Effects of Selective Serotonin Reuptake Inhibitors(SSRIs) on Serotonin-mediated Intracellular Ca2+ Mobilization in Human Platelets / 대한정신약물학회지

OBJECTIVE: The effects of treatment with selective serotonin reuptake inhibitors (SSRIs) on serotonin (5-HT)-mediated Ca(2+) mobilization were investigated in the platelets of human healthy volunteers. METHOD: The serotonin (5-HT)-mediated Ca(2+) mobilization in the platelets was assessed by the fluorescence technique with fura-2/AM. RESULTS: SSRIs (fluoxetine, paroxetine and sertraline) themselves mobilized intracellular Ca(2+)([Ca(2+)]i) in a dose-dependent fashion. The increment of [Ca(2+)]i, might be induced partly by the release from the intracellular rat[ism store, but mostly induced by the calcium transport through membrane. Stimulation of platelets with 10 micrometer 5-HT caused a rapid and sustained increase in [Ca(2+)]i levels. Resting [Ca(2+)]i, before 5-HT treatment was 43.37+/-1.25 nM. Fluoxetine inhibited the increment of [Ca2+]i induced by 10 micrometer5-HT with an IC50 value of 6.36 micrometer. Paroxetine augmented 5-HT-mediated increases in [Ca2+]i, ranging from 117.76+/-2.79% to 316.22+/-8.39%, with an EC50 value of 19.68 micrometer. Sertraline also augmented 5-HT-mediated increases in [Ca(2+)]i in a dose-dependent fashion, ranging from 106.29+/-.40% to 269.29+/-4.96%, with an EC50it value of 11.40 micrometer. CONCLUSIONS: It is likely that SSRIs increase in intracellular free calcium level directly and show the inhibiting and augmenting effects on 5-HT-mediated Ca(2+) movements. The precise mechanisms underlying the effects of 5-HT-mediated[Ca(2+)]i response after treatment with SSRIs remain unclear however, the present finding suggests the possibility that a direct, or indirect, effort to intracellular Ca(2+) signaling may be at least partly involved in the mechanism of action of SSRIs.

Calcium Antagonist-like Action of Antidepressants Including Sertraline in PCl2 Cells / 신경정신의학

It has been known that antidepressants have calcium antagonist-like action in neuronal tissues. However, their mechanisms are still obscure. For the study of neurochemical machanism of antidepressants, the authors examined the effects of antidepressants(1-100 microM ) on the intracellular Ca2+ concentration ([Ca2+]i) and the membrane potential in PCl2 cells using fluorescent dyes, fura-2/AM and bisoxonol, respectively. The results were as follows : 1) Sertraline, a selective serotonin reuptake inhibitor (SSRI), inhibited the increment of [Ca2+]i induced by high 60 mM KCI and 100 microM ATP with an IC50 value of 2.5 microM and 5.4 microM, respectively. 2) SSRIs(sertraline, paroxetine and fluoxetine) and tricyclic antidepressants(imipramine and amitriptyline) had strong effects on the inhibition of both voltage-dependent Ca2+ channel and receptor-dependent Ca2+ channel, whereas atypical antidepressant(trazodone) and MAO inhibitor(moclobemide) had lisle effects. 3) Sertraline itself depolarized the membrane potential in a sustained manner depending on its own concentration and it also increased the basal level of [Ca2+]i. 4) The increment of [Ca2+]i might be induced partly by the release from the intracellular calcium store, but mostly induced by the calcium transport through membrane. 5) Among those antidepressants tested, sertraline was the most potent one. Other SSRIs(paroxetine and fluoxetine) and tricyclic antidepressants(imipramine and amitriptyline) were moderately potent. Atypical antidepressant(trazodone) had little effects, and MAO inhibitor (moclobemide) had no effect on the depolarization. 6) External application of ATP induced temporary depolarization. This effect was blocked by prior treatment with sertraline with an IC50 value of 30 microM. 7) The increment of [Ca2+]i through voltage-dependent Ca2+ channel was almost inhibited by a selective calcium channel blocker(nimodipine). However, the ATP-induced increment of [Ca2+]i was partially inhibited by nimodipine. These inhibitory effects were potentiated by the addition of sertraline. In the light of these results, it is likely that SSRIs and tricyclic antidepressants could show the blocking effects on both voltage-dependent and receptor-dependent calcium channel by depolarizing neuronal cell membrane potential in a sustained manner and by increasing intracellular free calcium level.

Hemodynamic characteristics of extracellular UTP in the perfused rat liver

Uridine 5'-triphosphate (UTP) is stored in the granules of cells such as platelets and is released into the extracellular space upon cell stimulation. Extracellular UTP is known to influence many biological processes. We investigated the hemodynamic effects of UTP on the perfused rat liver and characterized its receptors. Liver perfusions were performed in a recirculation system under constant pressure (28 cmH2O). The perfusion flow and oxygen consumption rate were measured at 30 second intervals. UTP decreased the perfusion flow and the oxygen consumption rate, dose-dependently. UTP-induced changes were transient and disappeared in about 10 minutes. Suramin (P2-purinergic antagonist, 100 uM) and indomethacin (cyclooxygenase inhibitor, 20 uM) blocked UTP-induced hemodynamic changes significantly. The effects of UTP were also inhibited when Kupffer cells were damaged with treatment of gadolinium chloride (10 mg/kg iv). L-NAME (1 mM), a potent inhibitor of nitric oxide synthase, markedly enhanced and prolonged the contractile response of UTP in the hepatic vessel. These results suggest that UTP acts mainly on suramin-sensitive UTP receptors on the Kupffer cell through prostanoid synthesis. The nitric oxide systems in the endothelium seem to counteract the vasoconstrictile action of UTP in the hepatic circulation.