1. Animal kidneys are exquisitely sensitive to the vasoconstrictor and antinatriuretic effects of the endogenous vascular peptide endothelin. Animal studies have implicated endothelin in cyclosporin A and ischaemia-mediated renal damage. 2. In man, endothelin levels are raised in various disorders. Orally active endothelin antagonists are now being developed, but little was known of endothelin'...

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA)...

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA)...

Twenty-five years ago, a groundbreaking paper from Tsukuba University in Japan was published, identifying the sequence of the endothelin gene and peptide (Nature 332, 411-415, 1988). This work opened the way for the discovery of the endothelin receptors and the development of orally active endothelin receptor antagonists (ERAs). Today, ERAs are part of medical therapy of patients around the wor...

Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortal...

In this study the endothelin (ET) receptors mediating contractions produced by ET-1, ET-3 and the selective ET(B) ligands sarafotoxin 6c (S6c) and BQ-3020 in guinea pig bronchus were investigated using SB 209670, a nonpeptide, mixed ET(A)/ET(B) receptor antagonist, and the peptide ET receptor antagonists BQ-123 (ET(A) receptor-selective), BQ-788 (ET(B) receptor-selective) and RES-701 (ET(B) rec...

Endothelins (ETs) are a family of potent vasoactive peptides found in at least three distinct isoforms: ET-1, ET-2, and ET-31}. Two major subtypes of endothelin receptors, termed ETAand ETB, have been identified in various target cells2). It is well known that ETs act on these G protein-coupled receptors and exert multiple pharmacological effects3). As the development of potent and selective en...

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonis...

response in cardiac index as displayed in Figure 4, oxygen delivery did improve consistent with the patient’s clinical improvement. Of course, with systemic-to-pulmonary communications, the determination of pulmonary vs systemic blood flow depends upon several factors in addition to pulmonary vascular resistance vs systemic vascular resistance: obligatory shunting, effects of streaming, as well...

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 pote...