title: Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn.
abstract: Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment (P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment (P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment (P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.
authors.affiliation: Pediatric Heart Lung Center, Section of Neonatology, University of Colorado Denver, Aurora, CO 80045, USA. cassidy.delaney@childrenscolorado.org
authors.forename: Cassidy
authors.initials: C
authors.lastname: Delaney
authors.forename: Jason
authors.initials: J
authors.lastname: Gien
authors.forename: Gates
authors.initials: G
authors.lastname: Roe
authors.forename: Nicole
authors.initials: N
authors.lastname: Isenberg
authors.forename: Jenai
authors.initials: J
authors.lastname: Kailey
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007231:Infant, Newborn; D007650:Ketanserin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D020280:Sertraline / Q000494:pharmacology; D034561:Sheep, Domestic; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D007650:Ketanserin; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D014365:Tryptophan Hydroxylase
keywords: ketanserin; newborn; pulmonary hypertension; selective serotonin reuptake inhibitors; serotonin