Bosentan对培养乳鼠心肌细胞肥大的抑制作用

目的 :以内皮素 (ET 1)诱导培养的乳鼠心肌细胞肥大 ,观察内皮素受体拮抗剂bosentan对肥大心肌细胞的抑制作用。方法 :以胰酶消化法分离乳鼠心肌细胞 ,分 4组进行细胞培养。对照组常规培养 ,不加任何干预因素 ,其余 3组分别加入bosentan10 -8mol·L-1、ET 110 -10 mol·L-1、ET 110 -10 +bosentan10 -8mol·L-1,培养 72h后观察心肌细胞生长情况并用放免法测定培养液中ET 1和心钠素 (ANP)含量。结果 :各组ANP测定水平分别为 :对照组 6.4 6±0 .38μg·L-1,bosentan组 4 .87± 0 .5 6μg·L-1,ET 1组 13.60±1.12 μg·L-1,ET 1+bosentan组 9.4 2± 0 .5 8μg·L-1。镜下观察见ET 1刺激乳鼠心肌细胞肥大 ,加用bosentan能使心肌细胞肥大程度减轻。结论 :ET 1可刺激乳鼠心肌细胞肥大 ,bosentan可使心肌细胞分泌心钠素减少 ,抑制ET 1诱导的心肌细胞肥大作用。     

Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) is a deadly disease with limited treatment options.Objectives: The objectives of this study were to assess the effects of bosentan, an orally active dual endothelin receptor antagonist, on exercise capacity and cardiopulmonary hemodynamics, as well as to assess its safety and tolerability in patients with severe PAH.Methods: In this double-blind, placebo-controlled, multicenter study, 32 patients with PAH (primary or associated with scleroderma) were randomized to receive bosentan for a minimum of 12 weeks (62.5 mg BID for 4 weeks, then 125 mg BID) or placebo. The primary end point was the change in exercise capacity. Secondary end points included changes in cardiopulmonary hemodynamics, Borg dyspnea index, and modified New York Heart Association (NYHA) functional class, as well as withdrawal due to clinical worsening.Results: Patients treated with bosentan improved their 6-minute walking distance. Fifteen bosentan-treated patients (71%) improved their walking distance from baseline to week 12 by >30 m, which is considered a clinically relevant improvement. The difference between treatment groups in the mean (±SEM) change at week 12 was 76 ± 31 m in favor of bosentan (95% CI, 12 to 139; P = 0.021). The improvement was maintained for at least 20 weeks. For cardiac index, the difference was 1.0 ± 0.2 L/min/m² in favor of bosentan (95% CI, 0.6 to 1.4; P < 0.001). Bosentan significantly decreased pulmonary vascular resistance, whereas it was increased with placebo (P ≤ 0.001). Bosentan improved both the Borg dyspnea index and the NYHA functional class. All 3 withdrawals due to clinical worsening were in the placebo group (P = 0.033). The number and nature of adverse events were similar in the 2 groups.Conclusions: In these patients with PAH, bosentan increased exercise capacity and improved hemodynamics. These results, which have been summarized previously in a brief report, include all data up to 28 weeks of treatment and support the potential clinical value of endothelin receptor antagonists in the treatment of patients with PAH.     

Endothelin receptor antagonists for the treatment of pulmonary arterial hypertension

Introduction: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH.

Areas covered: The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested.

Expert opinion: The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ ‘harder’ clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.     

Medical therapeutics for pulmonary arterial hypertension: from basic science and clinical trial design to evidence-based medicine

Pulmonary arterial hypertension is a severe disease with poor prognosis, caused by obliteration of the pulmonary vasculature as a result of pulmonary-vascular remodeling, active vasoconstriction and in situ thrombosis. Left untreated, pulmonary arterial hypertension results in right-ventricular failure and death. There has been dramatic progress in the treatment of pulmonary arterial hypertension during recent years. A remarkable number of randomized-controlled trials with agents known to target specific abnormalities present in pulmonary arterial hypertension have been completed. Most commonly, therapeutic efficacy was judged by the ability of the drug under study to improve exercise capacity and to decrease the rate of severe complications. Completed clinical trials have mainly evaluated patients with relatively advanced disease. Despite these advances, responses to therapy in pulmonary arterial hypertension are not uniformly favorable and frequently incomplete. In addition, the methods of delivery and the adverse effect profile of the currently available pulmonary arterial hypertension-specific drugs create further management difficulties. Based on newly identified pathobiologic abnormalities in the pulmonary vasculature, future studies are likely to focus on the discovery of new therapeutic targets. Clinical trial design will continue to evolve in an attempt to enable inclusion of patients with less advanced disease and evaluation of treatment combinations or comparisons of the currently approved drugs.     

Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure.

BACKGROUND: The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. METHODS: Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. RESULTS: Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only approximately 35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. CONCLUSIONS: These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF.     

Effect of endothelin receptor antagonist on parathyroid gland growth, PTH values and cell proliferation in azotemic rats.

BACKGROUND: A variety of stimuli are involved in the pathogenesis of parathyroid gland hyperplasia in renal failure. Recently, it was shown that blocking the signal from the endothelin-1 (ET-1) receptor (ET(A)R/ET(B)R) by a non-selective receptor antagonist, bosentan, reduced parathyroid cell proliferation, parathyroid gland hyperplasia and parathyroid hormone (PTH) levels in normal rats on a calcium deficient diet. Our goal was to determine whether in 5/6 nephrectomized (NPX) rats with developing or established hyperparathyroidism, the endothelin receptor blocker, bosentan, reduced the increase in parathyroid cell proliferation, parathyroid gland hyperplasia and PTH values. METHODS: High (HPD, 1.2%) or normal phosphorus diets (PD) (NPD, 0.6%) were given to 5/6 NPX rats for 15 days (NPX(15)). In each dietary group, one-half the rats were given bosentan (B) i.p. 100 mg/kg/day. The four groups of rats were: (1) NPX(15)-1.2% P; (2) NPX(15)-1.2% P+B; (3) NPX(15)-0.6% P; and (4) NPX(15)-0.6% P+B. In a second study in which hyperparathyroidism was already established in 5/6 NPX rats fed a HPD for 15 days, rats were divided into two groups in which one group was maintained on a HPD and the other group was changed to very low PD (VLPD, <0.05%) for an additional 15 days. In each dietary group, one-half the rats were given bosentan i.p. 100 mg/kg-day. The four groups of rats were: (1) NPX(30)-1.2% P; (2) NPX(30)-1.2% P+B; (3) NPX(30)-0.05% P and (4) NPX(30)-0.05% P+B. Parathyroid cell proliferation was measured by proliferating cell nuclear antigen (PCNA) staining and ET-1 expression by immunohistochemical techniques. RESULTS: In the study of developing hyperparathyroidism, bosentan reduced ET-1 expression in the parathyroid glands of rats on the NPD and HPD (P<0.05). But only in rats on the NPD did bosentan result in a reduced increase in parathyroid gland weight (P<0.05). In the study of established hyperparathyroidism, in which 5/6 NPX rats were given a HPD for 15 days, bosentan started on day 15 reduced (P<0.05) ET-1 expression in rats maintained for 15 additional days on the HPD or the VLPD. On the VLPD, parathyroid gland weight was less (P<0.05) than that in rats on the HPD sacrificed at 15 or 30 days. Bosentan did not reduce parathyroid cell proliferation or parathyroid gland weight in rats maintained on the HPD or further reduce these parameters beyond that obtained with dietary phosphorus restriction. PTH values were lowest in the VLPD group, intermediate in the NPD group, and highest in the HPD group, but in none of the three groups did bosentan decrease PTH values. CONCLUSIONS: In azotemic rats with developing hyperparathyroidism, bosentan resulted in a reduced increase in parathyroid gland weight when dietary phosphorus content was normal. Despite a reduction in ET-1 expression in rats on a HPD with developing or established hyperparathyroidism, bosentan did not reduce the increase in parathyroid cell proliferation, parathyroid gland growth or PTH values. Thus, ET-1 blockade with bosentan did not prevent parathyroid gland growth in the azotemic rat.     

Initial experience with bosentan therapy in patients considered ineligible for heart transplantation because of severe pulmonary hypertension

BACKGROUND: Pre-operative elevated pulmonary vascular resistance (PVR) has been associated with increased right ventricular failure and mortality after heart transplantation. The aim of this study was to assess the efficacy of bosentan, an oral endothelin-receptor antagonist, to reduce PVR in patients considered ineligible for heart transplantation because of severe pulmonary hypertension. METHODS: Seven patients with end-stage congestive heart failure and considered ineligible for heart transplantation because of severe pulmonary hypertension (PVR>2.5 Wood units after nitroprusside infusion) were included in the study. They received bosentan 62.5 mg b.i.d. for four wk and 125 mg b.i.d. thereafter. Right heart catheterization was repeated after six wk of therapy. RESULTS: After six wk of bosentan therapy, there was a significant decrease in PVR (6.0 +/- 2 vs. 3.8 +/- 2 Wood units, before vs. after bosentan; p = 0.02), in PVR during nitroprusside infusion (3.3 +/- 1 vs. 2.1 +/- 1 Wood units, before vs. after bosentan; p = 0.02) and in diastolic pulmonary artery pressure (33 +/- 7 vs. 23 +/- 7 mmHg, before vs. after bosentan; p = 0.04). No significant adverse events were observed. After bosentan therapy, five patients had PVRbosentan after surgery. CONCLUSIONS: In patients considered ineligible for heart transplantation because of high PVR, bosentan therapy significantly reduced PVR. These data suggest that therapy with endothelin-receptor blockers might be useful to identify a subgroup of patients with high PVR who can benefit from heart transplantation.