Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice.

Abstract

Decreasing the bioavailability of serotonin (5-HT) by inhibiting its biosynthesis may represent a useful adjunctive treatment of pulmonary hypertension (PH). We assessed this hypothesis using LP533401, which inhibits the rate-limiting enzyme tryptophan hydroxylase 1 (Tph1) expressed in the gut and lung, without inhibiting Tph2 expressed in neurons. Mice treated repeatedly with LP533401 (30-250 mg/kg per day) exhibited marked 5-HT content reductions in the gut, lungs, and blood, but not in the brain. After a single LP533401 dose (250 mg/kg), lung and gut 5-HT contents decreased by 50%, whereas blood 5-HT levels remained unchanged, suggesting gut and lung 5-HT synthesis. Treatment with the 5-HT transporter (5-HTT) inhibitor citalopram decreased 5-HT contents in the blood and lungs but not in the gut. In transgenic SM22-5-HTT+ mice, which overexpress 5-HTT in smooth muscle cells and spontaneously develop PH, 250 mg/kg per day LP533401 or 10 mg/kg per day citalopram for 21 days markedly reduced lung and blood 5-HT levels, right ventricular (RV) systolic pressure, RV hypertrophy, distal pulmonary artery muscularization, and vascular Ki67-positive cells (P < 0.001). Combined treatment with both drugs was more effective in improving PH-related hemodynamic parameters than either drug alone. LP533401 or citalopram treatment partially prevented PH development in wild-type mice exposed to chronic hypoxia. Lung and blood 5-HT levels were lower in hypoxic than in normoxic mice and decreased further after LP533401 or citalopram treatment. These results provide proof of concept that inhibiting Tph1 may represent a new therapeutic strategy for human PH.

• Authors: Shariq Abid, Amal Houssaini, Caroline Chevarin, Elisabeth Marcos, Claire-Marie Tissot, Guillaume Gary-Bobo, Feng Wan, Nathalie Mouraret, Valerie Amsellem, Jean-Luc Dubois-Randé, Michel Hamon, Serge Adnot
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 6 Pg. L500-8 (Sep 15 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22797248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• LP533401
• Pyrimidines
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Uptake Inhibitors
• Citalopram
• Serotonin
• Tph1 protein, mouse
• Tryptophan Hydroxylase

Topics

• Animals
• Citalopram (pharmacology)
• Duodenum (drug effects, metabolism)
• Hypertension, Pulmonary (prevention & control)
• Hypoxia (physiopathology)
• Lung (drug effects)
• Mice
• Mice, Inbred C57BL
• Pyrimidines (pharmacology)
• Serotonin (biosynthesis, blood, metabolism)
• Serotonin Plasma Membrane Transport Proteins (biosynthesis)
• Selective Serotonin Reuptake Inhibitors (pharmacology)
• Tryptophan Hydroxylase (antagonists & inhibitors)