In a larger study of patients with nondiabetic proteinuric

In a larger study of 22 patients with nondiabetic proteinuric chronic kidney disease, BQ-123 produced significant natriuresis, resulting from increased renal blood flow. In addition, ETA antagonism reduced blood pressure and proteinuria, and, a new finding, decreased arterial stiffness. However, in diabetic patients with chronic kidney disease, avosentan (ETA-selective nonpeptide antagonist) was reported to be detrimental as a result of fluid overload.
ET-Receptor Blockade in Chronic Kidney Disease Receptor antagonists have emerged as the only strategy in the clinic for blocking the unwanted actions of ET-1. To date, no alternative strategies, such as inhibitors of ET converting pcpt australia or combined endothelin-converting enzyme (ECE)/neutral endopeptidase (NEP) inhibitors, have been approved. Four compounds, bosentan, ambrisentan, sitaxentan, and macitentan, originally were approved for clinical use in pulmonary arterial hypertension (PAH) (Table 2). Sitaxentan, however, was withdrawn from clinical use in 2010 after idiosyncratic hepatitis occurred resulting from acute liver failure, leading to death. PAH affects approximately 100,000 patients in the United States and Europe and currently there is no cure. The disease is characterized by constriction and remodeling of pulmonary vessels, with high blood pressure in the lungs. This leads to right heart failure, which is the ultimate cause of death. Interestingly, although ETA are increased significantly in the failing right ventricle of patients with PAH and the failing left ventricle of patients with heart failure, clinical trails have failed to show a benefit in patients from the latter group. The reasons for this are unclear, but the action of ET antagonists on the vasculature may be more important in restoring the imbalance between ET-induced constriction and opposing vasodilatation of blood vessels. In theory, the selectivity of antagonists should have pharmacologic and pathophysiological consequences. Selectively blocking smooth muscle ETA would be expected to lead to vasodilatation and attenuate proliferation, migration, fibrosis, and hypertrophy. Endothelial ETB, particularly in kidney, lung, and liver, should continue to bind and remove ET-1 where it is overexpressed in pathophysiological conditions, as well as releasing vasodilators to mediate their antiproliferative and antithrombotic actions.
How do we Define Antagonist-Receptor Selectivity? These four antagonists represent a spectrum of selectivity ranging from bosentan, which is classified by the pharmaceutical company Actelion (Allschwil, Switzerland) as a mixed or balanced ETA/ETB antagonist, to sitaxentan, the most ETA selective. No consensus has emerged about the relative merits of mixed versus ETA-selective compounds in PAH.61, 62 Some animal studies have suggested that selective ETA antagonism that leaves ETB unopposed and unblocked is beneficial, whereas other studies have shown mixed and ETA-selective antagonists have similar outcomes. The advantage of animal studies are that compounds can be compared head to head, but given differences in cell expression of subtypes these may not necessarily be informative of clinical studies in human beings. No clear-cut advantage of one over another has been reported for selective versus nonselective antagonism in PAH. However, in chronic kidney disease, the function and distribution of receptors suggests an ETA antagonist would be preferable in blocking ETA-mediated constriction and proliferation but sparing endothelial cell vasodilatation, clearing ET from the plasma, and natriuresis. The selectivity of a ligand for two receptors usually is calculated by measuring the equilibrium dissociation constant (KD) for the two subtypes, in this case ETA and ETB, to provide a ratio of selectivity65, 66 in ligand-binding assays. There is no standardized method or general agreement among pharmaceutical companies to determine which compound should be classified as ETA selective versus a mixed antagonist. Accurate information is essential in interpreting results from experiments in animal models and clinical trials as to whether the doses used are likely to result in a compound occupying only ETA or both subtypes. We have proposed that ETA-selective compounds should have at least a 100-fold selectivity for the ETA subtype whereas mixed antagonists should have less than 100-fold ETA selectivity. The reason for this is that the degree of receptor occupancy achieved when an antagonist is administered in vivo or in vitro is proportional to the concentration and can be calculated from the affinity using the following formula: L*/(KD + L*), where L* is the free ligand concentration and KD is the affinity constant. For example, a compound that has an affinity measured in a ligand-binding assay of 1 nmol/L for ETA but 100 nmol/L for ETB would have 100-fold selectivity for ETA. By using this equation, at a concentration of 10 nmol/L, 90% of ETA are calculated to be blocked but less than 10% of the ETB. Although this concentration can be achieved accurately under controlled in vitro conditions, 100-fold selectivity is likely to represent the minimum that can be used in vivo to achieve selective ETA blockade. If the plasma concentration of this antagonist was increased to 100 nmol/L, 50% of ETB then would be occupied. Compounds of greater than 1,000-fold selectivity are likely to be needed for clinical or in vivo studies to ensure ETA selectivity is maintained.