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Background and Purpose: Pulmonary arterial hypertension (PAH), a rare fatal disorder characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure but not mortality. The G-protein coupled formyl peptide receptors (FPRs) mediates vasodilatation and resolution of inflammation, actions possibly beneficial in PAH. We investigated dilator and anti-inflammatory effects of the FPR biased agonist compound 17b in pulmonary vasculature using mouse precision-cut lung slices (PCLS).

Experimental Approach: PCLS from 8-week-old male and female C57BL/6 mice, intrapulmonary arteries were pre-contracted with 5-HT for concentration-response curves to compound 17b and 43, and standard-of-care drugs, sildenafil, iloprost and riociguat. Compound 17b-mediated relaxation was assessed with FPR antagonists or inhibitors and in PCLS treated with TNF-α or LPS. Cytokine release from TNF-α- or LPS-treated PCLS ± compound 17b was measured.

Key Results: Compound 17b elicited concentration-dependent vasodilation, with potencies of iloprost > compound 17b = riociguat > compound 43 = sildenafil. Compound 17b was inhibited by the FPR1 antagonist cyclosporin H but not by soluble guanylate cyclase, nitric oxide synthase or cyclooxygenase inhibitors. Under inflammatory conditions, the efficacy and potency of compound 17b were maintained, while iloprost and sildenafil were less effective. Additionally, compound 17b inhibited secretion of PAH-relevant cytokines via FPR2.

Conclusions and Implications: Vasodilation to compound 17b but not standard-of-care vasodilators, is maintained under inflammatory conditions, with additional inhibition of PAH-relevant cytokine release. This provides the first evidence that targeting FPR, with biased agonist, simultaneously targets vascular function and inflammation, supporting the development of FPR-based pharmacotherapy to treat PAH.

Linked Articles: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

Titel:	The small-molecule formyl peptide receptor biased agonist, compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices.
Autor/in / Beteiligte Person:	Studley, WR ; Lamanna, E ; Martin, KA ; Nold-Petry, CA ; Royce, SG ; Woodman, OL ; Ritchie, RH ; Qin, CX ; Bourke, JE
Link:	Full Text Finder (Volltext)
Zeitschrift:	British journal of pharmacology, Jg. 181 (2024-07-01), Heft 14, S. 2287-2301
Veröffentlichung:	London : Wiley ; <i>Original Publication</i>: London, Macmillian Journals Ltd., 2024
Medientyp:	academicJournal
ISSN:	1476-5381 (electronic)
DOI:	10.1111/bph.16231
Schlagwort:	Animals Male Mice Female Dose-Response Relationship, Drug Vasodilation drug effects Receptors, Formyl Peptide agonists Receptors, Formyl Peptide antagonists & inhibitors Receptors, Formyl Peptide metabolism Mice, Inbred C57BL Vasodilator Agents pharmacology Lung drug effects Lung metabolism Anti-Inflammatory Agents pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Br J Pharmacol] 2024 Jul; Vol. 181 (14), pp. 2287-2301. <i>Date of Electronic Publication: </i>2023 Sep 26. MeSH Terms: Receptors, Formyl Peptide* / agonists ; Receptors, Formyl Peptide* / antagonists & inhibitors ; Receptors, Formyl Peptide* / metabolism ; Mice, Inbred C57BL* ; Vasodilator Agents* / pharmacology ; Lung* / drug effects ; Lung* / metabolism ; Anti-Inflammatory Agents* / pharmacology ; Animals ; Male ; Mice ; Female ; Dose-Response Relationship, Drug ; Vasodilation / drug effects References: Alexander, S. P., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Abbracchio, M. P., Alexander, W., Al‐hosaini, K., Bäck, M., Barnes, N. M., Bathgate, R., … Ye, R. D. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein‐coupled receptors. 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Grant Information: ID1187989 National Health and Medical Research Council; Victorian Government of Australia's Operational Infrastructure Support Program; National Heart Foundation of Australia Future Leader Fellowship; Australian Government Research Training Program (RTP) Scholarship Contributed Indexing: Keywords: formyl peptide receptor; inflammation; precision‐cut lung slice; pulmonary arterial hypertension; respiratory pharmacology; vasodilation Substance Nomenclature: 0 (Receptors, Formyl Peptide) ; 0 (Vasodilator Agents) ; 0 (Anti-Inflammatory Agents) Entry Date(s): Date Created: 20230902 Date Completed: 20240619 Latest Revision: 20240625 Update Code: 20240626

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