Serotonin uptake via plasma membrane monoamine transporter during myocardial ischemia‐reperfusion in the rat heart in vivo

Abstract

Serotonin (5‐HT) accumulates in the heart during myocardial ischemia and induces deleterious effects on the cardiomyocytes through receptor‐dependent and monoamine oxidase‐dependent pathways. We aimed to clarify the involvement of extra‐neuronal monoamine transporters in the clearance of 5‐HT during ischemia and reperfusion in the heart. Using a microdialysis technique in the anesthetized Wistar rat heart, we monitored myocardial interstitial 5‐HT and 5‐hydroxyindole acetic acid (5‐HIAA) concentration by means of electro‐chemical detection coupled with high‐performance liquid chromatography (HPLC‐ECD). Effects of inhibitors of the plasma membrane monoamine transporter (PMAT) and the organic cation transporter 3 (OCT3) (decynium‐22 and corticosterone) on the 5‐HT and 5‐HIAA concentrations during baseline, coronary occlusion, and reperfusion were investigated. Basal dialysate 5‐HT concentration were increased by local administration of decynium‐22, but not by corticosterone. Addition of fluoxetine, a serotonin transporter (SERT) inhibitor further increased the 5‐HT concentration upon during administration of decynium‐22. Decynium‐22 elevated the background level of 5‐HT during coronary occlusion and maintained 5‐HT concentration at a high level during reperfusion. Production of 5‐HIAA in the early reperfusion was significantly suppressed by decynium‐22. These results indicate that PMAT and SERT independently regulate basal level of interstitial 5‐HT, and PMAT plays a more important role in the clearance of 5‐HT during reperfusion. These data suggest the involvement of PMAT in the monoamine oxidase‐dependent deleterious pathway in the heart.

Carrier‐mediated serotonin efflux induced by pharmacological anoxia in the rat heart in vivo

“…A similar catheter was inserted into the carotid artery for monitoring arterial blood pressure. With the rats in a lateral position, a left thoracotomy was performed, and a dialysis probe was implanted transversely into the lateral wall of the left ventricle 9,34,35 . Two probes were implanted at least 5 mm apart from each other.…”

“…Duration for each dialysate sampling was 15 min, which yielded a volume of 30 µL. Concentrations of 5‐HT in the dialysate samples were measured by high performance liquid chromatography with electro‐chemical detection (HPLC‐ECD 700 series, Eicom) as previously described 2,9 …”

“…In parallel with 5‐HT receptor‐dependent pathways, receptor‐independent pathways, in which 5‐HT transporters are involved, also play an important role in the exacerbation of ischaemic injury. Extracellular 5‐HT is internalised into the cardiac cells through an imipramine‐sensitive serotonin transporter, SERT 7,8 and a plasma membrane monoamine transporter, PMAT 9 . The internalised 5‐HT can be metabolised by monoamine oxidase to produce hydrogen peroxide, which in excess causes cellular damage initiated from inside of the cells 10 .…”

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

“…A unique aspect of ENT4 is the enhancement of substrate flux in acidic conditions, such as those associated with vascular ischemia‐reperfusion injury (Barnes et al, 2006; Tandio et al, 2019; Zhou, Duan, Engel, Xia, & Wang, 2010). ENT4 has been implicated in regulating 5‐HT levels in rat heart, particularly during the reperfusion stage of ischemia‐reperfusion (Sonobe, Akiyama, Du, & Pearson, 2019), and modulation of adenosine actions in the vasculature has long been proposed as a therapy to attenuate ischemia‐reperfusion injury (Abd‐Elfattah, Aly, Hanan, & Wechsler, 2012; Abd‐Elfattah et al, 2013; Hirai & Ashraf, 1998; Rose et al, 2010; Van Belle, 1995; Yang & Leung, 2015). Therefore, ENT4 may prove to be a novel drug target for therapeutic intervention in ischemia‐reperfusion injury.…”

Transporter-dependent uptake and metabolism of myocardial interstitial serotonin in the rat heart

“…A similar catheter was inserted into the carotid artery for measuring arterial blood pressure. With the rats in a lateral position, a left thoracotomy was performed, and a dialysis probe was implanted transversely into the lateral wall of the left ventricle [17][18][19][20]. Two probes were implanted at least 5 mm apart from each other.…”