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

Fig. 1. Schematic illustration of the microdialysis technique in the heart in vivo. A dialysis probe is implanted transversely into the lateral wall of the left ventricle. Myocardial interstitial 5-HT and 5-HIAA diffuses into perfusate across the dialysis membrane. Pharmacological agents diffuse into the interstitium according to a concentration gradient by reverse-microdialysis

Fig. 2. Experimental protocols. In protocol 1 (n = 7), after baseline dialysate sampling (baseline 1), perfusate (Ringer's solution) was switched to 1 mM fluoxetine. The drug administration was continued for 60 min, then second baseline dialysate sampling was performed (baseline 2). The perfusate was then switched to 1 mM fluoxetine mixed with 1 mM pargyline. The drug administration was continued for 90 min. In protocol 2 (n = 7) and 3 (n = 7), similar experiments as protocol 1 were performed in the presence of 100 µM decynium-22 and the mixture of fluoxetine and decynium-22, respectively

Fig. 3. Effect of local administration of 1 mM fluoxetine and following co-administration of 1 mM pargyline on dialysate concentrations of 5-HT and 5-HIAA. The data are shown as mean ± SD with individual data points (n = 7). *p < 0.05 vs baseline 1. †p < 0.05 vs baseline 2. Repeated-measures one-way ANOVA, Tukey’s multiple comparison test

Fig. 4. Effect of local administration of 100 µM decynium-22 and following co-administration of 1 mM pargyline on dialysate concentrations of 5-HT and 5-HIAA. The data are shown as mean ± SD with individual data points (n = 7). *p < 0.05 vs baseline 1. †p < 0.05 vs baseline 2. Repeated-measures one-way ANOVA, Tukey’s multiple comparison test

Fig. 5. Effect of local administration of the mixture of 1 mM fluoxetine and 100 µM decynium-22 and following co-administration of 1 mM pargyline on dialysate concentrations of 5-HT and 5-HIAA. The data are shown as mean ± SD with individual data points (n = 7). *p < 0.05 vs baseline 1. Repeated-measures one-way ANOVA, Tukey’s multiple comparison test

Fig. 6. Putative mechanisms regulating cardiac interstitial level of 5-HT in a physiological condition. Interstitial level of 5-HT in the heart is maintained low mostly by fluoxetine-sensitive transporter (SERT) dependent uptake into platelets and stored in intracellular vesicles. This stored 5-HT in the vesicle could be reused and less metabolized. Meanwhile, interstitial 5-HT is also taken up by decynium-22 sensitive transporter (PMAT) into cardiac cells. The transported 5-HT is then metabolized by MAO to produce 5-HIAA