Candesartan (CV-11974) dissociates slowly from the angiotensin AT1 receptor

Eur J Pharmacol. 1997 Jan 14;319(1):137-46. doi: 10.1016/s0014-2999(96)00837-0.

Abstract

The mechanisms of the insurmountable antagonism of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]1H-benzimid azole -7-carboxylic acid, candesartan (CV-11974), an angiotensin AT1 receptor antagonist, on angiotensin II-induced rabbit aortic contraction were examined in contraction and binding studies. Preincubation of the rabbit aorta with CV-11974 (0.1 nM) for 30 min reduced the maximal contractile response to angiostensin II by approximately 50%. This insurmountable antagonism of CV-11974 was reversed in the presence of losartan (1 microM), a surmountable angiotensin AT1 receptor antagonist. The inhibitory effect of CV-11974 on angiotensin II-induced contraction persisted longer after washing than did that of losartan but was irreversible. Scatchard analysis of [3H]CV-11974 binding in bovine adrenal cortical membranes indicated the existence of a single class of binding sites (Kd = 7.4 nM). Competition binding studies using angiotensin II receptor agonists and antagonists have demonstrated that [3H[CV-11974 binding sites may be identical to angiotensin AT1 receptors. The dissociation rate of [3H]CV-11974 binding (t1/2 = 66 min) was 5 times slower than that of [125I]angiotensin II binding (t1/2 = 12 min). These results suggest that the insurmountable antagonism by CV-11974 is due to its slow dissociation from angiotensin AT1 receptors.

MeSH terms

  • Adrenal Cortex / metabolism
  • Angiotensin II / metabolism*
  • Angiotensin II / pharmacology
  • Angiotensin Receptor Antagonists*
  • Animals
  • Benzimidazoles / metabolism*
  • Benzimidazoles / pharmacology
  • Biphenyl Compounds / pharmacology
  • Cattle
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Losartan
  • Male
  • Rabbits
  • Receptors, Angiotensin / metabolism*
  • Tetrazoles / metabolism*
  • Tetrazoles / pharmacology
  • Vasoconstriction / drug effects

Substances

  • Angiotensin Receptor Antagonists
  • Benzimidazoles
  • Biphenyl Compounds
  • Imidazoles
  • Receptors, Angiotensin
  • Tetrazoles
  • Angiotensin II
  • Losartan
  • candesartan