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Research ArticleCARDIOVASCULAR

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Marc P. Maillard, Christine Perregaux, Catherine Centeno, Joachim Stangier, Wolfgang Wienen, Hans-R. Brunner and Michel Burnier
Journal of Pharmacology and Experimental Therapeutics September 2002, 302 (3) 1089-1095; DOI: https://doi.org/10.1124/jpet.102.036772
Marc P. Maillard
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Christine Perregaux
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Catherine Centeno
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Joachim Stangier
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Wolfgang Wienen
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Hans-R. Brunner
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Michel Burnier
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Abstract

In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [3H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t1/2) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses >0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.

Footnotes

  • This study was supported by a research grant from Boehringer Ingelheim Pharma KG (Biberach an der Riss, Germany).

  • DOI: 10.1124/jpet.102.036772

  • Abbreviations:
    AngII
    angiotensin II
    AT1
    angiotensin II subtype-1 receptor
    SMC
    smooth muscle cells
    RVSMC
    rat vascular smooth muscle cells
    DMEM
    Dulbecco's modified Eagle's medium
    • Received March 28, 2002.
    • Accepted May 7, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 3
1 Sep 2002
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Research ArticleCARDIOVASCULAR

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Marc P. Maillard, Christine Perregaux, Catherine Centeno, Joachim Stangier, Wolfgang Wienen, Hans-R. Brunner and Michel Burnier
Journal of Pharmacology and Experimental Therapeutics September 1, 2002, 302 (3) 1089-1095; DOI: https://doi.org/10.1124/jpet.102.036772

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Research ArticleCARDIOVASCULAR

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Marc P. Maillard, Christine Perregaux, Catherine Centeno, Joachim Stangier, Wolfgang Wienen, Hans-R. Brunner and Michel Burnier
Journal of Pharmacology and Experimental Therapeutics September 1, 2002, 302 (3) 1089-1095; DOI: https://doi.org/10.1124/jpet.102.036772
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