Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.

Abstract

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.

• Authors: Tatsuya Muto, Haruki Usuda, Aya Yamamura, Koji Yoshida, Ai Ohashi, Kumiko Mitsui-Saitoh, Junichi Sakai, Yumi Sugimoto, Hideki Mizutani, Tsunemasa Nonogaki, Yoshihiro Hotta
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 37 Issue 5 Pg. 731-9 ( 2014) ISSN: 1347-5215 [Electronic] Japan
• PMID: 24789996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Serotonin Uptake Inhibitors
• Atractyloside
• Caspase 3
• Fluvoxamine
• Calcium

Topics

• Animals
• Apoptosis (drug effects)
• Atractyloside (pharmacology)
• Calcium (metabolism)
• Caspase 3 (metabolism)
• Fluvoxamine (pharmacology, therapeutic use)
• Guinea Pigs
• Heart (drug effects)
• In Vitro Techniques
• Mitochondria (metabolism)
• Myocardium (cytology, metabolism)
• Perfusion
• Reperfusion Injury (drug therapy, metabolism)
• Selective Serotonin Reuptake Inhibitors (pharmacology, therapeutic use)
• Ventricular Pressure (drug effects)