Analysis of ET‐A and ET‐B receptors using an isolated perfused rat lung preparation

Aims and Methods: The pulmonary and vascular effects of endothelin‐1 receptor activation were studied in isolated perfused and ventilated lung preparations from rat. The responses to endothelin‐1 (ET‐1) and the endothelin B (ET_B) receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A (ET_A)‐receptor antagonist FR 139317, the ET_B‐receptor antagonist BQ 788 and the combined ET_A/ET_B‐receptor antagonist Bosentan. The respiratory parameter airway conductance (G_aw) and the vascular parameter perfusion flow were analysed simultaneously. Results: Concentration–response curves for ET‐1 administered intra‐arterially revealed that its most potent effect was on the vascular side while S6c had a more potent effect on airway conductance. ET‐1, given as a bolus dose intra‐arterially (100 μL of 0.2 nm ), induced a strong‐ and long‐lasting contraction of the vasculature while only a less pronounced contraction was seen in the airways. Neither of the antagonists had a significant effect per se on G_aw or perfusion flow. FR 139317 reduced the effect of ET‐1 on perfusion flow by about 50%, while airway conductance was augmented. BQ 788 enhanced the decrease in perfusion flow by ET‐1 while G_aw was not influenced. The combined ET_A/ET_B antagonist Bosentan powerfully prevented the ET‐1‐induced decrease in G_aw but did not alter its reduction in perfusion flow. Conclusions: The potent effect of ET‐1 on the vascular side of the lung is mediated mainly through ET_A receptors, whereas both ET_A and ET_B receptors are involved in G_aw in the rat lung.     

Persistent pulmonary hypertension of the newborn

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge.     

波生坦对糖尿病大鼠的肾脏保护作用

目的：观察非选择性内皮素受体拮剂波生坦（Ｂｏｓｅｎｔａｎ）对糖尿病ＳＤ大鼠的肾脏保护作用。方法：设糖尿病非治疗组（ＤＭ组）、糖尿病Ｂｏｓｅｎｔａｎ治疗组（ＤＭ－Ｂ组）及正常对照组（ＳＤ组）,每组６只大鼠。予ＳＤ大鼠一次性腹腔注射链脲佐菌素６５ｍｇ／ｋｇ,诱导建立糖尿病模型。在ＤＭ－Ｂ组中,予大鼠Ｂｏｓｅｎｔａｎ１００ｍｇ／（ｋｇ．ｄ）灌胃,持续４周。４周后观察各组大鼠体重、肾重、平均动脉压、２４ｈ     

Successful treatment of persistent pulmonary hypertension of the newborn with bosentan

The sophisticated and expensive treatment modalities of persistent pulmonary hypertension of the newborn (PPHN), such as nitric oxide, are limited in developing countries. Alternative (less expensive) treatments are being sought and bosentan, an oral dual endothelin-1 receptor antagonist, may be an option for the treatment of PPHN. We report our experience of using bosentan in a neonate with severe PPHN.
Conclusion:  Bosentan may be a useful adjuvant therapy in neonates with PPHN, providing significant improvement in oxygenation, and thus may be particularly useful in the treatment of PPHN in countries with limited resources.     

Bosentan预防大鼠低氧性肺动脉高压形成的作用

目的研究Bosentan预防低氧诱导的肺动脉高压发生的药效作用,探讨内皮素-1(ET-1)在慢性高原病发病中的作用。方法30只Wistar大鼠随机均分为常氧对照组、低氧对照组和Bosentan组,将低氧对照组和Bosentan组放入模拟海拔为5.5 km的低氧、低压环境中。常氧对照组和低氧对照组ig 0.9%生理盐水,Bosentan组ig 100 mg.ml-1Bosentan水剂,每天2次。饲养15 d后,测量大鼠平均肺动脉高压(PAP)、左右心室比重[RV/(LV S)]比值。结果Bosentan组大鼠血红蛋白(Hb)、红细胞压积(Hct),ET-1与低氧对照组相比无差异,而PAP、RV/(LV S)均显著低于低氧对照组(P<0.01)。结论Bosentan可显著预防低氧性肺动脉压的升高,缓解低氧对心肌细胞和血管平滑肌细胞的损伤,但不能抑制红细胞的过度增生。     

波生坦治疗肺动脉高压疗效与安全性评价的Meta分析

目的根据现有随机对照临床试验，综合评价波生坦治疗肺动脉高压的疗效与安全性。方法在数据库中检索以肺动脉高压患者为研究对象，并进行了波生坦治疗（治疗组）与安慰剂（安慰剂组）比较的随机对照试验（RCT）研究，对其短、长期疗效和安全性进行Meta分析。结果（1）有2项研究进行了短期疗效与安全性评价。与安慰剂组比较，治疗组患者：①min步行距离平均增加了47．71m（95％ CI 为26．09～69．33，P〈0．0001）；②WHO心功能分级改善率的合并比数比（OR）值为1．84（95％CI为1．06～3．18，P=0．03）；③呼吸困难明显改善，Borg呼吸困难评分平均下降0．71分（95％CI为0．19～1．23，P=0．007）；④病死率差异无统计学意义，其合并OR值为2．45（95％CI为0．28～21．35，P=0．42）；⑤肝损害的发生率差异无统计学意义，其合并OR值为1．78（95％a为0．66～4．81，P=0．26）；⑥临床病情恶化率明显改善，其合并OR值为0．26（95％CI为0．11—0．60，P=0．002）。（2）有2项研究评价了波生坦治疗的长期疗效与安全性：与安慰剂组比较，治疗组患者1年生存率明娃改善，其合并OR值为2．57（95％CI为1．59～4．17，P=0．0001）；肝损害的发生情况：2项研究均报道了治疗组患者转氨酶明显升高的病例，由于缺乏安慰剂组的资料，未对其进行Meta分析。结论波生坦治疗可以提高肺动脉高压患者的运动能力，改善心功能和呼吸困难的症状，提高患者1年生存率。肝损害可能是其主要副作用。     

Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock

The role of endothelin peptides was evaluated on survival and organ injury in a model of polymicrobial sepsis, induced by caecal ligation and puncture with particular emphasis on the timing of the administration of its blocker bosentan in Swiss albino mice (20-40 g). The cardiovascular response pattern in this experimental model was characterized by an early, "hyperdynamic" phase starting at 5 h, followed by a late but "hypodynamic" phase that commence after 20 h, provided that the animals are "resuscitated" by injecting 1 ml of saline i.p. at the end of the surgery. However, if saline resuscitation is omitted, then only hypodynamic pattern is observed starting at 5 h without any hyperdynamic phase. Thus, mice were first allocated into saline-resuscitated or unresuscitated groups and endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 5 or 20 h after caecal ligation and puncture) was then administered. The control animals received the solvent of bosentan (i.e., saline: %0.9 NaCl, w/v). The survival rates in each group (n=14) were recorded over the following 144 h. In unresuscitated mice, the overall survival at 144 h was 14.3% in controls while bosentan treatment at 5 h (78.6%, P=0.0018) or 20 h (64.3%, P=0.0183) have both significantly improved the survival. However, in saline-resuscitated mice, bosentan administered at 20 h has significantly improved the survival (71.4%, P=0.0213) while its administration at 5 h has yielded exactly the same percent of survival (i.e., 21.4%) as observed in control animals. The beneficial effects of bosentan in preventing the tissue injury due to caecal ligation and puncture were also observed histopathologically in liver, spleen and kidney. Therefore, we concluded that the blockade of endothelin receptors by using bosentan during the later (hypodynamic) stages of septic shock is a promising therapeutic manoeuvre.     

The Safety and Effects of Bosentan in Patients with a Fontan Circulation

Objective. Adult patients with a Fontan circulation tend to have diminished exercise capacity. The principal objective of this study was to investigate the safety of the endothelin receptor antagonist bosentan in Fontan patients, and, secondarily, to assess effects on cardiovascular performance, New York Heart Association functional classification (NYHA FC), and ventricular function. Design. A 6‐month prospective, single‐center, pilot, safety study of bosentan in Fontan patients. Setting. Adult Congenital Heart Disease referral center. Patients. All patients ≥18 years old with a Fontan circulation and in NYHA FC ≥II were invited to enroll. Interventions. Patients started on 62.5 mg bid of bosentan, uptitrating to 125 mg bid after 2 weeks. Outcome Measures. Safety was assessed by the incidence of anticipated and unanticipated adverse events during the 6‐month study period; specifically those relating to hepatic, renal, or hematological dysfunction as measured by monthly blood tests. Other outcome measures included cardiopulmonary exercise test, 6‐minute walk distance test, Borg dyspnea index, NYHA FC, and ventricular function parameters using transthoracic echocardiography. Results. Of the eight patients enrolled, six completed the study. Two patients withdrew from the study (one for non–trial related reasons, one due to adverse events). No clinically significant adverse events relating to bosentan therapy occurred during this study and, in particular, no significant abnormalities in hepatic function tests were observed. Three patients reported transient adverse events. Improvements in NYHA FC and systolic ventricular function were observed after 6 months of bosentan treatment. Conclusions. The small number of patients with a Fontan circulation in our study was able to tolerate bosentan for 6 months. The safety and tolerability of bosentan in a larger patient population remains unknown. The results presented here justify further investigation in larger studies.     

Significant attenuation of macrovascular involvement by bosentan in a patient with diffuse cutaneous systemic sclerosis with multiple digital ulcers and gangrene

Abstract

Systemic sclerosis (SSc) is characterized by vascular injuries, and bosentan has recently been proved to be efficacious for the prevention of new digital ulcers in SSc. We herein report a case of SSc in a patient with refractory digital ulcers and gangrene treated with bosentan. Stenosis of the ulnar artery, evaluated by magnetic resonance angiography, was attenuated by the bosentan treatment, suggesting that bosentan exerts a reverse remodeling effect against the pathological organic changes of arteries in SSc.