The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts.
OBJECTIVE
We aimed to clarify the relation between sarpogrelate (SG), a 5-hydroxytryptamine (5-HT)-2 receptor blocker, and myocardial interstitial serotonin or infarct size during ischemia and reperfusion.


BACKGROUND
In cardiac tissues serotonin is rich in vascular platelets, mast cells, sympathetic nerve endings, and the receptors are present in platelets and cardiomyocytes.


METHODS
The myocardial interstitial serotonin levels were measured using a microdialysis technique during 30-min ischemia with and without SG in in vivo as well as isolated rabbit hearts. Other rabbits underwent 30 min of ischemia and 48 h of reperfusion, and the effect of SG on the infarct size was investigated in the absence and presence of a selective protein kinase C (PKC) inhibitor, chelerythrine (5 mg/kg, intravenously), or a mitochondrial adenosine triphosphate sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate (5-HD) (5 mg/kg, intravenously). In another series, the effect of SG on PKC isoforms in cytosol and membrane fraction was assessed after a 20-min global ischemia in isolated rabbit hearts.


RESULTS
Interstitial serotonin levels were markedly increased during 30-min ischemia in in vivo and isolated hearts, and the increases were inhibited by SG in each. The infarct size was reduced by SG (27 +/- 2% vs. 40 +/- 3% of control). This effect was blocked by chelerythrine and 5-HD, respectively. Sarpogrelate further enhanced the ischemia-induced translocation of PKC-epsilon to the membrane fraction.


CONCLUSIONS
Sarpogrelate reduces the myocardial infarct size by inhibiting the serotonin release followed by enhancement of PKC-epsilon translocation and opening of the mitochondrial KATP channel in ischemic myocytes.
Shimizu
Yasuko
Y
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Minatoguchi
Shinya
S
Hashimoto
Kazuaki
K
Uno
Yoshihiro
Y
Arai
Masazumi
M
Wang
Ningyuan
N
Chen
Xuehai
X
Lu
Chuanjian
C
Takemura
Genzou
G
Shimomura
Masaaki
M
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000255:Adenosine Triphosphate / Q000502:physiology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000032:analysis / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D010617:Phenanthridines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D051744:Protein Kinase C-epsilon; D011817:Rabbits; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013386:Succinates / Q000494:pharmacology / Q000627:therapeutic use*
D000470:Alkaloids; D053119:Benzophenanthridines; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007527:Isoenzymes; D010617:Phenanthridines; D026902:Potassium Channel Blockers; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; C016299:chelerythrine; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon