Continuous Infusion of Prostacyclin Normalizes Plasma Markers of Endothelial Cell Injury and Platelet Aggregation in Primary Pulmonary Hypertension

Friedman, Richard A.; Mears, JG; Barst, Robyn J.

doi:10.1161/01.cir.96.9.2782

Cited by 144 publications

(81 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The greater endothelial eNOS expression is more likely to be due to the epoprostenol therapy than to the activity of the ETB receptors. Long-term epoprostenol given as monotherapy has been shown to improve endothelial function, as judged by an improvement in the net balance between pulmonary ET-1 clearance and release and the coagulation profile [34]. In the present study, it is obviously impossible to dissect how the administration of bosentan and/ or prostacyclin might have influenced endothelial function.…”

Section: Discussionmentioning

confidence: 71%

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Hall¹,

Davie²,

Klein³

et al. 2011

Eur Respir J

View full text Add to dashboard Cite

Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children.Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ETA and ETB, respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n57), following extended combined bosentan and epoprostenol therapy (n55) and from normal subjects (n55).Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ETA was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ETA, ETB and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ETA and ETB were normal and eNOS increased. In smooth muscle, ETA expression was reduced in treated cases but ETB expression increased in all arteries of both treated and untreated cases.In summary, ETA is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.KEYWORDS: Endothelin receptor antagonists, endothelin receptor A and B, endothelium, paediatric idiopathic pulmonary arterial hypertension, peripheral pulmonary arteries I diopathic pulmonary arterial hypertension (IPAH) is a rare, incurable disorder occurring in both children and adults with a normally formed heart, characterised by irreversible occlusion of small intra-acinar pulmonary resistance arteries with development of plexiform lesions resulting in a sustained increase in pulmonary arterial pressure [1]. Death results from right heart failure. Treatment with prostacyclin, endothelin receptor antagonists and phosphodiesterase inhibitors aims to promote dilatation and reparative remodelling of the pulmonary arteries, and has improved survival and quality of life but is not curative [1]. The only therapeutic option for endstage disease is lung transplantation.The endothelin ET-1 is a potent vasoconstrictor and smooth muscle cell mitogen [2] that is important in the pathobiology of pulmonary arterial hypertension [3]. In humans with IPAH, plasma endothelin levels are elevated [4], endothelin-converting enzyme activity is enhanced [5] and lung expression of endothelin is increased [6]. Its action is mediated principally by two receptors, ETA and ETB [7]. Both mediate vasoconstriction of human smooth muscle cells whilst endothelial ETB receptors mediate vasorelaxation via endothelial nitric oxide synthase (eNOS) [8]. In experimentally induced pulmonary hypertension, the endothelin receptor antagonists diminish or abrogate endothelin-induced smooth muscle cell contract...

show abstract

Section: Discussionmentioning

confidence: 71%

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Hall¹,

Davie²,

Klein³

et al. 2011

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…30 Previous studies have also identified other nonvasodilator actions of epoprostenol in PPH, including improvement in coagulation and platelet function. 31,32 Future studies drawing on the results of these and the present study will shed light on the interactions between vasoactive and pro-or antimitogenic mediators in PPH, advancing our understanding of the mechanisms of action, other than vasodilatory, of therapies for the disease. …”

Section: Discussionmentioning

confidence: 74%

Continuous Infusion of Epoprostenol Improves the Net Balance Between Pulmonary Endothelin-1 Clearance and Release in Primary Pulmonary Hypertension

Langleben

Barst²,

Badesch³

et al. 1999

Circulation

Self Cite

View full text Add to dashboard Cite

Background-Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis. Methods and Results-Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (nϭ11 in the present study) with conventional therapy alone (nϭ7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio Ͻ1 than did the conventional therapy group, in which only 29% of patients had a ratio Ͻ1 (PϽ0.05). Conclusions-These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease. (Circulation. 1999;99:3266-3271.)Key Words: hypertension, pulmonary Ⅲ endothelin Ⅲ epoprostenol Ⅲ prostaglandins P rimary pulmonary hypertension (PPH) causes progressive elevation of pulmonary vascular resistance, leading to right heart failure and death. 1 Although vasoconstriction may play a role, microvascular narrowing and obliteration by cellular proliferation are important to the pathogenesis of PPH. 2 The cause of PPH is as-yet unidentified, but abnormalities of vascular and endothelial homeostasis, including reduced epoprostenol (formerly called prostacyclin) production, increased thromboxane production, possibly decreased nitric oxide synthase levels, and altered pulmonary handling of endothelin-1, have been identified in patients with established PPH. [3][4][5][6][7] It is not known whether any 1 of these abnormalities is the initiating cause of PPH, but all favor vasoconstriction and cellular proliferation and could contribute to the progression of the disease.Endothelin-1 (ET-1) is a vasoconstrictor peptide and smooth muscle mitogen 8,9 that has been implicated in the pathogenesis of several models of pulmonary hypertension. 10 -12 The human lung normally acts as a clearance organ for ET-1, 13,14 removing 60% to 70% of circulating ET-1 from the blood on each passage through the lungs. 14 However, as assessed by the ratio of ET-1 levels in systemic...

show abstract

“…Elevated plasma vWF and its antigen (vWF:Ag) have been used as markers of endothelial cell injury in a variety of conditions. Levels of vWF:Ag are elevated in PH [82,83] and baseline vWF:Ag correlates with the risk of death in the subsequent year [83]. In another study, vWF was also found to be elevated in severe PAH, and paralleled improvements in haemodynamics on prostacyclin therapy, although this was only in 10 patients [84].…”

Section: Plasma Von Willebrand Factormentioning

confidence: 96%

Biomarkers in pulmonary hypertension

Warwick

Thomas²,

Yates³

2008

Eur Respir J

140

View full text Add to dashboard Cite

There have been significant recent advances in the understanding of the pathophysiology of pulmonary hypertension, and a growing number of therapeutic agents have become available to the treating physician. Traditional methods of diagnosing and monitoring this condition have comprised echocardiography and right heart catheterisation, in addition to functional measures, such as estimation of functional class and the 6-min walk test. An increasing number of biomarkers have been described that are elevated in pulmonary hypertension and which may assist the clinician in diagnosis and in the assessment of disease severity and response to treatment.The present article details the more important biomarkers, their potential applications and the evidence supporting their use.

show abstract

Continuous Infusion of Prostacyclin Normalizes Plasma Markers of Endothelial Cell Injury and Platelet Aggregation in Primary Pulmonary Hypertension

Cited by 144 publications

References 11 publications

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Continuous Infusion of Epoprostenol Improves the Net Balance Between Pulmonary Endothelin-1 Clearance and Release in Primary Pulmonary Hypertension

Biomarkers in pulmonary hypertension

Contact Info

Product

Resources

About