title: The Xanthine Derivative KMUP-1 Attenuates Serotonin-Induced Vasoconstriction and K⁺-Channel Inhibitory Activity via the PKC Pathway in Pulmonary Arteries.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) is a potent pulmonary vasoconstrictor that promotes pulmonary artery smooth muscle cell (PASMC) proliferation. 5-HT-induced K(+) channel inhibition increases [Ca(2+)]i in PASMCs, which is a major trigger for pulmonary vasoconstriction and development of pulmonary arterial hypertension (PAH). This study investigated whether KMUP-1 reduces pulmonary vasoconstriction in isolated pulmonary arteries (PAs) and attenuates 5-HT-inhibited K(+) channel activities in PASMCs. In endothelium-denuded PA rings, KMUP-1 (1 μM) dose-dependently reduced 5-HT (100 μM) mediated contractile responses. Responses to KMUP-1 were reversed by K(+) channel inhibitors (TEA, 10 mM, 4-aminopyridine, 5 mM, and paxilline, 10 μM). In primary PASMCs, KMUP-1 also dose-dependently restored 5-HT-inhibited voltage-gated K(+)-channel (Kv1.5 and Kv2.1) and large-conductance Ca(2+)-activated K(+)-channel (BKCa) proteins, as confirmed by immunofluorescent staining. Furthermore, 5-HT (10 μM)-inhibited Kv1.5 protein was unaffected by the PKA inhibitor KT5720 (1 μM) and the PKC activator PMA (1 μM), but these effects were reversed by KMUP-1 (1 μM), 8-Br-cAMP (100 μM), chelerythrine (1 μM), and KMUP-1 combined with a PKA/PKC activator or inhibitor. Notably, KMUP-1 reversed 5-HT-inhibited Kv1.5 protein and this response was significantly attenuated by co-incubation with the PKC activator PMA, suggesting that 5-HT-mediated PKC signaling can be modulated by KMUP-1. In conclusion, KMUP-1 ameliorates 5-HT-induced vasoconstriction and K(+)-channel inhibition through the PKC pathway, which could be valuable to prevent the development of PAH.
authors.affiliation: 1. Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.affiliation: 2. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: 1. Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.affiliation: 2. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.affiliation: 2. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: 1. Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.affiliation: 2. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011651:Pulmonary Artery / Q000737:chemistry / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D010880:Piperidines; D015221:Potassium Channels; D014970:Xanthines; C439304:KMUP 1; D012701:Serotonin; D011493:Protein Kinase C
keywords: K+-channel inhibition; Kv1.5 protein; PKC signaling; Serotonin; pulmonary artery smooth muscle cells; pulmonary vasoconstriction