title: Long-lasting angiotensin type 1 receptor binding and protection by candesartan: comparison with other biphenyl-tetrazole sartans.
abstract: BACKGROUND
  The ability of biphenyl-tetrazole angiotensin type 1 (AT1) receptor antagonists (BTsartans) to block angiotensin II (Ang II)-mediated responses has been extensively investigated in vascular tissues and, more recently, in cell lines expressing the human AT1-receptor. When pre-incubated, BTsartans acted surmountably (shifting the Ang II concentration-response curve to the right) or insurmountably (also decreasing the maximal response). It was shown that their insurmountable behaviour is due to the formation of tight, long-lasting complexes with the receptor. Partial insurmountable antagonism is due to the co-existence of tight and loose complexes. The proportion of insurmountable antagonism, the potency and the dissociation rate of the BTsartans decreases in the order: candesartan > EXP3174 (losartan's active metabolite) > valsartan > irbesartan >> losartan.
  
  
  OBJECTIVE
  It is of interest to explore how tight AT1-receptor binding of BTsartans such as candesartan might contribute to their long-lasting clinical effect.
  
  
  METHODS
  Computer-assisted simulations (COPASI program) were performed to follow the receptor-occupation and protection by different antagonists as a function of time. Free antagonist concentrations were allowed to decrease exponentially with time.
  
  
  RESULTS
  The simulations suggest that slow dissociation does not tangibly prolong receptor occupancy if the free antagonist is eliminated at a slower pace (as is the case for BTsartans). Yet when surmountable and insurmountable antagonists occupy the same amount of receptors, insurmountable antagonists offer appreciably better protection against fluctuations in natural messenger concentration.
  
  
  CONCLUSIONS
  Slow receptor dissociation and slow antagonist elimination are likely to act in synergy to produce long-lasting receptor protection.
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Brussels, Belgium. gvauquel@vub.ac.be
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Frederik
authors.initials: F
authors.lastname: Fierens
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Liefde
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003198:Computer Simulation; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan