Nonselective Endothelin Research Articles

RAPID ENDOGENOUS PRODUCTION OF ENDOTHELIN-1 REVEALED BY AN ENDOTHELIN NEUTRALIZING ANTIBODY IN A SERIES OF EXPERIMENTAL AND MODELING STUDIES

Objective: The endothelin pathway is implicated in driving pathophysiological changes leading to pulmonary and systemic hypertension, chronic kidney disease and heart failure. Small molecule antagonists that selectively blocked endothelin A receptors (ETA) as well as non-selective ETA and endothelin B receptor (ETB) antagonists were successfully developed for the treatment of these vascular diseases. However, the treatment-related adverse events, such as fluid retention and edema, significantly limit the utility of this class of therapeutics, especially in the heart failure patients. Design and method: A monoclonal antibody that selectively neutralizes endothelin-1 (ET-1) may offer an attractive alternative therapeutic approach that remedies ETA-mediated vasoconstriction without impacting desirable ET-3/ETB mediated fluid regulation. A selective ET-1/2 neutralizing antibody, S69glC21 was discovered and optimized through protein engineering to 80 pM and 30 pM binding affinities to ET-1 and ET-2, respectively. Results: When administered into rats exogenously infused with ET-1, S69glC21 prevented blood pressure increase. In a hypoxia-induced pulmonary hypertension rat model, S69glC21 reduced pulmonary pressure. Compared to atrasentan, a selective small molecule ETA antagonist, S69glC21 had a distinct pharmacodynamic (PD) effect characterized by initial complete inhibition followed by a delayed rise of pulmonary pressure as the hypoxia condition persisted. To further dissect these findings, S69glC21 pharmacokinetics (PK) and circulating ET-1 target engagement (TE) analysis were performed. In the S69glC21 treated rats, antibody bound ET-1 was shown to accumulate relative to baseline plasma levels at all dose levels. In the 30 mpk group, the antibody bound ET-1 accumulated nearly 40,000-fold above the baseline plasma level of 2.25 ± 0.87 pg/mL indicating a rapid production rate of ET-1. Conclusions: Thus, PK/PD modeling reveals significant druggability challenges for the development of a highly effective, commercially viable ET-1 selective neutralizing antibody for the treatment of cardiovascular, pulmonary, and/or renal diseases.

Microfabricated potentiometric sensor based on a carbon nanotube transducer layer for selective Bosentan determination

Abstract In this work, a solid-state electrochemical sensor relying on potentiometric transduction was constructed and optimized to detect Bosentan (BOS) in its pharmaceutical dosage form and human plasma. BOS is useful in pulmonary hypertension management as a nonselective endothelin receptor antagonist. A printed circuit board has been constructed and used as a substrate for microfabricated Cu electrodes. In comparison to a microfabricated control (Cu/ISM) electrode, the sensor potential signal drift was enhanced, and the response time was reduced by using multi-walled carbon nanotubes (MWCNTs) as an ion-to-electron transducer layer. According to IUPAC requirements, the suggested BOS sensors have been electrochemically characterized, and the linear dynamic range is (1.0 × 10−8 to 1.0 × 10−5) M with a limit of detection of 6.28 × 10−9 M and 6.12 × 10−9 M for MWCNT-based sensor (Cu/CNT-NC/ISM) and control sensor (Cu/ISM), respectively. The described sensors have been used successfully to selectively determine BOS in dosage form and human plasma without any pre-treatment steps.

Bosentan Does Not Affect Renal Resistive Index in Scleroderma/Systemic Sclerosis Patients

Introduction: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Methods: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Results: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049–0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15–0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10–101 ± 11 mm Hg, p < 0.001), PP (76 ± 11–68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044–0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20–84 ± 24 mL/min/1.73 m2, p = 0.003). Discussion/Conclusion: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function.

Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

AbstractImmunotherapy efficacy depends on T cell trafficking to tumors and migrating to malignant cells to kill them. One barrier to T cell homing is the tumor blood vessel wall, which inhibits T cell attachment and transmigration through the endothelin B receptor, but antagonizing this receptor has not led to a clinically approved drug. One reason may be tumor hypo‐perfusion, which limits the area of perfused vessels for T cell attachment. If collapsed vessels can be decompressed and re‐perfused by alleviating tumor stiffness, then endothelin B receptor antagonism can improve immunotherapy. Here, it is tested whether the nonselective endothelin receptor blocker, bosentan, by simultaneously interfering with endothelin A receptor induced fibrosis, can normalize the tumor microenvironment thereby acting as a “mechanotherapeutic.” Tumor stiffness is monitored with ultrasound elastography and nanomechanical properties with atomic force microscopy to find an optimal dose, which reprograms cancer‐associated fibroblasts resulting in reduced collagen thereby decompressing vessels. Through this mechanism, T cell association with tumor vessels increases and immunosuppressive hypoxia is reduced. Additionally, bosentan increases the CD8+ T cells proliferating fraction. Ultrasound stiffness measurements correlate well with response to immunotherapy, suggesting the potential role of ultrasound elastography as a predictive biomarker of response to immune checkpoint inhibitors.

The effect of endothelin receptor antagonists in the endotoxin-induced uveitis rabbit model

Purpose: To investigate the effect of Bosentan (non-selective endothelin receptor antagonist) and BQ123 (ETA receptor antagonist) on intraocular inflammation in an endotoxin-induced uveitis (EIU) rabbit model.Methods: Uveitis was induced by intravitreal injection of lipopolysaccharide (LPS). The animals were divided into 7 groups and there were six rabbits in each group (saline, saline and ethanol, bosentan, BQ123, lipopolysaccharide (LPS), bosentan and LPS, BQ123 and LPS-injected groups). Bosentan and BQ123 were applied before LPS injection. Aqueous humour was collected at 24th hour post-injections and enucleation was performed for the evaluation of histopathological changes.Results: BQ123 decreased clinical score, cell counts and protein amount more than bosentan and it was significant for cell counts (p = 0.018). Bosentan significantly diminished inflammatory reactions more than BQ123 as shown in histopathological specimens (p = 0.002).Conclusions: ETA receptor blockage is effective on uveitis treatment by its protective effect on blood aqueous barrier.

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.

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.

Selective ETA receptor blockade protects against cisplatin-induced acute renal failure in male rats

The present study aims to investigate the possibility that inhibiting the physiological function of endothelin-1 (ET-1) by blocking its receptors would significantly decrease the nephrotoxic effect of cisplatin. Therefore the study was designed to investigate the effect of treatment with BQ-123, the selective endothelin receptor-A (ETA) blocker, and bosentan, the non-selective endothelin receptor blocker, on the cisplatin-induced structural, functional, and biochemical alterations in the rat kidney. Rats were divided into four groups: control (given a single dose of normal saline, i.p.), cisplatin (given a single dose of cisplatin, 6mg/kg, i.p.), cisplatin+BQ-123 (1mg/kg, i.p.), and cisplatin+bosentan (30mg/kg, orally via gavage). Each of the two blockers was administered in two doses; 1h before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in blood urea nitrogen and serum creatinine concentrations at 96h following cisplatin injection. Increased concentrations of malondialdehyde, tumor necrosis factor-α (TNF-α) and caspase-3, decreased nitric oxide (NO) production and superoxide dismutase (SOD) activity in kidney homogenates were observed at 96h following cisplatin injection, in addition to a typical ‘acute tubular necrosis’ pattern. BQ-123 ameliorated the structural and functional injuries caused by cisplatin mainly via restoring SOD activity, in addition to other antioxidant parameters, NO, TNF-α and caspase-3 concentrations. This study further proves that ETA but not ETB receptors are involved in cisplatin-induced nephrotoxicity. The selective ETA antagonist BQ-123 ameliorated the cisplatin-induced deleterious effects and showed reno-protective effect against cisplatin-induced acute renal damage.

Performance-enhancing effects of non-selective endothelin receptor antagonist

Performance-enhancing effects of non-selective endothelin receptor antagonist

The hypoxia-mimetic agent cobalt chloride induces the expression of intrinsic BMP antagonist noggin independent /INS;of the /INS;endothelin pathway

Background: Mutations in the bone morphogenetic protein type 2 receptor (BMPR2) are responsible for themajority of cases of heritable pulmonary arterial hypertension (PAH). Low penetrance of BMPR2 mutation in heritable PAH, however, suggests the involvement of second-hit elements in the pathogenesis of PAH. We have previously reported that treatment with endothelin-1 induced in vitro increased expression of noggin, an intrinsic bone morphogenetic protein antagonist, in human pulmonary artery smooth muscle cells (PA-SMCs). Moreover, chronic exposure to hypoxia is a well-known inducer of remodeling in pulmonary arteries. However, the potential link between chronic hypoxia exposure and noggin expression has not been elucidated. Aims: We hypothesized that hypoxia could induce, in PA-SMCs, the expression of endothelin-1 which could secondarily result in the upregulation of noggin. Methods and results: Cultured human PA-SMCs were treated for 3, 6, 24, and 48 h with the hypoxiamimetic agent, cobalt chloride (CoCl2; 100 μM) and gene expressions of preproendothelin-1 (ppET1), endothelin converting enzyme-1 (ECE1) and noggin were then evaluated by QRT-PCR. CoCl2 treatment progressively increased the expressions of ppET1 and noggin, with maximal response after 24 h and 48 h of stimulation respectively. Gene expression of ECE1 was not changed. After pretreatment or not with a non-selective endothelin receptor antagonist (bosentan), we stimulated PA-SMCs with CoCl2 for 5 h. Gene expression of noggin significantly increased after CoCl2 treatment and this reaction was not changed by pretreatment with bosentan. Conclusions: Noggin, an intrinsic bone morphogenetic protein antagonist, was upregulated by CoCl2, independent of hypoxia-induced endothelin-1 pathway at earlier timing (5 h).

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.

Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats

Increased renal artery contractility leads to renal vasospasm and ischaemia as well as kidney damage. This study was designed to examine the hypothesis that organ culture of renal arteries induces transcriptional up-regulation of endothelin type A (ETA ) and type B2 (ETB2 ) receptors in the smooth muscle cells via activation of nuclear factor-kappaB (NF-κB) and subsequently increases renal artery contractility. Rat renal artery segments were organ-cultured for 6 or 24hr to increase endothelin receptor-mediated contraction. To dissect molecular mechanisms involved in this process, inhibitors for NF-κB signalling pathway (MG-132 and BMS345541), transcription (actinomycin D) and translation (cycloheximide) were used during organ culture. Endothelin receptors were studied using a sensitive myograph (functional contractility), real-time PCR (mRNA analysis) and immunohistochemistry (protein localization). Compared with fresh segments, contractile responses to endothelin-1 (non-selective endothelin receptor agonist) and sarafotoxin 6c (selective ETB receptor agonist) were significantly increased in the segments after 24hr of organ culture; ETB2 receptor-mediated maximal contraction increased from 2.7±0.5 to 135.3±5.1 (p<0.001), and potency (pEC50 ) of ETA receptor agonist increased from 8.20±0.04 to 8.72±0.07 (p<0.001). This was in parallel with increased corresponding mRNA and protein expression for ETA and ETB2 receptors. BMS345541, MG-132, actinomycin D or cyclohexamide, respectively, suppressed the up-regulation of ETA and ETB2 receptors. Immunostaining performed with specific antibody showed that IκB was phosphorylated during organ culture. In conclusion, activation of NF-κB mediates up-regulation of ETA and ETB2 receptors and subsequently increases renal artery contractility, which may contribute to renal vasospasm and ischaemia as well as kidney damage.

Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility.

We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)]. Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49). Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy. Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified.

Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro

Macitentan is a new non-selective endothelin-1 receptor antagonist under development for the treatment of pulmonary arterial hypertension. Information on the potential for macitentan to influence the pharmacokinetics of concomitantly administered drugs by inhibition or induction of drug metabolising enzymes or drug transporters is sparse. We therefore studied the potential of macitentan to inhibit and induce critical targets of drug metabolism and drug distribution (transporters) in vitro. Induction was quantified at the mRNA level by real-time RT-PCR in LS180 cells and revealed that macitentan significantly induced mRNA expression of cytochrome P450 3A4 (CYP3A4), P-glycoprotein (P-gp, ABCB1), solute carrier of organic anions 1B1 (SLCO1B1), and uridinediphosphate-glucuronosyltransferase 1A3 (UGT1A9). By means of a reporter gene assay our study establishes macitentan as a potent activator of pregnane X receptor (PXR). Inhibition of drug transporters was evaluated by using transporter over-expressing cell lines and fluorescent specific substrates of the respective transporters and revealed that macitentan is an inhibitor of P-gp, breast cancer resistance protein (BCRP), SLCO1B1, and SLCO1B3. Using commercial kits macitentan was demonstrated to be a moderate inhibitor of CYP3A4 and CYP2C19. In conclusion our data provide a comprehensive analysis of the interaction profile of macitentan with drug metabolising and transporting enzymes in vitro. Although macitentan has a similar or higher potency for induction and inhibition of drug metabolising enzymes and transporters than bosentan, its low plasma concentrations and minimal accumulation in the liver suggest that it will be markedly less prone to drug–drug interactions than bosentan.

EndothelinA–EndothelinB Receptor Cross Talk in Endothelin-1–Induced Contraction of Smooth Muscle

The efficacy of selective endothelin (ET) receptor antagonists may be limited by a functional interaction between the ET(A) and ET(B) receptors. This interaction, also termed "cross talk", is characterized by the dependency of the inhibition of an ET-1 response due to antagonism of one ET receptor subtype upon concomitant antagonism of the other ET receptor subtype. Although a reduction in ET(A)-ET(B) receptor cross talk would presumably increase the efficacy of selective ET receptor antagonists, an approach that accomplishes this aim is largely absent due to a lack of mechanistic understanding. Toward this goal, we evaluated the characteristics and potential dependencies of cross talk in smooth muscle. Smooth muscle was adopted as an exemplar not only because cross talk is widely reported in this tissue type, thereby allowing numerous comparisons, but also significant controversy surrounds the use of selective versus nonselective ET receptor antagonists in ET-1-related pathophysiologies involving smooth muscle. Based on this evaluation, we suggest that ET(A)-ET(B) receptor cross talk is a dynamic process directed by either or both ET receptor subtypes and expressed to varying magnitudes depending on the ET-1 and selective ET receptor antagonist concentrations, tone due to intraluminal pressure/stretch, agonists acting at receptors other than the ET(A)/ET(B) receptors, and endothelial/epithelial function. It is speculated that ET(A)-ET(B) receptor cross talk occurs through signal transduction pathways along with changes at the receptor level. Pharmacologic intervention of the signaling pathways could increase the therapeutic efficacy of ET receptor antagonists.

Effect of intra‐abdominal pressure on hepatic microcirculation: Implications of the endothelin‐1 receptor

To investigate the effect of endothelin receptor A (ET(A)) and endothelin receptor B (ET(B)) blockade on liver microcirculation and oxygenation during intra-abdominal pressure (IAP) increase. Fifteen anesthetized pigs were randomized to receive either nonselective endothelin-1 (ET-1) blocker tezosentan (TG, n = 7) or saline (CG, n = 8). Helium was insufflated to increase IAP from 0 to 25 mmHg. Stroke volume variability was maintained ≤ 12% with colloid infusion. Total liver blood flow (TLBF), hepatic microcirculatory blood flow (MBF), hepatic tissue oxygenation (HpO(2)), hyaluronic acid and plasma disappearance rate (PDR) of indocyanine green (ICG) were recorded. TLBF remained mostly unaltered in both groups at low IAP and decreased only in CG at the IAP of 25 mmHg. As IAP increased, a significant decline in MBF was observed without correlation with cardiac output or TLBF. In CG, HpO(2) decreased as early as IAP of 10 mmHg to high levels of pressure. However, in TG the decrease was significant only at the IAP of 25 mmHg. PDR of ICG decreased in both groups at IAP of 25 mmHg (P = 0.046 and P = 0.009 in TG and CG, respectively). These changes correlated with MBF (r = 0.793). Blocking ET(A) and ET(B) receptors partially protects sinusoidal circulation and tissue oxygenation against stress induced by high IAP.

Ambrisentan and Tadalafil Synergistically Relax Endothelin-Induced Contraction of Rat Pulmonary Arteries

Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.

Pathological Importance of the Endothelin-1/ETBReceptor System on Vascular Diseases

Activation of the endothelin (ET)-1/ET receptor system is involved in the development of vascular diseases such as atherosclerosis, vascular hypertrophy, and restenosis. Some issues still remain unresolved including whether ET receptor antagonists are expected to become the new therapeutic tools for the treatment of vascular diseases. One of the unresolved critical points is the functional role of ET receptor subtypes on each vascular disease, in particular the pathophysiological roles of the ETB receptor. We recently demonstrated that selective inhibition of the ETB receptor system showed harmful effects in the development of neointimal formation after vascular injury. However, there was no apparent difference in the therapeutic effects between a nonselective ETA/ETB receptor antagonist and selective ETA receptor antagonist. These findings indicate that antagonism of the ETA receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ETB-receptor-mediated actions, although the selective ETB receptor antagonist worsens vascular remodeling. In addition, we found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes. In this paper, we outline the roles of the ET-1/ETB receptor system on vascular diseases and its sex differences.

Comportamiento de la actividad física cotidiana en pacientes con hipertensión arterial pulmonar en tratamiento con antagonistas de los receptores de la endotelina

IntroductionThe assessment of daily physical activity is important to prevent and treat many diseases more effectively. Objectivesto evaluate daily physical activity using Tri-axial accelerometers in patients with pulmonary arterial hypertension and treated with endothelin receptor antagonists. Material and methodsSix patients with pulmonary arterial hypertension diagnosed by right heart catheterization were included. World Health Organization functional class, 6-minute walking test, daily physical activity evaluated with the London Chest Activity of Daily Living Scale and with RT3 accelerometers devices were assessed in two opportunities, before and after three months of treatment with nonselective endothelin receptor antagonist drugs. ResultsMean scores of the London Chest Activity of Daily Living Scale scale before and after three months treatment were 35.0 (26.8–43.5) [median and interquartilic range] and 22.0 (16.5–28.3), respectively (p=0.068). Daily physical activity measured by accelerometer was associated with the minimum oxygen saturation during the 6-minute walking test (r=0.825, p=0.043). The total period of low intensity physical activity registered was associated with pulmonary vascular resistances (r=0.989; p=0.001) and the total period of heavy intensity physical activity registered with the systemic vascular resistances (r=0.0890; p=0.043). ConclusionDaily physical activity of patients with pulmonary arterial hypertension could be evaluated with accelerometers. In this way, physical activity is associated with the exercise tolerance and with hemodynamic measures.

What Is the Prognostic Significance of Pulmonary Hypertension in Heart Failure?

Increased left ventricular filling pressure is a hallmark of heart failure (HF) caused by left ventricular dysfunction (LVD). Within the closed hemodynamic system, increased LV filling pressure results in elevated pressures in the left atrium and pulmonary venous vasculature. When pulmonary hypertension (PH, defined by mean pulmonary artery pressure [mPAP] >25 mm Hg) is associated with an abnormally elevated pulmonary capillary wedge pressure (PCWP >15 mm Hg) or left ventricular end-diastolic pressure (LVEDP >18 mm Hg),1 it has been variably termed World Health Organization (WHO) Group 2 PH,1 pulmonary venous hypertension,2 “postcapillary PH,”3 or “passive PH.”4 Article see p 644 Patients with LVD also have a propensity to develop a precapillary pulmonary arterial contribution to PH, reflected by an increased transpulmonary gradient (TPG, defined as mPAP-PCWP that exceeds 12 to 15 mm Hg) or an elevated pulmonary vascular resistance (PVR, defined as TPG/cardiac output that exceeds 2.5 to 3 Wood units [WU]).5,6 This type of PH, which is “out of proportion” to underlying left-sided disease in the setting of normalized volume status, has been termed “mixed PH,” given both precapillary and postcapillary contributions to elevated PAP.7 PH in HF can be simplistically organized along 2 sequential dyads: (1) the presence or absence of a significant precapillary contribution to elevated PAP (ie, mixed PH as opposed to purely passive PH) and (2) if present, the relative fixed (ie, nonreversible with lowering left-sided filling pressures) or reactive (ie, reversible with reduction of left-sided filling pressures) character of the precapillary contribution to PH (Figure). Figure. Diagnostic framework for pulmonary hypertension in heart failure (HF). mPAP indicates mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; and PH, pulmonary hypertension. There are no widely established cut-points to define PVR and transpulmonary …