Inhibition of ACE inhibitor-induced vascular permeability following a single dose subcutaneous administration of ALN-F12. Female C57BL/6J mice were subcutaneously administered a single dose of ALN-F12 at dose levels of 0, 0.1, 0.3, 1, or 3 mg/kg (n = 10 per group). Seven days after administration, animals were IV injected with the ACE inhibitor captopril (2.5 mg/kg); the vascular permeability tracer, Evans blue dye (30 mg/kg), was IV injected 15 min after captopril injection. Animals were euthanized 15 min after Evans blue dye injection. Blood (A) and intestine (B) were collected to evaluate Evans blue extravasation; livers were collected for F12 mRNA analysis (C). In panels A, B, and C, symbols denote data from individual animals, the group mean ± SD are also plotted. Statistical analysis performed using one-way ANOVA with Dunnett's post-hoc test with respect to PBS-treated animals in the captopril treatment group. (**) P < 0.01; (****) P < 0.0001. A correlation of intestinal Evans blue uptake and F12 mRNA levels (D). Panels E and F are the correlation of intestinal Evans blue extraction and PK (and HK) mRNA levels (Supplemental Figs. S2, S3).
