Characterization of angiotensin II antagonism displayed by SK-1080, a novel nonpeptide AT1-receptor antagonist

The pharmacologic profile of SK-1080, a nonpeptide AT(1)-selective angiotensin-receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in pithed rats. SK-1080 inhibited the specific binding of [I-125]-[Sar(1), Ile(8)]-angiotensin II to human recombinant AT(1) receptor with a 12-fold greater potency than losartan [median inhibitory concentration (IC50): 1.01 and 12.3 nM, respectively], but it did not inhibit the binding of [I-125]-CGP 42112A to human recombinant AT(2) receptor (IC50: >10 mu M for both). The Hill coefficient for the competition curve of SK-1080 against AT(1) receptor was not significantly different from unity (0.96). Scatchard analysis showed that SK-1080 interacted with human recombinant AT(1) receptor in a competitive manner, as with losartan. In functional studies with rat and rabbit aorta, SK-1080 competitively inhibited the contractile response to angiotensin II (pK(B) values: 9.97 and 9.51, respectively) with 15-25% decrease in the maximal contractile responses, unlike losartan, which showed competitive antagonism without any change in the maximal contractile responses to angiotensin II (pA(2) values, 8.02 and 7.59, respectively). In pithed rats, SK-1080 (i.v.) induced a nonparallel right shift in the dose-presser response curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reduction in the maximal responses; this antagonistic effect was similar to 25 times more potent than losartan (ID50, 1.74 mg/kg), which showed competitive antagonism. SK-1080 did not alter the responses induced by other agonists such as norepinephrine, KCl, and vasopressin in isolated rabbit aorta and pithed rats. These results suggest that SK-1080 is a highly potent AT(1)-selective angiotensin II-receptor antagonist with a mode of insurmountable antagonism.