Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.
Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts.
College of Pharmacy, Kinjo Gakuin University.
Tatsuya
T
Muto
Haruki
H
Usuda
Aya
A
Yamamura
Koji
K
Yoshida
Ai
A
Ohashi
Kumiko
K
Mitsui-Saitoh
Junichi
J
Sakai
Yumi
Y
Sugimoto
Hideki
H
Mizutani
Tsunemasa
T
Nonogaki
Yoshihiro
Y
Hotta
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001278:Atractyloside / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010477:Perfusion; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017725:Ventricular Pressure / Q000187:drug effects
D001278:Atractyloside; D002118:Calcium; D053148:Caspase 3; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors