Jpet # 98269 1

A correlation between high plasma serotonin levels and total pulmonary resistance was reported in more than 80% of pulmonary hypertensive patients. When submitted to chronic hypoxia (10% O2 for more than 3 weeks), wildtype mice develop lung vascular remodeling and pulmonary hypertension. We previously reported that, by contrast, the development of these hypoxiadependent alterations is totally abolished in mice with permanent (genetic) or transient (pharmacologic) inactivation of the serotonin 5-HT2B receptor. In the present study, we asked whether 5-HT2B receptors could be involved in the control of plasma serotonin levels. Further investigating the chronic-hypoxic-mouse model of pulmonary hypertension, we first show that in wildtype mice, plasma serotonin levels and 5-HT2B receptors expression were significantly increased after chronic exposure to hypoxia. This increase appeared before significant changes in remodeling factors could be detected and persisted when the pathology was established. Conversely, in mice with either genetically or pharmacologically inactive 5-HT2B receptors, plasma serotonin levels were not modified by chronic hypoxia. We then confirmed that 5-HT2B receptors can control plasma serotonin levels by providing in vivo evidence that an acute agonist stimulation of 5-HT2B receptor triggers a transient increase in plasma serotonin that is serotonin transporter dependent and blocked by 5-HT2B receptor selective antagonist or genetic abalation. Our data support the notion that a 5-HT2B receptor-dependent regulation of serotonin uptake is implicated in the control of plasma serotonin levels. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on February 3, 2006 as DOI: 10.1124/jpet.105.098269 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from