The Effect of an Endothelin-Receptor Antagonist, Bosentan, on Blood Pressure in Patients with Essential Hypertension

Krum, Henry; Viskoper, Reuven J.; Lacourcière, Yves; Budde, M.; Charlon, Vincent

doi:10.1056/nejm199803193381202

Cited by 519 publications

(269 citation statements)

References 19 publications

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“…52,53 A 4-week treatment trial with bosentan at a fairly high dose of 1000 mg twice per day produced a fall in ambulatory diastolic blood pressure of approximately 10 mm Hg, an effect similar to treatment with 20 mg enalapril. 54 Large clinical trials of ET receptor antagonists have not been conducted for hypertension.…”

Section: Essential Hypertensionmentioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

202

128

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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...

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Section: Essential Hypertensionmentioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

202

128

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“…6 Studies in humans show the importance of ET-1 in the maintenance of vascular tone 7 and blood pressure 8 and suggest therapeutic potential for endothelin receptor antagonists in pathophysiological states characterized by vasoconstriction, such as essential hypertension and pulmonary arterial hypertension. 9,10 Chronic renal failure (CRF) is characterized by systemic and renal vasoconstriction and commonly associated with hypertension. Given that endothelin receptor antagonists cause vasodilation, 7,11 lower blood pressure, 9,11 and ameliorate renal dysfunction in experimental models of kidney disease, 12 they may be useful in the treatment of CRF.…”

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confidence: 99%

“…9,10 Chronic renal failure (CRF) is characterized by systemic and renal vasoconstriction and commonly associated with hypertension. Given that endothelin receptor antagonists cause vasodilation, 7,11 lower blood pressure, 9,11 and ameliorate renal dysfunction in experimental models of kidney disease, 12 they may be useful in the treatment of CRF. The aim of the present study was to show whether endothelin receptor antagonists would produce beneficial systemic or renal hemodynamic effects in CRF.…”

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confidence: 99%

Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure

et al. 2004

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Background-Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade. Methods and Results-We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls Ϫ4Ϯ2%, CRF Ϫ13Ϯ2%, PϽ0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8Ϯ23.9%, PϽ0.01 versus placebo) and reduced renal vascular resistance (Ϫ44.5Ϯ11.3%, PϽ0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls. Conclusions-ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

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“…Endothelin receptor antagonists have been found to reduce blood pressure in hypertensive animals (Nishikibe et al, 1993) and in patients with essential hypertension (Krum et al, 1998;Cardillo et al, 1999). Both selective ET A and ET B receptor antagonists and non-selective endothelin receptor antagonists induce a greater vasodilatation in the forearm of hypertensive patients 16 than in normotensive subjects (Cardillo et al, 2002;Taddei et al, 1999) …”

Section: Hypertensionmentioning

confidence: 99%

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

Xu¹,

Sun²,

Edvinsson³

2010

Pharmacology & Therapeutics

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Cardiovascular disease remains as the leading cause of death in the developed world.However, there is limited knowledge about how cardiovascular risk factors actually cause vascular disease. Traditional cardiovascular risk factors include increased circulating levels of low-density lipoproteins, cigarette smoking and hypertension (both strongly related to arterial wall injury), inflammation and atherosclerosis.

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The Effect of an Endothelin-Receptor Antagonist, Bosentan, on Blood Pressure in Patients with Essential Hypertension

Cited by 519 publications

References 19 publications

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

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