The small-molecule formyl peptide receptor biased agonist, Compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH), a rare but fatal disorder, is characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure (PAP) but not mortality. The G protein-coupled formyl peptide receptors (FPR) mediate vasodilatation and resolution of inflammation, actions likely to be beneficial in PAH. We investigated dilator and anti-inflammatory effects of the FPR biased agonist Compound 17b (Cmpd17b) in the pulmonary vasculature using mouse precision-cut lung slices (PCLS).

EXPERIMENTAL APPROACH: Using PCLS from 8-week-old male and female C57BL/6 mice, intrapulmonary arteries were pre-contracted with 5-HT for concentration-response curves to FPR agonists Cmpd17b and Cmpd43, and standard-of-care sildenafil, iloprost and riociguat. Cmpd17b-mediated relaxation was assessed ± FPR antagonists or pharmacological inhibitors, and in PCLS treated with TNF-α or LPS. Cytokine release into media from TNF-α- or LPS-treated PCLS ± Cmpd17b was determined.

KEY RESULTS: Cmpd17b elicited concentration-dependent vasodilation, with potencies of iloprost > Cmpd17b = riociguat > Cmpd43 = sildenafil. Cmpd17b was inhibited by the FPR1 antagonist Cyclosporin-H but not by inhibitors of sGC, NOS or COX. Under inflammatory conditions, the efficacy and potency of Cmpd17b were maintained, while iloprost and sildenafil were less effective. Additionally, Cmpd17b inhibited secretion of PAH-relevant cytokines via FPR2.

CONCLUSION AND IMPLICATIONS: Vasodilation to Cmpd17b, but not standard-of-care vasodilators, is maintained under inflammatory conditions, with additional inhibition of PAH-relevant cytokine release. Our study provides the first evidence that targeting FPR, using a biased agonist, simultaneously targets vascular function and inflammation, supporting the development of FPR-based pharmacotherapy to treat PAH.