Mechanisms of insurmountable antagonism vary among AT1-receptor antagonists, with 606A, EXP3174, and CV11974 showing noncompetitive inhibition of AII-induced contraction unlike E4177.
The mechanisms of insurmountable antagonism differ among various AT1-receptor antagonists, as demonstrated by their distinct binding and functional profiles in rabbit tissues.
Angiotensin AT1-receptor antagonists can be classified into two types, surmountable and insurmountable ones, based on the way they inhibit angiotensin II (AII)-induced vasoconstriction. To elucidate the causes of the difference, we studied how several antagonists associate with and dissociate from AT1-receptor sites by using rabbit adrenal cortical membrane. Four antagonists, 606A, EXP3174, CV11974, and E4177, showed equipotent competitive antagonism when they were added simultaneous with 125I-AII in binding experiments. However, in AII-induced contraction studies with rabbit aorta, 606A, EXP3174, and CV11974 inhibited the contraction noncompetitively, whereas E4177 inhibited competitively. The longer the pretreatment period with EXP3174 or CV11974, the more effectively the antagonists suppressed AII-induced contraction. However, the suppression of contraction by 606A and E4177 changed little with the length of the pretreatment period. AII-induced contraction of 606A- or E4177-treated aorta recovered easily by washout, but that of CV11974-treated aorta was hard to recover by washout. These results obtained in the aorta were consistent with their characteristics observed in the AII binding study in the rabbit adrenal cortical membrane in cases of EXP3174 and CV11974. The differences between association rate with and dissociation rate from the AT1 receptor of E4177 and 606A were slight, in spite of the clear difference between their action in the contraction study. Because of the variations observed with the four compounds, mechanisms of insurmountable antagonism may not be uniform among AT1-receptor antagonists.
Kurosawa et al. (Thu,) conducted a other in Angiotensin II-induced vasoconstriction. AT1-receptor antagonists (606A, EXP3174, CV11974, E4177) was evaluated on Inhibition of angiotensin II-induced contraction and receptor binding. Mechanisms of insurmountable antagonism vary among AT1-receptor antagonists, with 606A, EXP3174, and CV11974 showing noncompetitive inhibition of AII-induced contraction unlike E4177.