title: Ex vivo relaxations of pulmonary arteries induced by prostacyclin mimetics are highly dependent of the precontractile agents.
abstract: Prostacyclin (PGI2) mimetics (iloprost, treprostinil) are potent vasodilators (primarily via IP-receptor activation) and major therapeutic interventions for pulmonary hypertension (PH). Increased plasma levels of endothelin (ET-1), thromboxane (TxA2) and catecholamines have been demonstrated from patients with PH. In this study, we aimed to compare relaxant effects of iloprost and treprostinil on human (HPA) and rat pulmonary arteries precontracted with either ET-1, thromboxane (U46619) or an α-adrenergic receptor agonist (Norepinephrine, NE or phenylephrine, PE). Treprostinil and iloprost induced vasorelaxation of HPA precontracted with NE, ET-1 or U46619. We obtained greater relaxation response and sensitivity to treprostinil when ET-1 or U46619 were used to induce the precontraction in comparison to NE. In contrast, iloprost showed less relaxation response and sensitivity in HPA precontracted with U46619 versus NE. In the rat, treprostinil and iloprost induced vasorelaxation of pulmonary arteries precontracted with PE and U46619 but minimally with ET-1. However, in rat pulmonary arteries, PE-induced precontractions were comparatively low amplitude. Our study showed that the ex vivo relaxation or sensitivity of pulmonary arteries induced by PGI2 mimetics is highly dependent on both the pre-contraction agent and the species. To best extrapolate to effects on human tissue, our results suggest that U46619 is the appropriate contractile agent for assessing the relaxant effect of PGI2 mimetics in rat pulmonary arteries. Finally we suggest that in PH patients with high plasma concentration of TxA2, treprostinil (not iloprost) would be a preferential treatment. On the other hand, if the ET-1 plasmatic level is high, either treprostinil or iloprost will be effective.
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France; Paris Nord University, Sorbonne Paris Cité, UMR-S1148, Paris F-75018, France.
authors.forename: Chabha
authors.initials: C
authors.lastname: Benyahia
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France; Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Beyazit, 34116 Istanbul, Turkey.
authors.forename: Gulsev
authors.initials: G
authors.lastname: Ozen
authors.affiliation: Anti-doping Lab, Doha, Qatar.
authors.forename: Nelson
authors.initials: N
authors.lastname: Orie
authors.affiliation: Department of Medicine, University College London, London WC1E 6JF, UK.
authors.forename: Agatha
authors.initials: A
authors.lastname: Ledwozyw
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France.
authors.forename: Liliane
authors.initials: L
authors.lastname: Louedec
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France; Paris Descartes University, Sorbonne Paris Cité, UMR-S1148, Paris F-75018, France.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Li
authors.affiliation: Alexandria University, Faculty of Pharmacy, Department of Pharmacology and Toxicology, Alexandria, Egypt.
authors.forename: Amira M
authors.initials: AM
authors.lastname: Senbel
authors.affiliation: United Therapeutics, Research Triangle Park, NC 27709, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Silverstein
authors.affiliation: CHU X. Bichat, Assistance Publique-Hôpitaux de Paris, Paris Diderot University, Sorbonne Paris Cité, UMR-1148, Paris F-75018, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Danel
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France; Paris Nord University, Sorbonne Paris Cité, UMR-S1148, Paris F-75018, France; CHU X. Bichat, Assistance Publique-Hôpitaux de Paris, Paris Diderot University, Sorbonne Paris Cité, UMR-1148, Paris F-75018, France.
authors.forename: Dan
authors.initials: D
authors.lastname: Longrois
authors.affiliation: Department of Medicine, University College London, London WC1E 6JF, UK.
authors.forename: Lucie H
authors.initials: LH
authors.lastname: Clapp
authors.affiliation: INSERM U1148, CHU X. Bichat, 46 rue H. Huchard, F-75018 Paris, France; Paris Nord University, Sorbonne Paris Cité, UMR-S1148, Paris F-75018, France. Electronic address: xnorel@hotmail.com.
authors.forename: Xavier
authors.initials: X
authors.lastname: Norel
authors.affiliation: Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Beyazit, 34116 Istanbul, Turkey.
authors.forename: Gökçe
authors.initials: G
authors.lastname: Topal
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D014665:Vasodilator Agents; D011464:Epoprostenol; D016285:Iloprost; C427248:treprostinil
keywords: Endothelin; Iloprost; Norepinephrine; Pulmonary artery; Thromboxane; Treprostinil