By using BQ-788 as a selective endothelin ETB-receptor antagonist and FR139317 as a selective endothelin ETA-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist (succinyl-[Glu9,Ala11,5]-endothelin-1(8-21)), in anesthetized rats. Bolus intravenous injection of e...

Endothelin-1 (ET-1), a potent vasoactive peptide, plays an important role in the pathogenesis of liver disease and portal hypertension. Two major endothelin receptors (ET-A and ET-B) mediate biological effects, largely on the basis of their known downstream signaling pathways. We hypothesized that the different receptors are likely to mediate divergent effects in portal hypertensive mice. Liver...

The failure of endothelin antagonists to show benefit in heart failure cannot be understood until all the clinical trials are fully published.

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endot...

of Heart Failure To the Editor: We have read with interest the report by Lüscher et al1 on the Heart Failure Endothelin A Receptor Blockade Trial (HEAT). Administration of an endothelin A receptor antagonist, darusentan (30, 100, or 300 mg/d), for 3 weeks significantly decreased systemic vascular resistance with concomitant increase in cardiac index in patients with chronic heart failure (HF). ...

Pulmonary hypertension is the most ominous complication of connective tissue diseases and its treatment has been a big challenge to clinicians. Vasodilators including epoprostenol (prostacyclin), bosentan (endothelin-receptor antagonist), and a sildenafil (phosphodiesterase type 5 inhibitor) have recently become available in Japan. These vasodilators may improve exercise tolerance, hemodynamics...

BACKGROUND Although an initial study of endothelin receptor blockade reported positive findings, subsequent experiments and clinical trials in humans found little or no benefit. METHODS We applied meta-analytic methods to assess the methodologic rigor of preclinical studies of endothelin blockade and to quantitatively evaluate the totality of evidence regarding the effect of endothelin recept...

Pulmonary Arterial Hypertension (PAH) is a devastating disease that, until recently, had no effective medical therapy. In 1996, a prostacyclin, epoprostenol, was approved; since then, several therapies, including prostacyclin analogues and agents that modulate other vasoactive pathways – endothelin receptor antagonists and phosphodiesterase inhibitors – have received approval. In this issue of ...

WS009 A and B, produced by Streptomyces sp. No. 89009, were found to be competitive and specific antagonists against endothelin (ET)-1 receptors in in vitro studies and also active in in vivo studies. Furthermore, WS009 A and B were specific antagonists for vascular ET-1 receptors (ETA receptors) and significantly prevented the accumulation of intracellular inositol 1,4,5-triphosphate (IP3) in ...

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 co...