Review
Selective and mixed endothelin receptor antagonism in cardiovascular disease

https://doi.org/10.1016/j.tips.2007.10.002Get rights and content

Within five years of discovering endothelin (ET-1) in 1988, the first report of an orally available ET receptor antagonist was published. Within twelve years, bosentan, the first ET receptor antagonist to gain marketing authorisation, was made available for the treatment of pulmonary artery hypertension (PAH). Since this milestone in ET biology, several ET receptor antagonists have been developed, principally to target cardiovascular disease states. ET-1 acts through two receptors – ETA and ETB. Currently, the mixed antagonist, bosentan, and the selective ETA antagonist, sitaxsentan, are both licensed for the treatment of PAH, and clinical trials with these and other agents are ongoing for many diseases, including scleroderma, diabetic nephropathy and prostate cancer. Although there has been no argument about the importance of blocking ETA receptors, there remains a long-running debate as to whether additional ETB antagonism is of benefit, and this is the topic of the following review.

Section snippets

ET-1: receptors and actions

Endothelins (ETs) are a family of three 21-amino acid peptides (ET-1, ET-2 and ET-3), each with distinct gene and tissue distributions [1]. ET-1 is the major cardiovascular isoform [2], and an extremely powerful vasoconstrictor [3]. In each case, the gene product is a 212-amino acid preproET, which is cleaved by endothelin-converting enzymes (ECE) first to big ET, and then to the biologically active peptide and a C-terminal fragment (Figure 1).

The biological effects of ETs are mediated by two

ET receptor antagonists

Several selective ETA and mixed ETA/B receptor antagonists are in clinical development. Selectivity is calculated from in vitro competitive receptor assays. ‘Mixed’ antagonists have a ratio of ETA to ETB affinity <100-fold greater for ETA than ETB 1, 11, compared with ≥100-fold for ETA-selective agents. Thus, selectivity could depend on dose, with higher doses of marginally ETA-selective antagonists providing functionally important inhibitory effects at the ETB receptor.

In models of disease in

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a debilitating disease affecting young women. Left untreated, most patients with PAH die within 2–3 years of diagnosis [13]. Many studies provide evidence for a role of the ET system in PAH, and ET receptor antagonism has emerged as a promising development in its treatment [14].

Plasma ET-1 is increased in animal models, and patients, with PAH, probably reflecting both reduced clearance and increased production [9], and this correlates with disease

Chronic heart failure

Chronic heart failure (CHF) is a major cause of cardiovascular morbidity and mortality. In most cases, it is characterised by low cardiac output, leading to progressive haemodynamic and neurohumoral modifications, such as peripheral vasoconstriction and salt and water retention.

Circulating ET-1 is elevated in animal models of, and patients with, CHF. Similar to PAH, this has been shown to correlate inversely with functional state and survival [15]. Also, ET-1 protein and ET receptors are

Hypertension

Established hypertension is characterised by arteriolar vasoconstriction, vascular remodelling and left ventricular hypertrophy, with risk of myocardial infarction and stroke. Initial evidence of a pressor action of ET-1 led to the speculation that ET-1 might be implicated in hypertension [3]. Vascular production of ET-1 is increased in some, but not all, animal models of hypertension (mainly, but not exclusively, salt-dependent types) [4], which are associated with increased vascular growth

Chronic kidney disease

In the kidney, ET-1 is produced by several cell types (Table 1). Furthermore, the renal medulla is not only an important site of ET-1 generation, but also contains among the highest concentrations of immunoreactive ET-1 of any organ [43]. ET receptors are widely distributed within the human kidney, with the ETA subtype localised to vascular smooth muscle, notably in the glomeruli, vasa recta and arcuate arteries, whereas ETB receptors are more numerous (ETB to ETA ratio 2:1), and widespread,

Atherosclerosis

ET-1 is proinflammatory [7] and is implicated in the development of atherosclerosis. Increased expression of ET-1 and ECE is seen in human arteries at different stages of atherosclerosis [58], and both ETA and ETB receptors are highly expressed in smooth muscle cells and foamy macrophages in atherosclerotic models [59]. Importantly, not only is restoration of the impaired activity of the NO system seen following ET receptor antagonism in a range of animal models of atherosclerosis 59, 60, 61,

Cerebral vasospasm

Cerebral vasospasm is the only medically treatable cause of disability and death in patients suffering a subarachnoid haemorrhage (SAH). Although ET-1 does not generally contribute to cerebral vascular tone [66], its synthesis increases, and ET receptors are upregulated, following cerebral ischaemia and this might contribute to vascular dysfunction and brain injury 67, 68. Although the preclinical data favour use of selective ETA receptor antagonists in this condition, early clinical trials

Safety of ET receptor antagonists

Side-effects with ET receptor antagonists in clinical trials are common. The most frequently reported clinical adverse events are headache, dizziness, nausea and nasal congestion. These seem to be a class effect and probably relate to vasodilatation. The mechanism of peripheral oedema with ET receptor antagonism remains unclear. ET-1 acts in the renal tubule via the ETB receptor to promote natriuresis and diuresis. Thus, peripheral oedema associated with vasodilatation could be aggravated by

Conclusion

ET receptor antagonism remains a promising therapeutic approach. However, it is unclear when to use selective ETA receptor antagonists and when to use mixed ETA/B blockers. To this end, further information regarding the role of the ETB receptor, both in health and disease, will be beneficial. It also remains unclear, for example, whether an increase in circulating ET-1 following ET receptor antagonism reflects ETB receptor blockade [72]. Clinical studies using selective ETB receptor agonists

Acknowledgement

The authors thank Gramling Medical Illustration (USA) for help with the production of Figure 1.

References (72)

  • E.L. Schiffrin

    Role of endothelin-1 in hypertension and vascular disease

    Am. J. Hypertens.

    (2001)
  • A.P. Davenport

    Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtype-selective ligands BQ123 and BQ3020: evidence for expression of ETB receptors in human vascular smooth muscle

    J. Cardiovasc. Pharmacol.

    (1993)
  • G. DeNucci

    Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor

    Proc. Natl. Acad. Sci. U. S. A

    (1988)
  • N. Dhaun

    The endothelin system and its antagonism in chronic kidney disease

    J. Am. Soc. Nephrol.

    (2006)
  • S. Gasic

    Regional haemodynamic effects and clearance of endothelin-1 in humans: renal and peripheral tissues may contribute to overall disposal of the peptide

    J. Cardiovasc. Pharmacol.

    (1992)
  • J. Dupuis

    Human pulmonary circulation is an important site for both clearance and production of endothelin-1

    Circulation

    (1996)
  • T. Attina

    Endothelin antagonism in pulmonary hypertension, heart failure, and beyond

    Heart

    (2005)
  • R. Lahav

    An endothelin receptor B antagonist inhibits growth and induces cell death in human melanoma cells in vitro and in vivo

    Proc. Natl. Acad. Sci. U. S. A

    (1999)
  • G.E. D’Alonzo

    Survival in patients with primary pulmonary hypertension. Results from a national prospective registry

    Ann. Intern. Med.

    (1991)
  • L.J. Rubin

    Bosentan therapy for pulmonary arterial hypertension

    N. Engl. J. Med.

    (2002)
  • D. Ivy

    Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction

    Am. J. Physiol.

    (2001)
  • D.D. Ivy

    Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus

    Am. J. Physiol.

    (2000)
  • K. Sato

    Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs

    Am. J. Physiol.

    (1995)
  • S. Eddahibi

    Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats

    Am. J. Physiol.

    (1995)
  • S.J. Chen

    The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats

    J. Cardiovasc. Pharmacol.

    (1997)
  • R.J. Barst

    Sitaxsentan therapy for pulmonary arterial hypertension

    Am. J. Respir. Crit. Care Med.

    (2004)
  • H. Krum

    The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension

    N. Engl. J. Med.

    (1998)
  • B. Hocher

    Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice

    Am. J. Respir. Cell Mol. Biol.

    (2000)
  • N. Davie

    ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells

    Am. J. Respir. Crit. Care Med.

    (2002)
  • M. Nishida

    Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension

    J. Cardiovasc. Pharmacol.

    (2004)
  • S. Sakai

    Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart

    Circulation

    (1996)
  • T. Kobayashi

    Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart

    Am. J. Physiol.

    (1999)
  • B. Pieske

    Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium

    Circulation

    (1999)
  • P. Mulder

    Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure

    Circulation

    (2000)
  • M. Ohnishi

    Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure

    Cardiovasc. Res.

    (1998)
  • Cited by (66)

    • The endothelin system as target for therapeutic interventions in cardiovascular and renal disease

      2020, Clinica Chimica Acta
      Citation Excerpt :

      In this brief review, we summarize the physiologic properties of endothelin and discuss its potential roles in the pathophysiology of diseases and associated therapeutic options. Endothelin is generated and released in response to a range of stimulating factors, as depicted in Fig. 2 [16,22]. Since endothelin is not stored, its secretion is managed by gene expression; first, the mRNA is formed approximately within fifteen minutes in the endothelial cells by passing through various processing steps, then the active endothelin peptide is generated.

    View all citing articles on Scopus
    View full text