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O-28: Molecular basis for the insurmountable AT-1 receptor antagonism of telmisartan

Maillard, Marc P. ; Centeno, Catherine ; Wienen, Wolfgang ; Brunner, Hans R. ; Burnier, Michel

In: American Journal of Hypertension, 2001, vol. 14, no. S1, p. 12A-13A

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    Titre
    • O-28: Molecular basis for the insurmountable AT-1 receptor antagonism of telmisartan
    Auteur
    • Maillard, Marc P.. Division of Hypertension and Vascular Medicine Lausanne University Hospital, Lausanne, Switzerland
    • Centeno, Catherine. Division of Hypertension and Vascular Medicine Lausanne University Hospital, Lausanne, Switzerland
    • Wienen, Wolfgang. Division of Hypertension and Vascular Medicine Lausanne University Hospital, Lausanne, Switzerland
    • Brunner, Hans R.. Division of Hypertension and Vascular Medicine Lausanne University Hospital, Lausanne, Switzerland
    • Burnier, Michel. Division of Hypertension and Vascular Medicine Lausanne University Hospital, Lausanne, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:293812
    Summary
    In vitro studies have shown that telmisartan is an insurmountable angiotensin II AT-1 receptor antagonist. In this study we have investigated the molecular basis of this insurmountable antagonism. The association and dissociation kinetics of telmisartan to angiotensin AT-1 receptors were measured using an in vitro radio-receptor binding assay. These radioligand binding studies were conducted either directly on rat vascular (aorta) smooth muscle cells (RVSMC) expressing solely the AT-1 receptor or on membrane preparation obtained from the same cells. The specific binding of3H-telmisartan to the surface of living RVSMC or membranes was saturable. From these data, a Kd value of 1.7 nM was estimated. Scatchard analysis of the3H-telmisartan binding on RVSMC indicated the existence of a single class of binding sites. The affinity of telmisartan for AT-1 receptor is only poorly affected by the presence of proteins (0.4% of rat plasma proteins) in the binding buffer, indicating that no great competition between telmisartan binding to its specific AT-1 receptor and to non-specific proteins binding sites occurs. In association experiments, the specific binding of3H-telmisartan increases quickly and reaches equilibrium within less than 1 hour, with an association rate constant calculated to be 0.006 min-1nM-1. Telmisartan dissociates very slowly from the AT-1 receptor, either in RVSMC membrane preparation or in living cells with a dissociation rate constant of ca. 0.01 min-1 resulting in a dissociation half-life (t1/2) of about 60 min, which is comparable to the previously published data for candesartan in bovine adrenal cortical membranes and almost 5 times slower than that of 125I-angiotensin II binding (t1/2=12 min). In contrast to candesartan that has been shown to re-associate with the AT-1 receptor, telmisartan does not appear to re-associate. Indeed, when the dissociation of labeled-telmisartan from AT-1 receptors was induced by washing the cells with cold-binding buffer, followed by addition of fresh binding buffer containing either cold telmisartan, Ang II or losartan, or nothing, no difference were observed in the dissociation rate constants measured with telmisartan whatever the composition of the binding buffer after removal of labeled-telmisartan. In conclusion, these results suggest that the insurmountable antagonism of telmisartan is due mainly to its very slow dissociation from angiotensin AT-1 receptors