scholarly journals Distinctions between non-peptide angiotensin II AT1-receptor antagonists

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S24-S31 ◽  
Author(s):  
Georges Vauquelin ◽  
Frederik LP Fierens ◽  
Ilse Verheijen ◽  
Patrick ML Vanderheyden
Keyword(s):  
Angiotensin Ii ◽  
Inositol Phosphate ◽  
At1 Receptor ◽  
Maximal Response ◽  
Ang Ii ◽  
Receptor Antagonists ◽  
Experimental Conditions ◽  
At1 Receptors ◽  
At1 Receptor Antagonists ◽  
Slow Dissociation

A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct [3H]-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonist-bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or `rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor.

scholarly journals Characterisation of angiotensin II receptors in isolated human subcutaneous resistance arteries

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S37-S41 ◽  
Author(s):  
Hoa Ytterberg ◽  
Lars Edvinsson
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
At1 Receptor ◽  
Receptor Subtypes ◽  
At2 Receptor ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Receptor Antagonists ◽  
Response Curves ◽  
At1 Receptor Antagonists

Subcutaneous arteries have been used as a model for resistance arteries, which are potentially involved in enhanced blood pressure (BP) regulation in man. Angiotensin II (Ang II) is an important regulator of tone, acting via type 1 (AT1-) and type 2 (AT2-) receptor subtypes. The aim of this study was to characterise the Ang II receptors in isolated human subcutaneous arteries, using pharmacological and molecular methods. Subcutaneous arteries were obtained from patients undergoing elective gut surgery and were carefully dissected from the abdominal wall. Cylindrical segments were mounted on two L-shaped metal prongs, one of which was connected to a force-displacement transducer for continuous recording of isometric tension. Concentration-response curves to Ang II were constructed in the presence and absence of various selective AT1-receptor antagonists, candesartan, EXP3174, irbesartan and losartan, and the AT2-receptor antagonist, PD 123319. Responses to Ang II were measured as increases in force (mN) and expressed as a percentage of the response to 60 mM of KCl. Ang II caused a concentration-dependent contraction (pEC50=9.45±0.48, Emax=120±13%). Candesartan and EXP3174 caused concentration-dependent depression of the Emax of Ang II without any major shift of pEC50. Losartan and irbesartan caused a significant, dose-dependent rightward shift of the Ang II contraction-response curve in human subcutaneous arteries. The results show that contractile responses of human subcutaneous arteries are mediated via the AT1-receptor. The AT1-receptor antagonists, candesartan and EXP3174, acted in an insurmountable manner, while losartan and irbesartan were surmountable AT1-receptor antagonists. The AT2-receptor antagonist, PD 123319, (10, 100 nM) had no effect on Ang II-induced contraction. This is supported by the positive identification of mRNA for the human AT 1-receptor by RT-PCR.

scholarly journals Does protein binding modulate the effect of angiotensin II receptor antagonists?

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S54-S58 ◽  
Author(s):  
Marc P Maillard ◽  
Catherine Centeno ◽  
Åsa Frostell-Karlsson ◽  
Hans R Brunner ◽  
Michel Burnier
Keyword(s):  
Angiotensin Ii ◽  
Protein Binding ◽  
Plasma Proteins ◽  
Dissociation Rate ◽  
At1 Receptor ◽  
Ang Ii ◽  
Receptor Antagonists ◽  
At1 Receptor Antagonists ◽  
Dissociation Rate Constants

Introduction Angiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%). With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists. Methods A radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II) antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin. Results The in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists. Conclusion Although the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

Synthesis of N-Alkyl-1,2,4-oxadiazinones as Angiotensin-II (AT1) Receptor Antagonists

Heterocycles ◽  
1993 ◽  
Vol 36 (5) ◽  
pp. 1027 ◽  
Author(s):  
Harold N. Weller ◽  
Arthur V. Miller ◽  
Kenneth E. J. Dickinson ◽  
S. Anders Hedberg ◽  
Carol L. Delaney ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Receptor Antagonists ◽  
At1 Receptor Antagonists

Modulation of K+ and Ca2+ currents in cultured neurons by an angiotensin II type 1a receptor peptide

1997 ◽  
Vol 273 (3) ◽  
pp. C1040-C1048 ◽  
Author(s):  
M. Zhu ◽  
R. R. Neubig ◽  
S. M. Wade ◽  
P. Posner ◽  
C. H. Gelband ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
At1 Receptor ◽  
Delayed Rectifier ◽  
Cultured Neurons ◽  
Ang Ii ◽  
Cytoplasmic Loop ◽  
At1 Receptors ◽  
The Third ◽  
Intracellular Changes

Angiotensin II (ANG II) inhibits delayed rectifier K+ current (IK) and stimulates total Ca2+ current (ICa) in neurons cocultured from newborn rat hypothalamus and brain stem, effects mediated via ANG II type 1 (AT1) receptors. Here, we identify potential G protein activator regions of the AT1 receptor responsible for initiating the intracellular changes that lead to alterations in these currents. Intracellular application into cultured neurons of a peptide corresponding to the third cytoplasmic loop of the AT1 receptor (AT1a/i3) mimicked the actions of ANG II on IK and ICa, whereas application of a peptide corresponding to the second cytoplasmic loop (AT1a/i2) did not alter these currents. This modulation of IK and ICa by AT1a/i3 involves intracellular messengers (G alpha q, protein kinase C, and intracellular Ca2+) that are identical to those involved in the modulation of IK and ICa following ANG II activation of AT1 receptors. These data provide functional evidence for a role of the third cytoplasmic loop of the AT1 receptor in G protein coupling and subsequent modulation of ion channel effectors.

Angiotensin II AT1 receptor antagonists and platelet activation

2001 ◽  
Vol 16 (suppl_1) ◽  
pp. 45-49 ◽  
Author(s):  
Antonio López‐Farré ◽  
Lourdes Sánchez de Miguel ◽  
Mercedes Montón ◽  
Ana Jiménez ◽  
Almudena Lopez‐Bloya ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Platelet Activation ◽  
At1 Receptor ◽  
Receptor Antagonists ◽  
At1 Receptor Antagonists

Comparative QSAR and pharmacophore analysis for a series of 2,4-dihydro-3H-1,2,4-triazol-3-ones derivatives as angiotensin II AT1 receptor antagonists

2013 ◽  
Vol 23 (5) ◽  
pp. 2486-2502 ◽  
Author(s):  
Mukesh C. Sharma ◽  
Smita Sharma ◽  
Pratibha Sharma ◽  
Ashok Kumar ◽  
Kamlendra Singh Bhadoriya
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Receptor Antagonists ◽  
At1 Receptor Antagonists
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