Sertraline protects against monocrotaline-induced pulmonary hypertension in rats
1. Serotonin (5-HT), as a type of mitogen for smooth muscle cells, plays an important role in the development of pulmonary hypertension. It is known that selective serotonin re-uptake inhibitors (SSRI) inhibit 5-HT internalization. Therefore, the aim of the present study was to investigate the protective effect and mechanism of the SSRI sertraline against pulmonary hypertension. 2. Monocrotaline (MCT)-induced chronic 'inflammatory' pulmonary hypertension in Wistar rats was established. Pulmonary haemodynamic measurement and lung tissue morphological investigations were undertaken. Serotonin transporter (SERT) mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). 3. The results showed that pulmonary artery pressure (PAP) was significantly increased by MCT treatment from 12.6 +/- 2.1 to 20.1 +/- 3.4 mmHg (P < 0.01 vs control) and sertraline attenuated the MCT-induced increase in PAP from 20.1 +/- 3.4 to 16.4 +/- 1.8 mmHg (P < 0.05 vs MCT). The right ventricular index was increased in the MCT-treated group from 0.32 +/- 0.04 to 0.51 +/- 0.09 (P < 0.01 vs control) and was reduced to 0.42 +/- 0.04 by sertraline (P < 0.05 vs MCT). The degree of muscularization of the pulmonary artery in the MCT-treated group was significantly higher than control (P < 0.01) and was decreased by sertraline (P < 0.01 vs MCT). The RT-PCR assay showed that MCT increased SERT mRNA expression from 0.86 +/- 0.08 to 0.99 +/- 0.06 (P < 0.05 vs control), which was attenuated by sertraline (0.82 +/- 0.09; P < 0.05 vs MCT). 4. In conclusion, the SSRI sertraline protects against MCT-induced pulmonary hypertension by decreasing PAP, right ventricular index and pulmonary artery remodelling, which may be related to a reduction in SERT mRNA.
Available from: Hilde Pleym
- "Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, citalopram, paroxetine and sertraline are widely used in the treatment of depression and anxiety disorders. In animal models, serotonin-induced proliferation of pulmonary artery smooth muscle cells as well as experimentally induced pulmonary arterial hypertension is inhibited by SSRIs [10-12]. Notably, the mechanism of action of these drugs is to block the function of the serotonin transporter. "
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ABSTRACT: Serotonin promotes pulmonary arterial vasoconstriction and pulmonary arterial smooth muscle cell proliferation, thereby having the potential to increase pulmonary arterial blood pressure. Although serotonin reuptake inhibitors (SRIs) might inhibit further deterioration in patients with manifest pulmonary arterial hypertension, they may induce pulmonary hypertension in healthy newborns after fetal exposure. As it is unclear whether treatment with SRIs affects pulmonary hemodynamics in adults without pulmonary hypertension, the aim of the present study was to investigate the effect of SRIs on pulmonary hemodynamics in such subjects.
Sixteen patients with stable angina pectoris scheduled for first time coronary artery bypass grafting were included in the study. Of these 8 were currently treated with an SRI (the SRI group) and 8 were not (the control group). Pulmonary arterial pressures were measured before induction of anesthesia by means of a pulmonary artery catheter. Serotonin transporter and 5-HT(2A) receptor gene polymorphisms and platelet 5-HT(2A) receptor expression were studied to elucidate their possible role as modifying factors.
No patients in any of the groups had pulmonary arterial hypertension. Mean pulmonary artery pressure was 15.0 mmHg in the SRI group and 14.5 mmHg in the control group (P = 0.50; 95% confidence interval for the difference, -2.9 to +3.9 mmHg). Neither were there any significant differences between the groups for any of the other hemodynamic variables studied. The various gene polymorphisms and the extent of platelet 5-HT(2A) receptor expression did not influence the hemodynamic variables.
SRI treatment did not significantly influence pulmonary hemodynamics in patients without pulmonary hypertension.
Serotonin; Selective serotonin reuptake inhibitors; Pulmonary hemodynamics; Pulmonary hypertension.
Journal of Clinical Medicine Research 10/2011; 3(5):230-8. DOI:10.4021/jocmr654w
Available from: nrcresearchpress.com
- "Modulation of SERT has shown to be a risk factor for PAH (Crona et al. 2009). We have previously shown that the selective serotonin reuptake inhibitors (SSRIs) sertraline and fluoxetine inhibited monocrotaline (MCT)-induced pulmonary hypertension and pulmonary vascular remodeling in rats by inhibition of serotonin internalization via SERT (Li et al. 2006; Zhai et al. 2009). SERT is expressed in various cell types including neurons, blood platelets, and PAECs and pulmonary artery smooth muscle cells (Eddahibi et al. 2001). "
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ABSTRACT: Mutations in bone morphogenetic protein (BMP) receptor II (BMPR2) are associated with the apoptosis of the pulmonary artery endothelial cells and the loss of the pulmonary small vessels. The present study was designed to investigate the involvement of BMPR2 in the protective effect of fluoxetine against monocrotaline (MCT)-induced endothelial apoptosis in rats. Models of pulmonary arterial hypertension in rats were established by a single intraperitoneal injection of MCT (60 mg/kg). Fluoxetine (2 and 10 mg/kg) was intragastrically administered once a day. After 21 days, MCT caused pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling and significantly reduced the BMPR2 expression in lungs and pulmonary arteries. Fluoxetine dose-dependently inhibited MCT-induced pulmonary arterial hypertension and effectively protected the lungs against MCT-induced endothelial apoptosis, reduction in the number of alveolar sacs, and loss of the pulmonary small vessels. Fluoxetine reversed the expression of cyclic guanosine 3',5'-monophosphate-dependent kinase І, BMPR2, phospho-Smad1, β-catenin, and reduced the expression of caspase 3 in rat lungs. These findings suggest that BMPR2 is probably involved in the protective effect of fluoxetine against MCT-induced endothelial apoptosis in rats.
Canadian Journal of Physiology and Pharmacology 05/2011; 89(5):345-54. DOI:10.1139/y11-024 · 1.77 Impact Factor
Available from: PubMed Central
- "We have previously reported that serotonin induced PASMCs mitogenesis in vitro, and serotonin selective reuptake inhibitor (SSRI) fluoxetine inhibited serotonin-induced PASMCs proliferation via blocking SERT14. We have also found that SSRI fluoxetine and sertraline protected against pulmonary vascular remodeling by inhibiting pulmonary vascular muscularization in monocrotaline (MCT)-induced pulmonary hypertensive rats15, 16. However, whether SSRI has a protective effect against ECM remodeling in the pulmonary artery remains unknown. "
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ABSTRACT: To investigate the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine on extracellular matrix (ECM) remodeling of the pulmonary artery and inflammation of the lungs in pulmonary arterial hypertension (PAH) induced by monocrotaline in rats.
MCT-induced chronic PAH was established in Wistar rats. After treatment with fluoxetine for 3 weeks, pulmonary hemodynamic measurement and morphological investigation of lung tissues were undertaken. The main components of the ECM, elastin and collagen, were detected using Van Gieson stain and Orcein stain, respectively, or using Victoria-ponceau's double stain. The ECM proteolytic enzymes matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, were detected by Western blot. Inflammation of lung tissue was assayed using lung morphology and inflammatory cytokine expression.
Fluoxetine (2 and 10 mg/kg) significantly inhibited MCT-induced PAH, attenuated pulmonary arterial muscularization and ECM remodeling, and decreased MMP/TIMP expression. Fluoxetine also suppressed inflammatory responses in lung tissue and inhibited the expression of the inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP-1) and intercellular adhesion molecule-1 (ICAM-1).
Fluoxetine inhibited MCT-induced ECM remodeling of the pulmonary artery and inflammation of lung tissue. These effects were related to its inhibition on MMPs/TIMPs and cytokine productions.
Acta Pharmacologica Sinica 02/2011; 32(2):217-22. DOI:10.1038/aps.2010.187 · 2.91 Impact Factor
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