin receptor types A and B. Biomedical Reviews 2014; 25: 1-13.

Obligatory role of intraluminal O2- in acute endothelin-1 and angiotensin II signaling to mediate endothelial dysfunction and MAPK activation in guinea-pig hearts.

We hypothesized that, due to a cross-talk between cytoplasmic O2−-sources and intraluminally expressed xanthine oxidase (XO), intraluminal O2− is instrumental in mediating intraluminal (endothelial dysfunction) and cytosolic (p38 and ERK1/2 MAPKs phosphorylation) manifestations of vascular oxidative stress induced by endothelin-1 (ET-1) and angiotensin II (AT-II). Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2−. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2−, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II + tezosentan) triggered intraluminal O2−, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox) and XO activation. These effects were: (i) prevented by blocking PKC (chelerythrine), Nox (apocynin), mitochondrial ATP-dependent K+ channel (5-HD), complex II (TTFA), and XO (allopurinol); (ii) mimicked by the activation of Nox (NADH); and mitochondria (diazoxide, 3-NPA) and (iii) the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2− (SOD) and XO, and were mimicked by XO activation (hypoxanthine). Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2−.

Abstract 3779: Treatment of experimental brain metastasis of human breast cancer by macitentan, a dual antagonist of endothelin receptors combined with paclitaxel

Abstract Purpose: Breast cancer is a leading cause of cancer-related mortality among women in the United States. The major cause of death is due to metastasis that is resistant to conventional therapy. The median survival of women with brain metastases is measured in months due to resistance to all standard therapies. Thus, the development of effective treatment options for these patients is mandatory. We have reported that astrocytes can protect tumor cells from chemotherapeutic drugs by a mechanism involving the phosphorylation of endothelin receptors on tumor cells (Kim et al, AACR, 2012). Moreover, we observed a heterogeneous expression of endothelin receptors A and B in clinical samples of breast cancer brain metastasis. We therefore examined whether blockade of the endothelin axis by using macitentan, a dual endothelin antagonist, combined with paclitaxel can produce therapeutic effects in an orthotopic model of human breast cancer brain metastasis. Materials and Methods: Twenty thousand MDA-MB-231 human breast cancer cells were injected into the internal carotid artery of female nude mice to produce orthotopic brain metastasis. Two weeks later, the mice were randomized into 4 groups (n=10): (1) control group - mice receiving vehicle (p.o., daily; i.p. injection once per week); (2) paclitaxel group - mice receiving paclitaxel (8 mg/kg; i.p. injection once per week) and vehicle (p.o.; daily); (3) macitentan group - mice receiving macitentan (10 mg/kg; p.o.; daily) and vehicle (i.p. injection, once per week); and (4) paclitaxel plus macitentan group. Moribund mice were euthanized, days of survival were recorded, and the brains were harvested and processed for histology and immunohistochemical analyses. The study was repeated with luciferase-labeled MDA-MB-231 cells and produced similar therapeutic results supported by IVIS imaging. Results: After 130-140 days of treatment, the survival was significantly higher in mice treated with the combination of paclitaxel and macitentan (80%) as compared with control (20%), paclitaxel (20%), and macitentan alone (40%) (p&amp;lt;0.0001, log-rank test). Immunohistochemical analyses revealed that the phosphorylation of endothelin receptors A and B on tumor cells and tumor-associated endothelial cells were inhibited by macitentan. Treatment with macitentan also suppressed the expression of survival proteins such as pAKT, pMAPK, BCL2L1, TWIST1, and GSTA5 in tumor cells. More importantly, only the combination therapy induced significant apoptosis of tumor cells and tumor-associated endothelial cells and reduced the number of KI67 positive tumor cells. IVIS imaging confirmed regression of brain lesions. Conclusion: Treatment with macitentan, a dual endothelin receptor antagonist, combined with paclitaxel leads to regression of experimental breast cancer brain metastasis and therefore should be considered for clinical development. Citation Format: Ho Jeong Lee, Sun Jin Kim, Seung Wook Kim, Junqin He, Qiuyu Wu, Erica J. Lawson, Francois Lehembre, Urs Regenass, Isaiah J. Fidler. Treatment of experimental brain metastasis of human breast cancer by macitentan, a dual antagonist of endothelin receptors combined with paclitaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3779. doi:10.1158/1538-7445.AM2014-3779

VEGF Signaling of the Diabetic Heart by Endothelin Antagonism: Endothelin- A Antagonism and Endothelin-A/-B Antagonism

VEGF Signaling of the Diabetic Heart by Endothelin Antagonism: Endothelin- A Antagonism and Endothelin-A/-B Antagonism

Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome.

Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl salt-sensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1(+) cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.

Extensive coronary arterial fistula development in patients with univentricular circulation

We describe two children, each with a univentricular circulation who had evidence of elevated pulmonary arterial pressure at cardiac catheterization. Both children developed extensive coronary arterial fistulae detected at cardiac catherization. Each child was medically treated with a combination of phosphodiesterase-5 inhibitor and endothelin antagonist pulmonary vasodilators. The presence of chronic hypoxaemia, elevated filling pressures, and the use of pulmonary vasodilators may contribute to coronary endothelial dysfunction, which may result in coronary vasculopathy. This may necessitate early referral for orthotopic cardiac transplantation. © 2013 Wiley Periodicals, Inc.

Current clinical management of pulmonary arterial hypertension.

During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.