Effect of bosentan on leptin and endothelin‐1 concentration in plasma and brain after cardiac arrest in rats

In previous studies, bosentan was found to decrease plasma leptin concentrations after myocardial infarction (MI) in rats and had decreased mortality. The present study was undertaken to examine the effect of bosentan on leptin and endothelin‐1 (ET‐1) concentrations in plasma and ET‐1 concentrations in the hippocampus after cardiac arrest (CA) in rats. Studies were performed in 72 rats divided into treated and untreated animals in the following experimental groups: control, 3 min, 10 min, 1 h, 24 h, and 7 days after CA. Bosentan was given daily 2 h before CA or decapitation, 7 days, by gavage at a dose of 100 mg/kg. Plasma leptin concentration decreased in the early period after CA, and being elevated in 24 h, normalized 1 week later. Bosentan kept plasma leptin concentration at the control level in the postischemic period. Plasma ET‐1 concentration significantly increased during the postischemic period. Bosentan produced the elevation of plasma ET‐1 concentration in the preischemic period and kept the level of ET‐1 at control values after CA. Concentration of ET‐1 in the hippocampus was significantly lower 24 h after CA and was elevated after 1 week. The most dramatic effect of bosentan on ET‐1 concentration was in the hippocampus, where it significantly decreased during the entire postischemic recovery period. We postulate an important effect of bosentan on concentration of ET‐1 and leptin in plasma and ET‐1 in the brain after global cerebral ischemia caused by CA. Drug Dev Res 64:137–144, 2005. © 2005 Wiley‐Liss, Inc.     

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.     

Hemodynamic Effects of Bosentan in Patients with Chronic Heart Failure

A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET_A/ET_B-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET_A receptor only.     

Diagnostic and Therapeutic Potential of the Endothelin System in Patients with Chronic Heart Failure

There is now considerable evidence to support a role for the endothelin (ET) system in the pathogenesis and progression of chronic heart failure (CHF). As such, the potential exists for this system to be useful in both diagnosis (by measurement of peptide levels in plasma and other body fluids) and treatment (by pharmacological blockade) of this condition.Plasma levels of endothelin-1 (ET-1) are elevated in CHF and the magnitude of elevation correlates with disease severity. ET-1 levels in plasma predict subsequent mortality in patients with CHF. ET-1 may also contribute to symptoms associated with CHF, such as exercise intolerance. In the diagnosis of CHF, plasma levels of ET-1 appear to be a less powerful discriminator between patients with mild disease and control subjects with normal ventricular function on multivariate analyses, compared to brain natriuretic peptide (BNP), or its N-terminal fragment. ET-1 concentrations are also elevated in the saliva of patients with CHF and may represent an alternative approach to assessment of the status of the ET system in these patients.Specific ET receptor antagonists (both mixed and ET_A-selective) have been developed. Studies with these agents in animal models of CHF have demonstrated beneficial effects via both haemodynamic and non-haemodynamic pathways. A number of short-term clinical studies have been performed demonstrating improvements in haemodynamic parameters without neurohormonal activation. Long-term clinical studies with ET receptor antagonists are currently underway to definitively test the impact of blockade of this system on mortality and major cardiovascular endpoints. Endothelin converting enzyme (ECE) inhibitors represent an alternative strategy of ET blockade, and early data from animal models suggest these agents may be of clinical utility, either alone or, more likely, in combination with other zinc metallopeptidases.     

Endothelin and Heart Failure

The availability of potent and orally active nonpeptide endothelin (ET) receptor antagonists has generated a host of information on the pathophysiological role of ET-1 in a number of preclinical models including hypertension, renal failure, heart failure and pulmonary hypertension. Convincing data are available to show that ET-1 receptor antagonists are beneficial in humans as far as reversal of deranged systemic and regional hemodynamics associated with CHF and pulmonary hypertension. As in other disease areas, the issue of whether ET_A-selective or ET_A/B antagonists are more suited for CHF treatment remains unresolved. ET_B receptors may mediate some critical processes in the kidney such as sodium and water excretion in addition to releasing vasodilator substances such as NO and prostacyclin from endothelial cells. In heart failure and chronic renal diseases, preservation of ET_B-mediated responses in the kidney and pulmonary endothelium might be beneficial. On the other hand, blockade of ET_B-mediated vasoconstriction, smooth muscle cell proliferation and fibrosis by ET_B antagonists might be beneficial. In clinical trials so far, the hemodynamic effects of mixed antagonists of ET receptors and ET_A selective antagonists seem equivalent.     

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.