Trends in Pharmacological Sciences
ReviewSelective and mixed endothelin receptor antagonism in cardiovascular disease
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.
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