title: Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus.
abstract: Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 μg) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation.
authors: Pediatric Heart Lung Center, Aurora, CO, USA. cassidy.delaney@childrenscolorado.org
authors: Cassidy
authors: C
authors: Delaney
authors: Jason
authors: J
authors: Gien
authors: Theresa R
authors: TR
authors: Grover
authors: Gates
authors: G
authors: Roe
authors: Steven H
authors: SH
authors: Abman
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D020883:Hysterotomy; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology* / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D005473:Fluoxetine; D007211:Indoles; D007650:Ketanserin; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D054460:rho-Associated Kinases; C090701:GR 127935; C094868:SB 206553; C049347:fasudil