title: A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor.
abstract: Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.
authors.affiliation: INSERM U698, CHU X. Bichat, 46 rue H. Huchard, Paris 75018, France; Paris Nord University, Sorbonne Paris Cité, UMR-S698, Paris F-75018, France.
authors.forename: Chabha
authors.initials: C
authors.lastname: Benyahia
authors.forename: Kamel
authors.initials: K
authors.lastname: Boukais
authors.forename: Ingrid
authors.initials: I
authors.lastname: Gomez
authors.forename: Adam
authors.initials: A
authors.lastname: Silverstein
authors.forename: Lucie
authors.initials: L
authors.lastname: Clapp
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.forename: Claire
authors.initials: C
authors.lastname: Danel
authors.forename: Guy
authors.initials: G
authors.lastname: Leséche
authors.forename: Dan
authors.initials: D
authors.lastname: Longrois
authors.forename: Xavier
authors.initials: X
authors.lastname: Norel
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000368:Aged; D004353:Drug Evaluation, Preclinical; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000085:Acetates; C113936:PTGIR protein, human; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014665:Vasodilator Agents; C048081:beraprost; D011464:Epoprostenol; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid; D016285:Iloprost; C427248:treprostinil; C036293:prostaglandin D2 receptor
keywords: HPA; HPV; Human pulmonary artery; Human pulmonary vein; PAH; PCH; PVOD; Prostacyclin mimetic; Prostanoid receptors; Pulmonary hypertension; Vasorelaxation; human pulmonary artery; human pulmonary vein; pulmonary arterial hypertension; pulmonary capillary hemangiomatosis; pulmonary veno-occlusive disease