The present study sought to investigate the protective role of OA-NO₂ in angiotensin (Ang) II–induced hypertension.

We show that systemic administration of OA-NO₂ results in a sustained reduction of Ang II–induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO₂ significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT₁R)-mediated signaling because vascular contraction by other G-protein–coupled receptors is not altered in response to OA-NO₂ treatment. From the mechanistic viewpoint, OA-NO₂ lowers Ang II–induced hypertension independently of peroxisome proliferation-activated receptor (PPAR) activation. Rather, OA-NO₂, but not OA, specifically binds to the AT₁R, reduces heterotrimeric G-protein coupling, and inhibits IP₃ (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor.

These results demonstrate that OA-NO₂ diminishes the pressor response to Ang II and inhibits AT₁R-dependent vasoconstriction, revealing OA-NO₂ as a novel antagonist of Ang II–induced hypertension.