Hemodynamic Effects of Bosentan, an Endothelin Receptor Antagonist, in Patients With Pulmonary Hypertension

Williamson, Dominic J.; Wallman, Lucinda; Jones, Richard D.; Keogh, Anne; Scroope, F; Penny, Ronald; Weber, Cornelia; Macdonald, P.

doi:10.1161/01.cir.102.4.411

Cited by 173 publications

(92 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Its first reported use was in 7 female patients, 5 with primary pulmonary hypertension and 2 with pulmonary hypertension associated with scleroderma in an open-label dose-ranging study. 30 Bosentan infused intravenously in 50-, 150-, and 300-mg doses at 2-hour intervals produced a dose-dependent fall in pulmonary artery pressure and pulmonary vascular resistance and a slight increase in cardiac index. The trial, however, was prematurely terminated when 2 of the 7 patients died within 36 hours of entering the second part of the study.…”

Section: Pulmonary Hypertensionmentioning

confidence: 98%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

202

126

View full text Add to dashboard Cite

Abstract-The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. Key Words: endothelin Ⅲ heart failure Ⅲ pulmonary heart disease T he endothelin (ET) system, like other vascular regulatory systems, consists of a parent peptide that undergoes enzymatic activation and exerts its biologic effects by modulating specific receptors. Of the 4 active ETs (ET 1 through 4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. ET-1 is found in endothelial cells and is released toward the vascular smooth muscle consistent with a paracrine role, but it is also produced by smooth muscle cells and cardiomyocytes. 1,2 ET-1 has vasoconstrictive and mitogenic effects, stimulates the production of growth factors such as vascular endothelial growth factor and basic fibroblast growth factor, and potentiates the effects of transforming growth factor-␤ and platelet-derived growth factor. 3-7 Chronic ET-1 stimulation can result in myocardial fibrosis and hypertrophy and vascular fibrosis with extracellular matrix proliferation. 8 In the lung, ET-1 is abundantly expressed in the pulmonary vasculature and appears to play an important role in the regulation of pulmonary vascular tone. 9 ET-1 is also produced in leukocytes where it influences the production of a wide range of cytokines in the inflammatory response. 10 ET is regulated in an autocrine fashion by physiochemical factors such as blood flow, pulsatile stretch, sheer stress, and pH. 11-13 Acute hypoxia leads to selective stimulation of the ET-1 gene and ET synthesis in the pulmonary vasculature. 14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors. ET A receptors are found in the medial smooth muscle layers of the blood vessels, and atrial and ventricular myocardium. 21 When stimulated, the ET A receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.ET B receptors are localized on endothelial cells and, to some extent, smooth muscle cells and macrophages. 22 The activation of ET B receptors stimulates the release of nitric oxide and prostacyclin and prevents apoptosis. 23 Normally, t...

show abstract

Section: Pulmonary Hypertensionmentioning

confidence: 98%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

202

126

View full text Add to dashboard Cite

show abstract

“…15,16,60 In clinic, efficacy and safety of endothelin-receptor antagonist has been confirmed in PAH patients. [61][62][63][64] Because ET-1 (upregulated in PAH) activates NFATc1, which in turn increases bcl ¡ 2 expression, contributing to the prosurvival and antiapoptotic effects of ET-1, 65 endothelin-receptor antagonist might also inhibit NFAT activation. At present, most of studies found that interventions targeting NFAT pathway may be effective for PAH therapy.…”

Section: Targeting the Nfat Pathway For Pah Therapymentioning

confidence: 99%

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

View full text Add to dashboard Cite

Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor about 3 decades ago and was not well studied until the development of immunosuppressant. Numerous studies confirm that calcineurin/NFAT signaling is very important in the development of vasculature and cardiovascular system during embryogenesis and is involved in the development of vascular diseases such as hypertension, atherosclerosis and restenosis. Recent studies demonstrated that NFAT proteins also regulate immune response and vascular cells in the pulmonary microenvironment. In this review, we will discuss how different NFAT isoforms contribute to pulmonary vascular remodeling and potential new therapeutic targets for treating pulmonary arterial hypertension.

show abstract

“…Another group of substances that are currently being introduced in the treatment of pulmonary hypertension, are endothelin antagonists [50]. Plasma endothelin levels are increased in patients with systemic sclerosis but the association of increased endothelin levels and pulmonary hypertension is unclear [51].…”

Section: Treatmentmentioning

confidence: 99%

“…Plasma endothelin levels are increased in patients with systemic sclerosis but the association of increased endothelin levels and pulmonary hypertension is unclear [51]. Based on preliminary experiences in patients with PPH, these substances offer a promising perspective especially in conjunction with prostanoids [50]. A recently completed randomized, placebo-controlled multicentre trial showed that the dual endothelin receptor antagonist bosentan improves exercise capacity, pulmonary arterial pressure and cardiac output in patients with PPH and PAH associated with CREST/scleroderma [52].…”

Section: Treatmentmentioning

confidence: 99%

Pulmonary hypertension in collagen vascular disease: Table 1—

Hoeper¹

2002

Eur Respir J

View full text Add to dashboard Cite

Pulmonary hypertension in collagen vascular disease. M.M. Hoeper. #ERS Journals Ltd 2002. ABSTRACT: Pulmonary hypertension is a serious but often overlooked complication in collagen vascular disease. The understanding of the development of pulmonary hypertension has increased substantially during the last years.Abnormal proliferation of pulmonary vascular cells is now being regarded as a predominant process leading to pulmonary vascular obliteration. Medical therapy focuses on prostacyclin treatment, which has been shown to improve exercise capacity and haemodynamic variables in patients with several collagen vascular diseases and pulmonary arterial hypertension.Continuous intravenous prostacyclin remains the standard treatment of associated pulmonary hypertension but less invasive alternatives such as subcutaneous treprostinil, oral beraprost or aerosolized iloprost, as well as, novel substances such as endothelin receptor antagonists may be appropriate for selected patients.

show abstract

Hemodynamic Effects of Bosentan, an Endothelin Receptor Antagonist, in Patients With Pulmonary Hypertension

Cited by 173 publications

References 42 publications

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelin Receptor Blockers in Cardiovascular Disease

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

Pulmonary hypertension in collagen vascular disease: Table 1—

Contact Info

Product

Resources

About