Characterization of Angiotensin II Antagonism Displayed by SK-1080, a Novel Nonpeptide AT1-Receptor Antagonist

Abstract

The pharmacologic profile of SK-1080, a nonpeptide AT1-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 [125I]-[Sar1, Ile8]-angiotensin II to human recombinant AT1 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 [125I]-CGP 42112A to human recombinant AT2 receptor (IC50: >10 microM for both). The Hill coefficient for the competition curve of SK-1080 against AT1 receptor was not significantly different from unity (0.96). Scatchard analysis showed that SK-1080 interacted with human recombinant AT1 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 (pKB 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 (pA2 values, 8.02 and 7.59, respectively). In pithed rats, SK-1080 (i.v.) induced a nonparallel right shift in the dose-pressor response curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reduction in the maximal responses; this antagonistic effect was approximately 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, KCI, and vasopressin in isolated rabbit aorta and pithed rats. These results suggest that SK-1080 is a highly potent AT1-selective angiotensin II-receptor antagonist with a mode of insurmountable antagonism.

Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

“…As a control, parallel experiments were run in the presence of either zofenopril (ZOF), an ACE inhibitor (ACEI), homogenize the form with other references or olmesartan (OLM), an AR blocker (ARB). 21 …”

Effects of SK-1080 on Intimal Thickening and Impaired Vascular Relaxation after Ballon Injury in Rats

“…SK-1080 is structurally different from losartan and its series of imidazole analogues in having pyridylimidazole and pyridine N-oxide moieties. SK-1080 was shown to act by itself but not via its metabolites to exert a potent insurmountable antagonism [9,10] [9]. As in the binding assay, SK-1080 was shown to be significantly more potent than losartan in other experiments: over 50-fold in blocking the contractile effect of angiotensin II in rat and rabbit aorta (on the basis of calculated pK B ) and about 25-fold in blocking the pressor effect of angiotensin II in the pithed rat.…”

“…The aortic preparations were mounted for isometric force recording in an organ bath containing 20 ml of Krebs' bicarbonate buffer (mmol/l: NaCl, 118; KCl, 4.7; CaCl 2 , 2.5; NaHCO 3 , 25; MgSO 4 , 1.2; KH 2 PO 4 , 1.2; glucose, 11.0) bubbled with a mixture of gas (95% O 2 , 5% CO 2 ) and maintained at 37°C [9]. Force was measured using a force displacement transducer (Grass FT03; Grass Ins., Quincy, Mass., USA) and displayed on a chart recorder (Multicorder MC 6625; Hugo Sachs Electronic, March-Hugstetten, Germany).…”

Imaging the renin-angiotensin-aldosterone system in the heart

“…The difference in mean [ 18 F]fluorobenzoyl-lisinopril binding was significant between remote, noninfarct, and peri-infarct segments (P < 0.02). These preliminary data suggested that [ 18 F]fluorobenzoyl-lisinopril binds specifically to ACE, the binding is nonuniform in infarct, perinfarct, and remote noninfarct segments, and that there is apparent increased ACE activity in the juxtaposed areas of replacement fibrosis [46]. The increased ACE in the juxtaposed areas of replacement fibrosis may be a stimulus for collagen replacement and remodeling.…”