Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat

• Published in: American journal of respiratory and critical care medicine Vol. 176; no. 10; pp. 1035 - 1040
• Main Authors: Fornaro, Enrica, Li, Dongge, Pan, Jingyi, Belik, Jaques
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.11.2007; American Lung Association; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - adverse effects; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell growth; Cesarean section; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Drug dosages; Female; Fetal Diseases - chemically induced; Fetuses; Fluoxetine - administration & dosage; Fluoxetine - adverse effects; Gestational Age; Histology; Hypertension, Pulmonary - chemically induced; Intensive care medicine; Lung - drug effects; Lung - pathology; Lung - physiopathology; Lungs; Medical sciences; Muscle, Smooth, Vascular - drug effects; Pneumology; Pregnancy; Prenatal exposure; Prenatal Exposure Delayed Effects - chemically induced; Pulmonary arteries; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; Serotonin; Smooth muscle; Tissue Culture Techniques; Veins & arteries; Canada; Human; Intensive care; Rat; Serotonin; Respiratory disease; Fluoxetine; Psychotropic; Rodentia; Cardiovascular disease; Reuptake inhibitor; Pulmonary hypertension; Selective serotonin reuptake inhibitor; Prenatal; lung; Vertebrata; Mammalia; Newborn; Animal; Neurotransmitter; Antidepressant agent; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200701-163OC

Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents. To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate. Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation. Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 +/- 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 +/- 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01). In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.