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Binding characteristics of [3H]-irbesartan to human recombinant angiotensin type 1 receptors

Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), 65 Paardenstraat, B-1640 Sint-Genesius Rode, Belgium, pvandhey{at}vub.ac.be

Ilse Verheijen

Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), 65 Paardenstraat, B-1640 Sint-Genesius Rode, Belgium

Frederik LP Fierens

Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), 65 Paardenstraat, B-1640 Sint-Genesius Rode, Belgium

Jean-Paul De Backer

Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), 65 Paardenstraat, B-1640 Sint-Genesius Rode, Belgium

Georges Vauquelin

Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), 65 Paardenstraat, B-1640 Sint-Genesius Rode, Belgium

The aim of the present work was to investigate the binding properties of the selective AT₁-receptor antagonist irbesartan to human AT₁-receptors by direct radioligand binding. For this purpose the specific binding of [³H]-irbesartan to intact Chinese Hamster Ovary (CHO) cells expressing human recombinant AT₁-receptors was determined. Specific binding of [³H]-irbesartan rapidly reached equilibrium and was saturable with a K_D of 1.94 ± 0.12 to a homogeneous class of binding sites. Its binding was inhibited by other AT₁ antagonists (AIIAs) with the same potency order as previous results from [³H]-angiotensin II and [³H]-candesartan binding to human AT₁-receptors. Whereas the dissociation rate of [³H]-irbesartan was essentially independent of the radioligand concentration, it was much slower at 12°C when compared with 37°C. Moreover, the dissociation rate was similar, as determined in washout experiments in the absence or presence of unlabelled AT₁ antagonists. At 37°C the dissociation rate constant corresponded to a half-life of approximately seven minutes, which is sufficient to explain the partially insurmountable inhibition by irbesartan in previous studies. In contrast, other phenomena such as the plasma half life and tissue-related factors are necessary to explain its sustained in vivo antihypertensive effect.

Key Words: irbesartan • CHO cells • AT1-receptor binding

Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 2, 159-165 (2000)
DOI: 10.3317/jraas.2000.020


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