Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat.
BACKGROUND
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.


OBJECTIVE
To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate.


METHODS
Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation.


RESULTS
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).


CONCLUSIONS
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.
Fornaro
Enrica
E
Lung Biology Research Group, Physiology and Experimental Medicine Program, Hospital for Sick Children, Toronto, Ontario, Canada.
Li
Dongge
D
Pan
Jingyi
J
Belik
Jaques
J
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D005473:Fluoxetine / Q000008:administration & dosage* / Q000009:adverse effects*; D005865:Gestational Age; D006976:Hypertension, Pulmonary / Q000139:chemically induced*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques
D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine