Characterization of angiotensin II antagonism displayed by SK-1080, a novel nonpeptide AT(1)-receptor antagonist

The pharmacologic profile of SK-1080, a nonpeptide AT(1)-selective angioten sin-receptor antagonist, was investigated by receptor-binding studies, func tional in vitro assays with rabbit and rat aorta, and in vivo experiments i n pithed rats. SK-1080 inhibited the specific binding of [I-125]-[Sar(1), I le(8)]-angiotensin II to human recombinant AT(1) receptor with a 12-fold gr eater potency than losartan [median inhibitory concentration (IC50): 1.01 a nd 12.3 nM, respectively], but it did not inhibit the binding of [I-125]-CG P 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) recept or was not significantly different from unity (0.96). Scatchard analysis sh owed that SK-1080 interacted with human recombinant AT(1) receptor in a com petitive manner, as with losartan. In functional studies with rat and rabbi t aorta, SK-1080 competitively inhibited the contractile response to angiot ensin II (pK(B) values: 9.97 and 9.51, respectively) with 15-25% decrease i n the maximal contractile responses, unlike losartan, which showed competit ive antagonism without any change in the maximal contractile responses to a ngiotensin 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 respon se curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reducti on in the maximal responses; this antagonistic effect was similar to 25 tim es more potent than losartan (ID50, 1.74 mg/kg), which showed competitive a ntagonism. SK-1080 did not alter the responses induced by other agonists su ch as norepinephrine, KCl, and vasopressin in isolated rabbit aorta and pit hed rats. These results suggest that SK-1080 is a highly potent AT(1)-selec tive angiotensin II-receptor antagonist with a mode of insurmountable antag onism.