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.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) accumulates in the heart during cardiac ischemia (Du et al, 2017; Shimizu et al, 2002; Sonobe, Akiyama, Du, Zhan, & Shirai, 2013)
It has been considered that the accumulated interstitial 5-HT is taken up into cells via serotonin transporter (SERT) and metabolized by monoamine oxidase (MAO) to produce 5-hydroxyindole acetic acid (5-HIAA) and hydrogen peroxide (Pizzinat, Copin, Vindis, Parini, & Cambon, 1999), which causes myocardial cell injury (Bianchi et al, 2005; Kaludercic, Carpi, Menabò, Di Lisa, & Paolocci, 2011)
In our previous study using in vivo cardiac microdialysis technique in anesthetized rabbits (Sonobe et al, 2013) and rats (Du et al, 2017), we observed that local administration of SERT inhibitor fluoxetine had no effect on the clearance of accumulated 5-HT in the heart
Summary
Serotonin (5-hydroxytryptamine, 5-HT) accumulates in the heart during cardiac ischemia (Du et al, 2017; Shimizu et al, 2002; Sonobe, Akiyama, Du, Zhan, & Shirai, 2013). In our previous study using in vivo cardiac microdialysis technique in anesthetized rabbits (Sonobe et al, 2013) and rats (Du et al, 2017), we observed that local administration of SERT inhibitor fluoxetine had no effect on the clearance of accumulated 5-HT in the heart. This data implied the contribution of fluoxetine-resistant 5-HT transporters, such as extra-neuronal monoamine transporters (Furihata & Anzai, 2017), to remove 5-HT from the interstitial space. The effect of PMAT/OCT3 inhibition on the 5-HT and 5-HIAA kinetics was investigated during coronary occlusion and reperfusion
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