Insurmountable AT1-receptor antagonists reduce maximal response (30% for irbesartan to 95% for candesartan) due to slow dissociation rates (t1/2 of 7 minutes for irbesartan to 120 for candesartan).
The insurmountable inhibition of certain AT1-receptor antagonists like candesartan is driven by their slow dissociation rate and continuous recycling at the receptor.
A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct 3H-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonist-bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or `rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor.
Vauquelin et al. (Thu,) reported a other. AT1-receptor antagonists (losartan, irbesartan, valsartan, EXP3174, candesartan) was evaluated on Inhibition of agonist-induced responses and dissociation rate. Insurmountable AT1-receptor antagonists reduce maximal response (30% for irbesartan to 95% for candesartan) due to slow dissociation rates (t1/2 of 7 minutes for irbesartan to 120 for candesartan).