Pharmacological Properties of KT3–671, a Novel Nonpeptide Angiotensin II Receptor Antagonist

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors

“…Comparable values have been reported earlier for rabbit aortic strip contraction studies (Cazaubon et al, 1993;Mochizuki et al, 1995).…”

“…This suggests that the equilibrium binding between this antagonist and the receptors is already attained after a very short incubation time. In agreement, the slope of the Schild regression analysis for losartan is close to unity (0.92+0.05) and the pK B -value (7.90+0.06) is comparable to those (8.2 ± 8.5) reported in earlier contraction studies (Robertson et al, 1992;Renzetti et al, 1995;Mochizuki et al, 1995).…”

“…Under these conditions, the selective AT 1 receptor antagonists varied in the type of inhibition from almost completely insurmountable (candesartan, producing an over 90% decline of the maximal response) to completely surmountable (losartan, only producing a leftward shift of the agonist concentration-response curve). The same pattern for candesartan and losartan was observed when the IP accumulation was measured after a 5 or 30 min period, an observation in agreement with earlier rabbit aortic strip contraction studies (Cazaubon et al, 1993;Noda et al, 1993;Mochizuki et al, 1995). Kinetic experiments (Figure 9 and Noda et al, 1993) indicate that the inhibitory e ect of candesartan increases with the preincubation time and that optimal inhibition is obtained after prolonged incubation.…”

“…Most antagonists produce parallel rightward shifts of the angiotensin II concentration-response curve, without a ecting the maximal response. These are classi®ed as surmountable antagonists (Gaddum et al, 1955) and losartan is a typical example (Mochizuki et al, 1995). Insurmountable antagonists are able to depress the maximal response.…”

“…Insurmountable antagonists are able to depress the maximal response. The extent of this decline varies considerably from one antagonist to another and it seems to be unrelated to the potency of the antagonist to produce rightward shifts of the concentration-response curve (Liu et al 1992;Cazaubon et al, 1993;Noda et al, 1993;Mochizuki et al, 1995). The molecular basis for insurmountable antagonism is still a matter of debate.…”