Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: in vitro studies

2002 ◽  
Vol 103 (s2002) ◽  
pp. 107S-111S ◽  
Author(s):  
J. Ruth WU-WONG ◽  
Douglas B. DIXON ◽  
William J. CHIOU ◽  
Brian K. SORENSEN ◽  
Gang LIU ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Amino Acid ◽  
Small Molecule ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Arachidonic Acid Release ◽  
Functional Responses ◽  
Receptor Antagonists ◽  
Acid Release

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ETA and ETB 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 ETA and ETB receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting 125I-labelled ET-1 binding to cloned human ETA and ETB receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).

scholarly journals The influence of albumin and calcium on human platelet arachidonic acid metabolism

Blood ◽  
1980 ◽  
Vol 55 (3) ◽  
pp. 418-423 ◽  
Author(s):  
MJ Stuart ◽  
JM Gerrard ◽  
JG White
Keyword(s):  
Arachidonic Acid ◽  
Acid Metabolism ◽  
Human Platelet ◽  
Arachidonic Acid Metabolism ◽  
Albumin Concentration ◽  
Arachidonic Acid Release ◽  
Acid Release ◽  
External Calcium ◽  
Platelet Thromboxane

Abstract The effects of in vitro changes in calcium and albumin on human platelet arachidonic acid metabolism were evaluated. Hypoalbuminemia enhanced the conversion of released 14C-arachidonic acid from prelabeled platelet phospholipids to the metabolites of the platelet cyclooxygenase and lipoxygenase pathways. This effect was, however, associated with a decreased release of arachidonic acid in the presence of hypoalbuminemia, such that the overall conversion of released 14C- arachidonic acid to platelet thromboxane B2 was similar in the presence of physiologic albumin concentration (3.5 g/dl) or at decreased albumin concentrations of 0.7 and 0.0 g/dl. External calcium was shown to be important for optimal platelet arachidonic acid release, with maximal release occurring at 1 mM calcium.

scholarly journals Plasma from uninephrectomized rats stimulates phospholipid methylation and arachidonic acid release in renal-cortical slices

1989 ◽  
Vol 260 (2) ◽  
pp. 365-369 ◽  
Author(s):  
H Banfić ◽  
Z Gatalica
Keyword(s):  
Arachidonic Acid ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase A2 ◽  
Arachidonic Acid Release ◽  
Kinase C ◽  
Graded Response ◽  
Acid Release ◽  
Cortical Slices

Phospholipid methylation and arachidonic acid release in renal-cortical slices was investigated in vitro after addition of plasma from uninephrectomized or sham-operated rats. Plasma from uninephrectomized rats (‘uni-plasma’) stimulated phospholipid methylation when obtained within the first 3 h after uninephrectomy. With different amounts of added plasma a graded response in phospholipid methylation was obtained. Addition of 50 nM-12-O-tetradecanoylphorbol 13-acetate for 10 min to intact slices also stimulated phospholipid methylation, whereas incubation of slices before addition of ‘uni-plasma’ with 100 microM-1-(5-isoquinolinylsulphonyl)-2-methylpiperazine prevented it, suggesting that protein kinase C stimulates phospholipid methylation in renal-cortical slices. Plasma from uninephrectomized rats also stimulates [3H]arachidonic acid release from phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) via activation of phospholipase A2. Two mechanisms of phospholipase A2 activation are proposed: first, in which it is activated by protein kinase C and releases 3H radioactivity from PtdCho, and second, in which phospholipase A2 is stimulated by Ca2+ ions and releases 3H radioactivity from PtdEtn.

Arachidonic acid release: An in vitro alternative for dermal irritancy testing

1996 ◽  
Vol 34 (2) ◽  
pp. 167-176 ◽  
Author(s):  
V.A. Deleo ◽  
M.P. Carver ◽  
J. Hong ◽  
K. Fung ◽  
B. Kong ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Arachidonic Acid Release ◽  
Acid Release

Possible involvement of amino acid transporters on S-nitroso-cysteine-induced inhibition of arachidonic acid release in PC12 cells

2001 ◽  
Vol 311 (2) ◽  
pp. 117-120 ◽  
Author(s):  
Takanori Nemoto ◽  
Syunji Horie ◽  
Yasunobu Okuma ◽  
Yasuyuki Nomura ◽  
Toshihiko Murayama
Keyword(s):  
Arachidonic Acid ◽  
Amino Acid ◽  
Pc12 Cells ◽  
Amino Acid Transporters ◽  
Arachidonic Acid Release ◽  
Acid Release

Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: ex vivo and in vivo studies

2002 ◽  
Vol 103 (s2002) ◽  
pp. 112S-117S ◽  
Author(s):  
Jerry L. WESSALE ◽  
Andrew L. ADLER ◽  
Eugene I. NOVOSAD ◽  
Samuel V. CALZADILLA ◽  
Brian D. DAYTON ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Pressor Responses ◽  
Pharmacokinetic Properties ◽  
Isolated Arteries

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ETA and ETB 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 ETA and ETB 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.

In vitro stability and intestinal absorption characteristics of hexapeptide endothelin receptor antagonists

Life Sciences ◽  
1998 ◽  
Vol 63 (18) ◽  
pp. 1599-1609 ◽  
Author(s):  
Hyo-kyung Han ◽  
Barbra H. Stewart ◽  
Annette M. Doherty ◽  
Wayne L. Cody ◽  
Gordon L. Amidon
Keyword(s):  
Intestinal Absorption ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
In Vitro Stability ◽  
Absorption Characteristics
Sign in / Sign up

Export Citation Format

Share Document