Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET A and ET B receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627, ABT-546, A-182086 and A-192621, which exhibit difference in selectivity for ET A and ET B receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting 125 I-labelled ET-1 binding to cloned human ET A and ET B receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).

This study aims to investigate the role of endothelin-1 (ET-1) in the genesis of acute ischaemic arrhythmias. In anaesthetized cats and rats receiving continuous monitor of electrocardiogram and arterial blood pressure, the ischaemic arrhythmias during 60-min myocardial ischaemia elicited by the occlusion of the left anterior descending coronary artery (LAD) were analysed. To prevent the putative arrhythmic effects of endogenous ET-1, ET A receptor antagonist BQ610 (1.5–6.0nmol/kg) was intracoronary injected just before LAD occlusion in cats, and preproET-1 mRNA antisense oligodeoxynucleotide (AS-ODN; 30–90nmol/kg) was intravenously injected 2h before LAD occlusion in rats. The results showed that BQ610 dose-dependently decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF), and the numbers of ventricular ectopic beats (VEBs). At the dose of 6.0nmol/kg, the incidence of VT decreased significantly from 33.3% in normal saline (NS) control group to zero ( P <0.01), and total VEBs decreased significantly from 831±162 to 158±51 ( P <0.05). In rats receiving ET-1 AS-ODN, plasma ET-1 decreased significantly after 2h, and remained stable at 30min of LAD occlusion. However, in rats receiving the control, NS or sense ODN, plasma ET-1 remained unchanged after administration, but increased significantly during LAD occlusion. The ischaemic arrhythmias were dose-dependently suppressed in the presence of ET-1 AS-ODN. At the dose of 90nmol/kg, the incidence of VT decreased significantly from 100% in both the control groups to 30%. The numbers of single VEBs, consecutive VEBs, VT and total VEBs were also significantly decreased, from 60±15 in NS group to 19±12, 11±3 to 2±2, 155±41 to 11±11, and 239±49 to 35±25 respectively. In the present cat and rat models of coronary artery occlusion, antagonism of either ET A receptors or endogenous ET-1 synthesis prevented the ischaemic arrhythmias, indicating that ET-1 is possibly an important promotive factor in the genesis of acute ischaemic arrhythmias.

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET A and ET B receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET A and ET B receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.