Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero

Abstract

Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN. mouse; ductus arteriosus; SSRI; fluoxetine; sertraline; serotonin; PPHN NEW & NOTEWORTHY This study is the first to elucidate a mechanism by which serotonin reuptake inhibitors (SSRIs) alter ductus arteriosus tone. It also puts forth the notion that SSRIs may contribute to persistent pulmonary hypertension of the newborn by causing premature fetal ductus constriction.THE DUCTUS ARTERIOSUS (DA) is an essential fetal vessel connecting the pulmonary and systemic circulations. During fetal life, the DA, responding to low oxygen tension, nitric oxide, and prostaglandin signaling, remains patent to shunt blood to the aorta, bypassing the immature, uninflated lungs. At birth, increasing blood oxygen content and decreasing prostaglandin levels stimulate DA closure, allowing appropriate perfusion of the newly inflated lungs (7,8,43,52). The timing of DA closure is tightly regulated. If the DA fails to close (patent DA), serious consequences including pulmonary hemorrhage, parenchymal lung disease, intraventricular hemorrhage, and death can ensue. Conversely, premature DA constriction in utero is also undesirable and can lead to life-threatening conditions, including right ventricular hypertrophy, functional pulmonary atresia, absent pulmonary valve syndrome, hydrops fetalis, and persistent pulmonary hypertension of the newborn (PPHN) (18,20,23,31,32).PPHN is a disorder characterized by sustained elevated pulmonary vascular resistance (PVR). During fetal life, PVR is high due to a number of factors, including mechanical compression of the pulmonary arterioles by fluid-filled alveoli, low fetal oxygen tension, low levels of vasodilators (prostacyclin, nitric oxide), and elevated levels of vasoconstrictors (endothelin-1, thromboxane) (37). At birth, PVR should fall to facilitate a smooth transition from fetal to extrauterine life. However, in some cases, the pulmonary vasculature fails to relax, causing PPHN, a disorder accompanied by hypoxemia and right-...

Repeated Clozapine Increases the Level of Serotonin 5-HT1AR Heterodimerization with 5-HT2A or Dopamine D2 Receptors in the Mouse Cortex

“…All required positive and negative controls were done indicating that used antibodies are specific (data not shown). Antibodies were chosen based on literature (Ramírez et al, 2009 ; Noga et al, 2009 ; Yeung et al, 2010 ; Merlo et al, 2011 ; Hooper et al, 2016 ; Xiao et al, 2016 ). Moreover, we checked the specificity of antibodies by Western Blot, where different levels of receptors protein in different mouse brain structures were observed (data not shown).…”

Monochorionic diamniotic twin pregnancy complicated by discordant premature closure of ductus arteriosus

“…Like all selective serotonin reuptake inhibitors (SSRIs), sertraline (5‐hidroxitriptamina or 5‐HT) readily crosses the placenta, as reflected by fetal cord blood levels corresponding to 30%‐70% of maternal levels. A recent experimental study in mice showed that in utero sertraline exposure constricts the DA, and SSRI exposure constricts mouse DA in utero primarily via serotonin 2A (5‐HT2A) and by activation of 6 receptors (5‐HT6) …”

“…A recent experimental study in mice showed that in utero sertraline exposure constricts the DA, and SSRI exposure constricts mouse DA in utero primarily via serotonin 2A (5-HT2A) and by activation of 6 receptors (5-HT6). 5 In addition, prolonged exposure to SSRIs may lead to abnormal 5-HT metabolism, which may alter the expression of 5-HT receptors (the 2A receptor), leading to increased Rho kinase activity contributing to persistent anomalies of pulmonary vascular tone, reactivity, or structure. This may contribute to impaired transition of the pulmonary circulation at birth.…”

“…Clinical neonatal outcomes range from mild symptomatology to lethal respiratory insufficiency due to persistent pulmonary hypertension (PPHN) . Also, selective serotonin reuptake inhibitor use in pregnancy results in an increased likelihood of PPHN and a recent experimental animal's study shows that in utero sertraline exposure constricts the DA …”

Molecular, Genetic, and Pharmacological Modulation of the Ductus Arteriosus: KATP Channels as Novel Drug Targets

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